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Kano R, Takeda R, Sotani Y, Takagi R, Tabuchi A, Shirakawa H, Poole DC, Kano Y, Hoshino D. Cooling-induced changes in intracellular hydrogen peroxide and gene expression in mouse skeletal muscle in vivo. Am J Physiol Regul Integr Comp Physiol 2025; 328:R758-R766. [PMID: 40332827 DOI: 10.1152/ajpregu.00014.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/13/2025] [Accepted: 04/22/2025] [Indexed: 05/08/2025]
Abstract
Changes in intracellular hydrogen peroxide concentration ([H2O2]) constitute an important signal-controlling cellular adaptations. In response to cooling, decreases in [H2O2] and changes in antioxidant-related gene expression have been observed in skeletal muscle. However, the specific temperature dependence of cooling-induced [H2O2] changes and their quantitative relationship to induced gene expression are unknown. This investigation tested the hypothesis that differences in muscle cytosolic and mitochondrial [H2O2] changes during cooling/rewarming determine the pattern of H2O2-related gene expression. H2O2-sensitive cytosolic (HyPer7) and mitochondrial (MLS-HyPer7) fluorescent proteins were expressed into tibialis anterior (TA) muscle of male C57BL/6J mice. The temperature dependence of [H2O2] was determined via in vivo imaging during a 3-min cooling protocol from 35°C to 0°C. Two cooling patterns [6 bouts of intermittent cooling (I-Cool) vs. sustained cooling (S-Cool); both to 13°C] were applied over 60 min. Three hours after cooling, the muscles were removed, and gene expression was evaluated using real-time PCR. The decrease in [H2O2] was observed in both cytosolic and mitochondrial compartments from 35°C to 13°C but was of greater magnitude in the cytosol; in contrast, further cooling from 12°C to 0°C induced a rebound increase especially in cytosolic [H2O2]. I-Cool increased the mRNA level of Nrf2 (+15%, P < 0.001). S-Cool decreased the mRNA levels of Sod2, Cat, and Ucp3 (i.e., -20, -23, and -30%, respectively, P < 0.05). In conclusion, the greatest decrease in temperature-dependent [H2O2] occurred at 13°C in the cytosolic and mitochondrial compartments of muscle fibers, and I-Cool increased Nrf2 mRNA expression, whereas S-Cool decreased several antioxidant-related genes.NEW & NOTEWORTHY This in vivo model successfully characterized the effects of cooling on cytosolic and mitochondrial [H2O2] in mouse tibialis anterior skeletal muscle. Cooling decreased [H2O2] down to ∼13°C, but the effect was reversed at still lower temperatures. Sustained cooling decreased mRNA levels of antioxidant-related genes (Sod2, Cat, and Ucp3), whereas intermittent cooling increased Nrf mRNA expression. These results help elucidate the mechanistic bases for skeletal muscle adaptation to cooling.
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Affiliation(s)
- Ryotaro Kano
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
- Research Fellowship for Young Scientists, Japan Society for the Promotion of Science, Chiyoda, Japan
| | - Reo Takeda
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | - Yuta Sotani
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
| | - Ryo Takagi
- Department of Physical Therapy, Showa University School of Nursing and Rehabilitation Sciences, Kanagawa, Japan
| | - Ayaka Tabuchi
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
| | - Hideki Shirakawa
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
| | - David C Poole
- Department of Anatomy and Physiology and Kinesiology, Kansas State University, Manhattan, Kansas, United States
- Department of Kinesiology, Kansas State University, Manhattan, Kansas, United States
| | - Yutaka Kano
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
| | - Daisuke Hoshino
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
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2
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Machado IF, Palmeira CM, Rolo AP. Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging. Ageing Res Rev 2025; 109:102762. [PMID: 40320152 DOI: 10.1016/j.arr.2025.102762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 04/09/2025] [Accepted: 04/30/2025] [Indexed: 05/08/2025]
Abstract
Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.
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Affiliation(s)
- Ivo F Machado
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute of Interdisciplinary Research, Doctoral Program in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra, Portugal
| | - Carlos M Palmeira
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Anabela P Rolo
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
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3
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Wang Y, Gu C, Zhao H, Li Z, Thirupathi A. Redox signaling‑mediated muscle atrophy in ACL injury: Role of physical exercise (Review). Mol Med Rep 2025; 31:119. [PMID: 40052558 PMCID: PMC11904765 DOI: 10.3892/mmr.2025.13484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 02/03/2025] [Indexed: 03/15/2025] Open
Abstract
Muscle atrophy frequently occurs in patients with anterior cruciate ligament (ACL) injury, despite active participation in muscle strengthening programs. Without appropriate countermeasures such as exercise and pharmacological interventions, the atrophy may worsen. At the cellular and molecular levels, various protein synthesis‑related pathways and redox‑dependent molecules regulate processes associated with atrophy by activating or deactivating key signaling pathways. Muscle atrophy and the associated dysfunction can be reversed by physical exercise, which increases protein synthesis, thereby improving muscle strength and function around the ACL. However, the influence of different features of exercise protocols, including exercise type, intensity and duration, as well as the individual capacity of the patient, on the activity of the aforementioned pathways requires further investigation. Additionally, the mechanism by which redox‑sensitive molecules attenuate atrophy in ACL injury remains to be fully understood. The present review discusses exercise, signaling pathways and muscle atrophy in ACL injury, and highlights potential therapeutic strategies. These findings may also have implications for other joint diseases associated with ACL‑related injury.
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Affiliation(s)
- Yucong Wang
- Department of Joint Surgery, Ningbo No. 9 Hospital, Ningbo, Zhejiang 315020, P.R. China
| | - Chunxiao Gu
- Department of Joint Surgery, Ningbo No. 9 Hospital, Ningbo, Zhejiang 315020, P.R. China
| | - Hui Zhao
- Department of Joint Surgery, Ningbo No. 9 Hospital, Ningbo, Zhejiang 315020, P.R. China
| | - Zhongzheng Li
- Department of Joint Surgery, Ningbo No. 9 Hospital, Ningbo, Zhejiang 315020, P.R. China
| | - Anand Thirupathi
- Faculty of Sports Science, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
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Champsi S, Hood DA. Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes. Am J Physiol Cell Physiol 2025; 328:C335-C354. [PMID: 39672545 DOI: 10.1152/ajpcell.00669.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/15/2024] [Accepted: 12/03/2024] [Indexed: 12/15/2024]
Abstract
Mitochondria are metabolic hubs that govern skeletal muscle health. Although exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial reactive oxygen species (ROS) emission. Signaling toward biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggest that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.NEW & NOTEWORTHY Nrf-2 is a transcription factor that has been implicated in mitigating oxidative stress and regulating mitochondrial homeostasis. However, limited research has demonstrated how Nrf-2-mediated adaptations compare with those produced by exercise. To investigate this, we treated myotubes with Sulforaphane, a well-established Nrf-2 activator, and combined this with stimulation-induced chronic contractile activity to model exercise training. Our work is the first to establish that sulforaphane mimics training-induced mitochondrial adaptations, including enhancements in respiration, biogenesis, and dynamics.
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Affiliation(s)
- Sabrina Champsi
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
| | - David A Hood
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
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5
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Wernhart S, Rassaf T. Exercise, cancer, and the cardiovascular system: clinical effects and mechanistic insights. Basic Res Cardiol 2025; 120:35-55. [PMID: 38353711 PMCID: PMC11790717 DOI: 10.1007/s00395-024-01034-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/21/2024] [Accepted: 01/21/2024] [Indexed: 03/05/2024]
Abstract
Cardiovascular diseases and cancer are the leading causes of death in the Western world and share common risk factors. Reduced cardiorespiratory fitness (CRF) is a major determinant of cardiovascular morbidity and cancer survival. In this review we discuss cancer- induced disturbances of parenchymal, cellular, and mitochondrial function, which limit CRF and may be antagonized and attenuated through exercise training. We show the impact of CRF on cancer survival and its attenuating effects on cardiotoxicity of cancer-related treatment. Tailored exercise programs are not yet available for each tumor entity as several trials were performed in heterogeneous populations without adequate cardiopulmonary exercise testing (CPET) prior to exercise prescription and with a wide variation of exercise modalities. There is emerging evidence that exercise may be a crucial pillar in cancer treatment and a tool to mitigate cardiotoxic treatment effects. We discuss modalities of aerobic exercise and resistance training and their potential to improve CRF in cancer patients and provide an example of a periodization model for exercise training in cancer.
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Affiliation(s)
- Simon Wernhart
- West German Heart- and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
| | - Tienush Rassaf
- West German Heart- and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany
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6
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Acheson J, Joanisse S, Sale C, Hodson N. Recycle, repair, recover: the role of autophagy in modulating skeletal muscle repair and post-exercise recovery. Biosci Rep 2025; 45:1-30. [PMID: 39670455 PMCID: PMC12096956 DOI: 10.1042/bsr20240137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/03/2024] [Accepted: 12/11/2024] [Indexed: 12/14/2024] Open
Abstract
Skeletal muscle is a highly plastic tissue that can adapt relatively rapidly to a range of stimuli. In response to novel mechanical loading, e.g. unaccustomed resistance exercise, myofibers are disrupted and undergo a period of ultrastructural remodeling to regain full physiological function, normally within 7 days. The mechanisms that underpin this remodeling are believed to be a combination of cellular processes including ubiquitin-proteasome/calpain-mediated degradation, immune cell infiltration, and satellite cell proliferation/differentiation. A relatively understudied system that has the potential to be a significant contributing mechanism to repair and recovery is the autophagolysosomal system, an intracellular process that degrades damaged and redundant cellular components to provide constituent metabolites for the resynthesis of new organelles and cellular structures. This review summarizes our current understanding of the autophagolysosomal system in the context of skeletal muscle repair and recovery. In addition, we also provide hypothetical models of how this system may interact with other processes involved in skeletal muscle remodeling and provide avenues for future research to improve our understanding of autophagy in human skeletal muscle.
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Affiliation(s)
- Jordan Acheson
- Department of Sport and Exercise Sciences, Manchester Metropolitan University, Institute of Sport, Manchester, U.K.
| | - Sophie Joanisse
- School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, U.K.
| | - Craig Sale
- Department of Sport and Exercise Sciences, Manchester Metropolitan University, Institute of Sport, Manchester, U.K.
| | - Nathan Hodson
- Department of Sport and Exercise Sciences, Manchester Metropolitan University, Institute of Sport, Manchester, U.K.
- Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, Ontario, Canada
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7
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Wang J, Jia D, Zhang Z, Wang D. Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis. Metabolites 2025; 15:59. [PMID: 39852400 PMCID: PMC11767263 DOI: 10.3390/metabo15010059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 01/26/2025] Open
Abstract
Background/Objectives: Sarcopenia, characterized by the progressive loss of muscle mass and strength, is linked to physical disability, metabolic dysfunction, and an increased risk of mortality. Exercise therapy is currently acknowledged as a viable approach for addressing sarcopenia. Nevertheless, the molecular mechanisms behind exercise training or physical activity remain poorly understood. The disruption of mitochondrial homeostasis is implicated in the pathogenesis of sarcopenia. Exercise training effectively delays the onset of sarcopenia by significantly maintaining mitochondrial homeostasis, including promoting mitophagy, improving mitochondrial biogenesis, balancing mitochondrial dynamics, and maintaining mitochondrial redox. Exerkines (e.g., adipokines, myokines, hepatokines, and osteokines), signaling molecules released in response to exercise training, may potentially contribute to skeletal muscle metabolism through ameliorating mitochondrial homeostasis, reducing inflammation, and regulating protein synthesis as a defense against sarcopenia. Methods: In this review, we provide a detailed summary of exercise-induced exerkines and confer their benefit, with particular focus on their impact on mitochondrial homeostasis in the context of sarcopenia. Results: Exercise induces substantial adaptations in skeletal muscle, including increased muscle mass, improved muscle regeneration and hypertrophy, elevated hormone release, and enhanced mitochondrial function. An expanding body of research highlights that exerkines have the potential to regulate processes such as mitophagy, mitochondrial biogenesis, dynamics, autophagy, and redox balance. These mechanisms contribute to the maintenance of mitochondrial homeostasis, thereby supporting skeletal muscle metabolism and mitochondrial health. Conclusions: Through a comprehensive investigation of the molecular mechanisms within mitochondria, the context reveals new insights into the potential of exerkines as key exercise-protective sensors for combating sarcopenia.
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Affiliation(s)
- Jiayin Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (D.J.)
| | - Dandan Jia
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (D.J.)
| | - Zhiwang Zhang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (D.J.)
| | - Dan Wang
- School of Athletic Performance, Shanghai University of Sport, Shanghai 200438, China
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8
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Mueller BJ, Roberts MD, Mobley CB, Judd RL, Kavazis AN. Nitric oxide in exercise physiology: past and present perspectives. Front Physiol 2025; 15:1504978. [PMID: 39850450 PMCID: PMC11754211 DOI: 10.3389/fphys.2024.1504978] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 12/17/2024] [Indexed: 01/25/2025] Open
Abstract
Nitric oxide (NO) is a ubiquitous signaling molecule known to modulate various physiological processes, with specific implications in skeletal muscle and broader applications in exercise performance. This review focuses on the modulation of skeletal muscle function, mitochondrial adaptation and function, redox state by NO, and the effect of nitrate supplementation on exercise performance. In skeletal muscle function, NO is believed to increase the maximal shortening velocity and peak power output of muscle fibers. However, its effect on submaximal contraction is still undetermined. In mitochondria, NO may stimulate biogenesis and affect respiratory efficiency. NO also plays a role in the redox state within the skeletal muscle, partially through its interaction with respiratory chain enzymes and transcriptional regulators of antioxidant production. Nitrate supplementation leads to an increased bioavailability of NO in skeletal muscle. Thus, nitrate supplementation has been investigated for its ability to impact performance outcomes in endurance and resistance exercise. The effect of nitrate supplementation on endurance exercise is currently indecisive, although evidence indicates that it may extend the time to exhaustion in endurance exercise. Alternatively, the effect of nitrate supplementation on resistance exercise performance has been less studied. Limited research indicates that nitrate supplementation may improve repetitions to failure. Further research is needed to investigate the influence of training status, age, sex, and duration of supplementation to further elucidate the impact of nitrate supplementation on exercise performance.
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Affiliation(s)
| | | | | | - Robert L. Judd
- Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, AL, United States
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9
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Jackson MJ. Reactive oxygen species in age-related musculoskeletal decline: implications for nutritional intervention. Proc Nutr Soc 2024:1-9. [PMID: 39512110 DOI: 10.1017/s0029665124004877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
Musculoskeletal disorders and age-related musculoskeletal decline are major contributors to the burden of ill health seen in older subjects. Despite this increased burden, these chronic disorders of old age receive a relatively small proportion of national research funds. Much has been learned about fundamental processes involved in ageing from basic science research and this is leading to identification of key pathways that mediate ageing which may help the search for interventions to reduce age-related musculoskeletal decline. This short review will focus on the role of reactive oxygen species in age-related skeletal muscle decline and on the implications of this work for potential nutritional interventions in sarcopenia. The key physiological role of reactive oxygen species is now known to be in mediating redox signalling in muscle and other tissues and ageing leads to disruption of such pathways. In muscle, this is reflected in an age-related attenuation of specific adaptations and responses to contractile activity that impacts the ability of skeletal muscle from ageing individuals to respond to exercise. These pathways provides potential targets for identification of logical interventions that may help maintain muscle mass and function during ageing.
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Affiliation(s)
- Malcolm J Jackson
- MRC-Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing, Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
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Craige SM, Mammel RK, Amiri N, Willoughby OS, Drake JC. Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling. Redox Biol 2024; 77:103371. [PMID: 39357424 PMCID: PMC11474192 DOI: 10.1016/j.redox.2024.103371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 09/05/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Affiliation(s)
- Siobhan M Craige
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, 24061, USA.
| | - Rebecca K Mammel
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, 24061, USA
| | - Niloufar Amiri
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, 24061, USA; Institute for Critical Technology and Applied Science, Virginia Tech, Blacksburg, 24061, USA
| | - Orion S Willoughby
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, 24061, USA
| | - Joshua C Drake
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, 24061, USA.
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11
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Powers SK, Radak Z, Ji LL, Jackson M. Reactive oxygen species promote endurance exercise-induced adaptations in skeletal muscles. JOURNAL OF SPORT AND HEALTH SCIENCE 2024; 13:780-792. [PMID: 38719184 PMCID: PMC11336304 DOI: 10.1016/j.jshs.2024.05.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 10/26/2023] [Accepted: 11/09/2023] [Indexed: 05/22/2024]
Abstract
The discovery that contracting skeletal muscle generates reactive oxygen species (ROS) was first reported over 40 years ago. The prevailing view in the 1980s was that exercise-induced ROS production promotes oxidation of proteins and lipids resulting in muscle damage. However, a paradigm shift occurred in the 1990s as growing research revealed that ROS are signaling molecules, capable of activating transcriptional activators/coactivators and promoting exercise-induced muscle adaptation. Growing evidence supports the notion that reduction-oxidation (redox) signaling pathways play an important role in the muscle remodeling that occurs in response to endurance exercise training. This review examines the specific role that redox signaling plays in this endurance exercise-induced skeletal muscle adaptation. We begin with a discussion of the primary sites of ROS production in contracting muscle fibers followed by a summary of the antioxidant enzymes involved in the regulation of ROS levels in the cell. We then discuss which redox-sensitive signaling pathways promote endurance exercise-induced muscle adaptation and debate the strength of the evidence supporting the notion that redox signaling plays an essential role in muscle adaptation to endurance exercise training. In hopes of stimulating future research, we highlight several important unanswered questions in this field.
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Affiliation(s)
- Scott K Powers
- Department of Applied Physiology, University of Florida, Gainesville, FL 32608, USA.
| | - Zsolt Radak
- Research Institute of Sport Science, Hungarian University of Sport Science, Budapest 1123, Hungary
| | - Li Li Ji
- Department of Kinesiology, University of Minnesota, St. Paul, MN 55455, USA
| | - Malcolm Jackson
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK
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12
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Martinez-Canton M, Galvan-Alvarez V, Gallego-Selles A, Gelabert-Rebato M, Garcia-Gonzalez E, Gonzalez-Henriquez JJ, Martin-Rincon M, Calbet JAL. Activation of macroautophagy and chaperone-mediated autophagy in human skeletal muscle by high-intensity exercise in normoxia and hypoxia and after recovery with or without post-exercise ischemia. Free Radic Biol Med 2024; 222:607-624. [PMID: 39009244 DOI: 10.1016/j.freeradbiomed.2024.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/25/2024] [Accepted: 07/11/2024] [Indexed: 07/17/2024]
Abstract
Autophagy is essential for the adaptive response to exercise and physiological skeletal muscle functionality. However, the mechanisms leading to the activation of macroautophagy and chaperone-mediated autophagy in human skeletal muscle in response to high-intensity exercise remain elusive. Our findings demonstrate that macroautophagy and chaperone-mediated autophagy are stimulated by high-intensity exercise in normoxia (PIO2: 143 mmHg) and severe acute hypoxia (PIO2: 73 mmHg) in healthy humans. High-intensity exercise induces macroautophagy initiation through AMPKα phosphorylation, which phosphorylates and activates ULK1. ULK1 phosphorylates BECN1 at Ser15, eliciting the dissociation of BECN1-BCL2 crucial for phagophore formation. Besides, high-intensity exercise elevates the LC3B-II:LC3B-I ratio, reduces total SQSTM1/p62 levels, and induces p-Ser349 SQSTM1/p62 phosphorylation, suggesting heightened autophagosome degradation. PHAF1/MYTHO, a novel macroautophagy biomarker, is highly upregulated in response to high-intensity exercise. The latter is accompanied by elevated LAMP2A expression, indicating chaperone-mediated autophagy activation regardless of post-exercise HSPA8/HSC70 downregulation. Despite increased glycolytic metabolism, severe acute hypoxia does not exacerbate the autophagy signaling response. Signaling changes revert within 1 min of recovery with free circulation, while the application of immediate post-exercise ischemia impedes recovery. Our study concludes that macroautophagy and chaperone-mediated autophagy pathways are strongly activated by high-intensity exercise, regardless of PO2, and that oxygenation is necessary to revert these signals to pre-exercise values. PHAF1/MYTHO emerges as a pivotal exercise-responsive autophagy marker positively associated with the LC3B-II:LC3B-I ratio.
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Affiliation(s)
- Miriam Martinez-Canton
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira s/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Victor Galvan-Alvarez
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira s/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Angel Gallego-Selles
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira s/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Miriam Gelabert-Rebato
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira s/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Eduardo Garcia-Gonzalez
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira s/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Juan Jose Gonzalez-Henriquez
- Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain; Department of Mathematics, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira s/n, Las Palmas de Gran Canaria, 35017, Spain
| | - Marcos Martin-Rincon
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira s/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Jose A L Calbet
- Department of Physical Education, University of Las Palmas de Gran Canaria, Campus Universitario de Tafira s/n, Las Palmas de Gran Canaria, 35017, Spain; Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain; Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway.
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13
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Mikšiūnas R, Labeit S, Bironaite D. Class I and II Histone Deacetylase Inhibitors as Therapeutic Modulators of Dilated Cardiac Tissue-Derived Mesenchymal Stem/Stromal Cells. Int J Mol Sci 2024; 25:6758. [PMID: 38928463 PMCID: PMC11203858 DOI: 10.3390/ijms25126758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/14/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
The prevalence of dilated cardiomyopathy (DCM) is increasing globally, highlighting the need for innovative therapeutic approaches to prevent its onset. In this study, we examined the energetic and epigenetic distinctions between dilated and non-dilated human myocardium-derived mesenchymal stem/stromal cells (hmMSCs) and assessed the effects of class I and II HDAC inhibitors (HDACi) on these cells and their cardiomyogenic differentiation. Cells were isolated from myocardium biopsies using explant outgrowth methods. Mitochondrial and histone deacetylase activities, ATP levels, cardiac transcription factors, and structural proteins were assessed using flow cytometry, PCR, chemiluminescence, Western blotting, and immunohistochemistry. The data suggest that the tested HDAC inhibitors improved acetylation and enhanced the energetic status of both types of cells, with significant effects observed in dilated myocardium-derived hmMSCs. Additionally, the HDAC inhibitors activated the cardiac transcription factors Nkx2-5, HOPX, GATA4, and Mef2C, and upregulated structural proteins such as cardiac troponin T and alpha cardiac actin at both the protein and gene levels. In conclusion, our findings suggest that HDACi may serve as potential modulators of the energetic status and cardiomyogenic differentiation of human heart hmMSCs. This avenue of exploration could broaden the search for novel therapeutic interventions for dilated cardiomyopathy, ultimately leading to improvements in heart function.
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Affiliation(s)
- Rokas Mikšiūnas
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariškių 5, LT-08406 Vilnius, Lithuania;
| | | | - Daiva Bironaite
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariškių 5, LT-08406 Vilnius, Lithuania;
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14
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Wernhart S, Rassaf T. Relevance of Cardiovascular Exercise in Cancer and Cancer Therapy-Related Cardiac Dysfunction. Curr Heart Fail Rep 2024; 21:238-251. [PMID: 38696059 PMCID: PMC11090948 DOI: 10.1007/s11897-024-00662-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2024] [Indexed: 05/14/2024]
Abstract
PURPOSE OF THE REVIEW Cancer therapy-related cardiac dysfunction (CTRCD) has been identified as a threat to overall and cancer-related survival. Although aerobic exercise training (AET) has been shown to improve cardiorespiratory fitness (CRF), the relationship between specific exercise regimens and cancer survival, heart failure development, and reduction of CTRCD is unclear. In this review, we discuss the impact of AET on molecular pathways and the current literature of sports in the field of cardio-oncology. RECENT FINDINGS Cardio-oncological exercise trials have focused on variations of AET intensity by using moderate continuous and high intensity interval training, which are applicable, safe, and effective approaches to improve CRF. AET increases CRF, reduces cardiovascular morbidity and heart failure hospitalization and should thus be implemented as an adjunct to standard cancer therapy, although its long-term effect on CTRCD remains unknown. Despite modulating diverse molecular pathways, it remains unknown which exercise regimen, including variations of AET duration and frequency, is most suited to facilitate peripheral and central adaptations to exercise and improve survival in cancer patients.
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Affiliation(s)
- Simon Wernhart
- Department of Cardiology and Vascular Medicine, West German Heart- and Vascular Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, West German Heart- and Vascular Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany
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15
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Da W, Chen Q, Shen B. The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration. Biol Res 2024; 57:37. [PMID: 38824571 PMCID: PMC11143644 DOI: 10.1186/s40659-024-00494-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 04/03/2024] [Indexed: 06/03/2024] Open
Abstract
It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.
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Affiliation(s)
- Wacili Da
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Quan Chen
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Bin Shen
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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16
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Zhou Y, Zhang X, Baker JS, Davison GW, Yan X. Redox signaling and skeletal muscle adaptation during aerobic exercise. iScience 2024; 27:109643. [PMID: 38650987 PMCID: PMC11033207 DOI: 10.1016/j.isci.2024.109643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024] Open
Abstract
Redox regulation is a fundamental physiological phenomenon related to oxygen-dependent metabolism, and skeletal muscle is mainly regarded as a primary site for oxidative phosphorylation. Several studies have revealed the importance of reactive oxygen and nitrogen species (RONS) in the signaling process relating to muscle adaptation during exercise. To date, improving knowledge of redox signaling in modulating exercise adaptation has been the subject of comprehensive work and scientific inquiry. The primary aim of this review is to elucidate the molecular and biochemical pathways aligned to RONS as activators of skeletal muscle adaptation and to further identify the interconnecting mechanisms controlling redox balance. We also discuss the RONS-mediated pathways during the muscle adaptive process, including mitochondrial biogenesis, muscle remodeling, vascular angiogenesis, neuron regeneration, and the role of exogenous antioxidants.
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Affiliation(s)
- Yingsong Zhou
- Faculty of Sports Science, Ningbo University, Ningbo, China
| | - Xuan Zhang
- School of Wealth Management, Ningbo University of Finance and Economics, Ningbo, China
| | - Julien S. Baker
- Centre for Health and Exercise Science Research, Hong Kong Baptist University, Kowloon Tong 999077, Hong Kong
| | - Gareth W. Davison
- Sport and Exercise Sciences Research Institute, Ulster University, Belfast BT15 IED, UK
| | - Xiaojun Yan
- School of Marine Sciences, Ningbo University, Ningbo, China
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17
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Montserrat-Mesquida M, Ferrer MD, Pons A, Sureda A, Capó X. Effects of chronic hydrogen peroxide exposure on mitochondrial oxidative stress genes, ROS production and lipid peroxidation in HL60 cells. Mitochondrion 2024; 76:101869. [PMID: 38467292 DOI: 10.1016/j.mito.2024.101869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/25/2024] [Accepted: 03/07/2024] [Indexed: 03/13/2024]
Abstract
Hydrogen peroxide (H2O2) is a reactive species that is also involved in the redox regulation of cells because of it is relative stability. In numerous pathological situations, a chronic increase in the production of reactive species is observed, which is related to oxidative stress and cellular damage. This study aimed to evaluate the effects of long-term exposure to different H2O2 concentrations on oxidative stress biomarkers and mitochondrial dynamics in HL60 cells. HL60 cells were treated with a sustained production (0.1, 1.0 and 10.0 nM/s) of H2O2 for one hour. H2O2 production and malondialdehyde (MDA) levels, as a lipid peroxidation marker, increased progressively in HL60 cells in accordance with higher H2O2 exposure, with significant differences between the 10 nM/s H2O2 group and the control and 0.1 nM/s groups. Similarly, progressive increased expression in genes related to the mitochondrial antioxidant defences and mitochondrial dynamics were also observed. Significantly increased gene expression in the 10 nM/s H2O2 with respect to the control group was observed for manganese superoxide dismutase (MnSOD), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PCG1α), nuclear respiratory factor 2 (Nrf2), mitochondrial transcription factor A (Tfam), mitofusins 1 and 2 (Mfn1 and Mfn2) and uncoupling protein 3 (UCP3), whereas no significant changes were observed in the cytochrome c oxidase subunit IV (COXIV) gene expression. In conclusion, exposure to different sustained production of H2O2 is related to a progressive increase in the gene expression of mitochondrial dynamics and redox processes in HL60 cells, but also to oxidative damage at higher H2O2 production levels.
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Affiliation(s)
- M Montserrat-Mesquida
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain; Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - M D Ferrer
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain
| | - A Pons
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain; Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - A Sureda
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain; Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain.
| | - X Capó
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain; Translational Research in Aging and Longevity (TRIAL) Group, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain
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18
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Davids CJ, Roberts LA, Bjørnsen T, Peake JM, Coombes JS, Raastad T. Where Does Blood Flow Restriction Fit in the Toolbox of Athletic Development? A Narrative Review of the Proposed Mechanisms and Potential Applications. Sports Med 2023; 53:2077-2093. [PMID: 37578669 PMCID: PMC10587223 DOI: 10.1007/s40279-023-01900-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2023] [Indexed: 08/15/2023]
Abstract
Blood flow-restricted exercise is currently used as a low-intensity time-efficient approach to reap many of the benefits of typical high-intensity training. Evidence continues to lend support to the notion that even highly trained individuals, such as athletes, still benefit from this mode of training. Both resistance and endurance exercise may be combined with blood flow restriction to provide a spectrum of adaptations in skeletal muscle, spanning from myofibrillar to mitochondrial adjustments. Such diverse adaptations would benefit both muscular strength and endurance qualities concurrently, which are demanded in athletic performance, most notably in team sports. Moreover, recent work indicates that when traditional high-load resistance training is supplemented with low-load, blood flow-restricted exercise, either in the same session or as a separate training block in a periodised programme, a synergistic and complementary effect on training adaptations may occur. Transient reductions in mechanical loading of tissues afforded by low-load, blood flow-restricted exercise may also serve a purpose during de-loading, tapering or rehabilitation of musculoskeletal injury. This narrative review aims to expand on the current scientific and practical understanding of how blood flow restriction methods may be applied by coaches and practitioners to enhance current athletic development models.
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Affiliation(s)
- Charlie J Davids
- Sport, Performance, and Nutrition Research Group, School of Allied Health, Human Services and Sport, La Trobe University, Melbourne, Australia.
- School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD, Australia.
- Sport Performance Innovation and Knowledge Excellence (SPIKE), Queensland Academy of Sport, Brisbane, QLD, Australia.
| | - Llion A Roberts
- School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD, Australia
- Sport Performance Innovation and Knowledge Excellence (SPIKE), Queensland Academy of Sport, Brisbane, QLD, Australia
- School of Health Sciences and Social Work, Griffith University, Gold Coast, QLD, Australia
| | - Thomas Bjørnsen
- Department of Sport Science and Physical Education, University of Agder, Kristiansand, Norway
- Norwegian Olympic and Paralympic Committee and Confederation of Sports, Oslo, Norway
| | - Jonathan M Peake
- Sport Performance Innovation and Knowledge Excellence (SPIKE), Queensland Academy of Sport, Brisbane, QLD, Australia
- School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia
| | - Jeff S Coombes
- School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - Truls Raastad
- Norwegian Olympic and Paralympic Committee and Confederation of Sports, Oslo, Norway
- Department of Physical Performance, Norwegian School of Sport Science, Oslo, Norway
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19
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Espinosa A, Casas M, Jaimovich E. Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle. Antioxidants (Basel) 2023; 12:1624. [PMID: 37627619 PMCID: PMC10451830 DOI: 10.3390/antiox12081624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/27/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Exercise produces oxidants from a variety of intracellular sources, including NADPH oxidases (NOX) and mitochondria. Exercise-derived reactive oxygen species (ROS) are beneficial, and the amount and location of these ROS is important to avoid muscle damage associated with oxidative stress. We discuss here some of the evidence that involves ROS production associated with skeletal muscle contraction and the potential oxidative stress associated with muscle contraction. We also discuss the potential role of H2O2 produced after NOX activation in the regulation of glucose transport in skeletal muscle. Finally, we propose a model based on evidence for the role of different populations of mitochondria in skeletal muscle in the regulation of ATP production upon exercise. The subsarcolemmal population of mitochondria has the enzymatic and metabolic components to establish a high mitochondrial membrane potential when fissioned at rest but lacks the capacity to produce ATP. Calcium entry into the mitochondria will further increase the metabolic input. Upon exercise, subsarcolemmal mitochondria will fuse to intermyofibrillar mitochondria and will transfer the mitochondria membrane potential to them. These mitochondria are rich in ATP synthase and will subsequentially produce the ATP needed for muscle contraction in long-term exercise. These events will optimize energy use and minimize mitochondria ROS production.
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Affiliation(s)
- Alejandra Espinosa
- Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8320000, Chile; (A.E.)
- San Felipe Campus, School of Medicine, Faculty of Medicine, Universidad de Valparaiso, San Felipe 2172972, Chile
| | - Mariana Casas
- Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8320000, Chile; (A.E.)
| | - Enrique Jaimovich
- Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8320000, Chile; (A.E.)
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20
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Pandey J, Larson-Casey JL, Patil MH, Joshi R, Jiang CS, Zhou Y, He C, Carter AB. NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming. J Biol Chem 2023; 299:104695. [PMID: 37044213 PMCID: PMC10193017 DOI: 10.1016/j.jbc.2023.104695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 03/14/2023] [Accepted: 04/03/2023] [Indexed: 04/14/2023] Open
Abstract
Pulmonary fibrosis is a progressive lung disease characterized by macrophage activation. Asbestos-induced expression of nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) in lung macrophages mediates fibrotic progression by the generation of mitochondrial reactive oxygen species (ROS), modulating mitochondrial biogenesis, and promoting apoptosis resistance; however, the mechanism(s) by which NOX4 localizes to mitochondria during fibrosis is not known. Here, we show that NOX4 localized to the mitochondrial matrix following asbestos exposure in lung macrophages via direct interaction with TIM23. TIM23 and NOX4 interaction was found in lung macrophages from human subjects with asbestosis, while it was absent in mice harboring a conditional deletion of NOX4 in lung macrophages. This interaction was localized to the proximal transmembrane region of NOX4. Mechanistically, TIM23 augmented NOX4-induced mitochondrial ROS and metabolic reprogramming to oxidative phosphorylation. Silencing TIM23 decreased mitochondrial ROS and oxidative phosphorylation. These observations highlight the important role of the mitochondrial translocase TIM23 interaction with NOX4. Moreover, this interaction is required for mitochondrial redox signaling and metabolic reprogramming in lung macrophages.
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Affiliation(s)
- Jyotsana Pandey
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jennifer L Larson-Casey
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Mallikarjun H Patil
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rutwij Joshi
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Chun-Sun Jiang
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Yong Zhou
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Chao He
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - A Brent Carter
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Medicine, Birmingham VAMC, Birmingham, Alabama, USA.
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21
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Porto AA, Gonzaga LA, Benjamim CJR, Valenti VE. Absence of Effects of L-Arginine and L-Citrulline on Inflammatory Biomarkers and Oxidative Stress in Response to Physical Exercise: A Systematic Review with Meta-Analysis. Nutrients 2023; 15:nu15081995. [PMID: 37111214 DOI: 10.3390/nu15081995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND The repercussions on oxidative and inflammatory stress markers under the effects of arginine and citrulline in response to exercise are not fully reached. We completed a systematic review to investigate the effects of L-Citrulline or L-Arginine on oxidative stress and inflammatory biomarkers following exercise. EMBASE, MEDLINE (PubMed), Cochrane Library, CINAHL, LILACS, and Web of Science databases were used to record the trials. This study includes randomized controlled trials (RCTs) and non-RCTs with subjects over 18 years old. Those under the intervention protocol consumed L-Citrulline or L-Arginine, and the controls ingested placebo. We recognized 1080 studies, but only 7 were included (7 studies in meta-analysis). We observed no difference between pre- vs. post-exercise for oxidative stress (subtotal = -0.21 [CI: -0.56, 0.14], p = 0.24, and heterogeneity = 0%. In the sub-group "L-Arginine" we found a subtotal = -0.29 [-0.71, 0.12], p = 0.16, and heterogeneity = 0%. For the "L-Citrulline" subgroup we observed a subtotal = 0.00 [-0.67, 0.67], p = 1.00, and heterogeneity was not applicable. No differences were observed between groups (p = 0.47), and I² = 0%) or in antioxidant activity (subtotal = -0.28 [-1.65, 1.08], p = 0.68, and heterogeneity = 0%). In the "L-Arginine" sub-group, we found a subtotal = -3.90 [-14.18, 6.38], p = 0.46, and heterogeneity was not applicable. For the "L-Citrulline" subgroup, we reported a subtotal = -0.22 [-1.60, 1.16], p = 0.75, and heterogeneity was not applicable. No differences were observed between groups (p = 0.49), and I² = 0%), inflammatory markers (subtotal = 8.38 [-0.02, 16.78], p = 0.05, and heterogeneity = 93%. Tests for subgroup differences were not applicable, and anti-inflammatory markers (subtotal = -0.38 [-1.15, 0.39], p = 0.34 and heterogeneity = 15%; testing for subgroup differences was not applicable). In conclusion, our systematic review and meta-analysis found that L-Citrulline and L-Arginine did not influence inflammatory biomarkers and oxidative stress after exercise.
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Affiliation(s)
- Andrey A Porto
- São Paulo State University (UNESP), Presidente Prudente 19060-080, SP, Brazil
- Autonomic Nervous System Center, São Paulo State University (UNESP), Marília 17525-900, SP, Brazil
| | - Luana A Gonzaga
- São Paulo State University (UNESP), Presidente Prudente 19060-080, SP, Brazil
- Autonomic Nervous System Center, São Paulo State University (UNESP), Marília 17525-900, SP, Brazil
| | - Cicero Jonas R Benjamim
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Vitor E Valenti
- São Paulo State University (UNESP), Presidente Prudente 19060-080, SP, Brazil
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22
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Supruniuk E, Górski J, Chabowski A. Endogenous and Exogenous Antioxidants in Skeletal Muscle Fatigue Development during Exercise. Antioxidants (Basel) 2023; 12:antiox12020501. [PMID: 36830059 PMCID: PMC9952836 DOI: 10.3390/antiox12020501] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/09/2023] [Accepted: 02/15/2023] [Indexed: 02/18/2023] Open
Abstract
Muscle fatigue is defined as a decrease in maximal force or power generated in response to contractile activity, and it is a risk factor for the development of musculoskeletal injuries. One of the many stressors imposed on skeletal muscle through exercise is the increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which intensifies as a function of exercise intensity and duration. Exposure to ROS/RNS can affect Na+/K+-ATPase activity, intramyofibrillar calcium turnover and sensitivity, and actin-myosin kinetics to reduce muscle force production. On the other hand, low ROS/RNS concentrations can likely upregulate an array of cellular adaptative responses related to mitochondrial biogenesis, glucose transport and muscle hypertrophy. Consequently, growing evidence suggests that exogenous antioxidant supplementation might hamper exercise-engendering upregulation in the signaling pathways of mitogen-activated protein kinases (MAPKs), peroxisome-proliferator activated co-activator 1α (PGC-1α), or mammalian target of rapamycin (mTOR). Ultimately, both high (exercise-induced) and low (antioxidant intervention) ROS concentrations can trigger beneficial responses as long as they do not override the threshold range for redox balance. The mechanisms underlying the two faces of ROS/RNS in exercise, as well as the role of antioxidants in muscle fatigue, are presented in detail in this review.
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Affiliation(s)
- Elżbieta Supruniuk
- Department of Physiology, Medical University of Białystok, 15-222 Białystok, Poland
- Correspondence: ; Tel.: +48-(85)-748-55-85
| | - Jan Górski
- Department of Medical Sciences, Academy of Applied Sciences, 18-400 Łomża, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Białystok, 15-222 Białystok, Poland
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23
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Pappas G, Wilkinson ML, Gow AJ. Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy. Nitric Oxide 2023; 131:8-17. [PMID: 36470373 PMCID: PMC9839556 DOI: 10.1016/j.niox.2022.11.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/24/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Nitric oxide can interact with a wide range of proteins including many that are involved in metabolism. In this review we have summarized the effects of NO on glycolysis, fatty acid metabolism, the TCA cycle, and oxidative phosphorylation with reference to skeletal muscle. Low to moderate NO concentrations upregulate glucose and fatty acid oxidation, while higher NO concentrations shift cellular reliance toward a fully glycolytic phenotype. Moderate NO production directly inhibits pyruvate dehydrogenase activity, reducing glucose-derived carbon entry into the TCA cycle and subsequently increasing anaploretic reactions. NO directly inhibits aconitase activity, increasing reliance on glutamine for continued energy production. At higher or prolonged NO exposure, citrate accumulation can inhibit multiple ATP-producing pathways. Reduced TCA flux slows NADH/FADH entry into the ETC. NO can also inhibit the ETC directly, further limiting oxidative phosphorylation. Moderate NO production improves mitochondrial efficiency while improving O2 utilization increasing whole-body energy production. Long-term bioenergetic capacity may be increased because of NO-derived ROS, which participate in adaptive cellular redox signaling through AMPK, PCG1-α, HIF-1, and NF-κB. However, prolonged exposure or high concentrations of NO can result in membrane depolarization and opening of the MPT. In this way NO may serve as a biochemical rheostat matching energy supply with demand for optimal respiratory function.
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Affiliation(s)
- Gregory Pappas
- Department of Kinesiology & Applied Physiology, Rutgers the State University of New Jersey, NJ, 08854, USA.
| | - Melissa L Wilkinson
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers the State University of New Jersey, NJ, 08854, USA.
| | - Andrew J Gow
- Department of Kinesiology & Applied Physiology, Rutgers the State University of New Jersey, NJ, 08854, USA; Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers the State University of New Jersey, NJ, 08854, USA.
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24
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Wen P, Zheng B, Zhang B, Ma T, Hao L, Zhang Y. The role of ageing and oxidative stress in intervertebral disc degeneration. Front Mol Biosci 2022; 9:1052878. [PMID: 36419928 PMCID: PMC9676652 DOI: 10.3389/fmolb.2022.1052878] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 10/25/2022] [Indexed: 10/10/2023] Open
Abstract
Intervertebral disc degeneration (IDD) is the primary cause of intervertebral disc (IVD) disease. With the increased ageing of society, an increasing number of patients are plagued by intervertebral disc disease. Ageing not only accelerates the decreased vitality and functional loss of intervertebral disc cells but also increases intracellular oxidative stress. Moreover, the speed of intervertebral disc ageing is also linked to high levels of reactive oxygen species (ROS) production. Not only is the production of ROS increased in ageing intervertebral disc cells, but antioxidant levels in degenerative intervertebral discs also decrease. In addition to the intervertebral disc, the structural components of the intervertebral disc matrix are vulnerable to oxidative damage. After chronic mitochondrial dysfunction, ROS can be produced in large quantities, while autophagy can eliminate these impaired mitochondria to reduce the production of ROS. Oxidative stress has a marked impact on the occurrence of IDD. In the future, IDD treatment is aiming to improve oxidative stress by regulating the redox balance in intervertebral disc cells. In summary, ageing and oxidative stress promote the degeneration of IVD, but further basic and clinical trials are needed to determine how to treat oxidative stress. At present, although there are many in-depth studies on the relationship between oxidative stress and degeneration of intervertebral disc cells, the specific mechanism has not been elucidated. In this paper, the main causes of intervertebral disc diseases are studied and summarized, and the impact of oxidative stress on intervertebral disc degeneration is studied.
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Affiliation(s)
- Pengfei Wen
- Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Bolong Zheng
- Department of Spine Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Binfei Zhang
- Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Tao Ma
- Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Linjie Hao
- Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yumin Zhang
- Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, China
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25
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HAIBO X, ALBATTAT A, PHUOC JC, BAOGUI W. Explore the role of irisin in mitohormesis by PGC-1α. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2022. [DOI: 10.23736/s0393-3660.22.04790-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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26
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Green A, Hossain T, Eckmann DM. Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission. Front Cell Dev Biol 2022; 10:1010232. [PMID: 36340034 PMCID: PMC9626967 DOI: 10.3389/fcell.2022.1010232] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/06/2022] [Indexed: 11/13/2022] Open
Abstract
Mitochondria are cell organelles that play pivotal roles in maintaining cell survival, cellular metabolic homeostasis, and cell death. Mitochondria are highly dynamic entities which undergo fusion and fission, and have been shown to be very motile in vivo in neurons and in vitro in multiple cell lines. Fusion and fission are essential for maintaining mitochondrial homeostasis through control of morphology, content exchange, inheritance of mitochondria, maintenance of mitochondrial DNA, and removal of damaged mitochondria by autophagy. Mitochondrial motility occurs through mechanical and molecular mechanisms which translocate mitochondria to sites of high energy demand. Motility also plays an important role in intracellular signaling. Here, we review key features that mediate mitochondrial dynamics and explore methods to advance the study of mitochondrial motility as well as mitochondrial dynamics-related diseases and mitochondrial-targeted therapeutics.
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Affiliation(s)
- Adam Green
- Department of Anesthesiology, The Ohio State University, Columbus, OH, United States
| | - Tanvir Hossain
- Department of Anesthesiology, The Ohio State University, Columbus, OH, United States
| | - David M. Eckmann
- Department of Anesthesiology, The Ohio State University, Columbus, OH, United States
- Center for Medical and Engineering Innovation, The Ohio State University, Columbus, OH, United States
- *Correspondence: David M. Eckmann,
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27
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Delfan M, Vahed A, Bishop DJ, Amadeh Juybari R, Laher I, Saeidi A, Granacher U, Zouhal H. Effects of two workload-matched high intensity interval training protocols on regulatory factors associated with mitochondrial biogenesis in the soleus muscle of diabetic rats. Front Physiol 2022; 13:927969. [PMID: 36213227 PMCID: PMC9541894 DOI: 10.3389/fphys.2022.927969] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/29/2022] [Indexed: 11/15/2022] Open
Abstract
Aims: High intensity interval training (HIIT) improves mitochondrial characteristics. This study compared the impact of two workload-matched high intensity interval training (HIIT) protocols with different work:recovery ratios on regulatory factors related to mitochondrial biogenesis in the soleus muscle of diabetic rats. Materials and methods: Twenty-four Wistar rats were randomly divided into four equal-sized groups: non-diabetic control, diabetic control (DC), diabetic with long recovery exercise [4-5 × 2-min running at 80%-90% of the maximum speed reached with 2-min of recovery at 40% of the maximum speed reached (DHIIT1:1)], and diabetic with short recovery exercise (5-6 × 2-min running at 80%-90% of the maximum speed reached with 1-min of recovery at 30% of the maximum speed reached [DHIIT2:1]). Both HIIT protocols were completed five times/week for 4 weeks while maintaining equal running distances in each session. Results: Gene and protein expressions of PGC-1α, p53, and citrate synthase of the muscles increased significantly following DHIIT1:1 and DHIIT2:1 compared to DC (p ˂ 0.05). Most parameters, except for PGC-1α protein (p = 0.597), were significantly higher in DHIIT2:1 than in DHIIT1:1 (p ˂ 0.05). Both DHIIT groups showed significant increases in maximum speed with larger increases in DHIIT2:1 compared with DHIIT1:1. Conclusion: Our findings indicate that both HIIT protocols can potently up-regulate gene and protein expression of PGC-1α, p53, and CS. However, DHIIT2:1 has superior effects compared with DHIIT1:1 in improving mitochondrial adaptive responses in diabetic rats.
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Affiliation(s)
- Maryam Delfan
- Department of Exercise Physiology, Faculty of Sport Sciences, Alzahra University, Tehran, Iran
| | - Alieh Vahed
- Department of Exercise Physiology, Faculty of Sport Sciences, Alzahra University, Tehran, Iran
| | - David J. Bishop
- Institute for Sport and Health (iHeS), Victoria University, Melbourne, VIC, Australia
| | - Raheleh Amadeh Juybari
- Department of Exercise Physiology, Faculty of Sport Sciences, Alzahra University, Tehran, Iran
| | - Ismail Laher
- Department of Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Ayoub Saeidi
- Department of Physical Education and Sport Sciences, Faculty of Humanities and Social Sciences, University of Kurdistan, Sanandaj, Kurdistan, Iran
| | - Urs Granacher
- Division of Training and Movement Sciences, University of Potsdam, Potsdam, Germany
| | - Hassane Zouhal
- Movement, Sport, Health and Sciences Laboratory (M2S), UFR-STAPS, University of Rennes 2-ENS Cachan, Rennes Cedex, France
- Institut International des Sciences du Sport (2I2S), Irodouer, France
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Barbosa H, Ramadan W, Matzenbacher dos Santos J, Benite-Ribeiro SA. Effects of Physical Exercise on Mitochondrial Biogenesis of Skeletal Muscle Modulated by Histones Modifications in Type 2 Diabetes. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.10095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Epigenetic modification in skeletal muscle induced by environmental factors seems to modulate several metabolic pathways that underlie Type 2 Diabetes Mellitus (T2DM) development. Mitochondrial biogenesis is an important process for maintaining lipid metabolism homeostasis, as well as epigenetic modifications in proteins that regulate this pathway have been observed in the skeletal muscle of T2DM subjects. Moreover, physical exercise affects several metabolic pathways attenuating metabolic deregulation observed in T2DM. The pathways that regulate mitochondrial homeostasis are one of the key components for understanding such physical exercise beneficial effects. Thus, in this study, we investigate the epigenetic mechanisms underlying mitochondrial biogenesis in the skeletal muscle in T2DM, focusing on histone modifications and the possible mechanisms by which physical exercise delay or inhibit T2DM onset. The results indicate that exercise promotes improvements in cellular metabolism through increasing enzymes of the antioxidant system, AMPK and ATP-citrate lyase activity, Acetyl-CoA concentration, and enhancing the acetylation of histones. A key mediator of mitochondrial biogenesis such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC1) seems to be upregulated by exercise in T2DM and such factor positively regulates the skeletal muscle mitochondrial biogenesis, which improves energy metabolism and glucose homeostasis inhibiting or delaying insulin resistance and further T2DM.
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29
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Dogan SA, Giacchin G, Zito E, Viscomi C. Redox Signaling and Stress in Inherited Myopathies. Antioxid Redox Signal 2022; 37:301-323. [PMID: 35081731 DOI: 10.1089/ars.2021.0266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Significance: Reactive oxygen species (ROS) are highly reactive compounds that behave like a double-edged sword; they damage cellular structures and act as second messengers in signal transduction. Mitochondria and endoplasmic reticulum (ER) are interconnected organelles with a central role in ROS production, detoxification, and oxidative stress response. Skeletal muscle is the most abundant tissue in mammals and one of the most metabolically active ones and thus relies mainly on oxidative phosphorylation (OxPhos) to synthesize adenosine triphosphate. The impairment of OxPhos leads to myopathy and increased ROS production, thus affecting both redox poise and signaling. In addition, ROS enter the ER and trigger ER stress and its maladaptive response, which also lead to a myopathic phenotype with mitochondrial involvement. Here, we review the role of ROS signaling in myopathies due to either mitochondrial or ER dysfunction. Recent Advances: Relevant advances have been evolving over the last 10 years on the intricate ROS-dependent pathways that act as modifiers of the disease course in several myopathies. To this end, pathways related to mitochondrial biogenesis, satellite cell differentiation, and ER stress have been studied extensively in myopathies. Critical Issues: The analysis of the chemistry and the exact quantitation, as well as the localization of ROS, are still challenging due to the intrinsic labile nature of ROS and the technical limitations of their sensors. Future Directions: The mechanistic studies of the pathogenesis of mitochondrial and ER-related myopathies offer a unique possibility to discover novel ROS-dependent pathways. Antioxid. Redox Signal. 37, 301-323.
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Affiliation(s)
- Sukru Anil Dogan
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogazici University, Istanbul, Turkey
| | - Giacomo Giacchin
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Ester Zito
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.,Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Carlo Viscomi
- Department of Biomedical Sciences, University of Padova, Padova, Italy
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30
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Localized Heat Therapy Improves Mitochondrial Respiratory Capacity but Not Fatty Acid Oxidation. Int J Mol Sci 2022; 23:ijms23158500. [PMID: 35955635 PMCID: PMC9369322 DOI: 10.3390/ijms23158500] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 11/26/2022] Open
Abstract
AIM: Mild heat stress can improve mitochondrial respiratory capacity in skeletal muscle. However, long-term heat interventions are scarce, and the effects of heat therapy need to be understood in the context of the adaptations which follow the more complex combination of stimuli from exercise training. The purpose of this work was to compare the effects of 6 weeks of localized heat therapy on human skeletal muscle mitochondria to single-leg interval training. METHODS: Thirty-five subjects were assigned to receive sham therapy, short-wave diathermy heat therapy, or single-leg interval exercise training, localized to the quadriceps muscles of the right leg. All interventions took place 3 times per week. Muscle biopsies were performed at baseline, and after 3 and 6 weeks of intervention. Mitochondrial respiratory capacity was assessed on permeabilized muscle fibers via high-resolution respirometry. RESULTS: The primary finding of this work was that heat therapy and exercise training significantly improved mitochondrial respiratory capacity by 24.8 ± 6.2% and 27.9 ± 8.7%, respectively (p < 0.05). Fatty acid oxidation and citrate synthase activity were also increased following exercise training by 29.5 ± 6.8% and 19.0 ± 7.4%, respectively (p < 0.05). However, contrary to our hypothesis, heat therapy did not increase fatty acid oxidation or citrate synthase activity. CONCLUSION: Six weeks of muscle-localized heat therapy significantly improves mitochondrial respiratory capacity, comparable to exercise training. However, unlike exercise, heat does not improve fatty acid oxidation capacity.
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31
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Powers SK, Schrager M. Redox signaling regulates skeletal muscle remodeling in response to exercise and prolonged inactivity. Redox Biol 2022; 54:102374. [PMID: 35738088 PMCID: PMC9233275 DOI: 10.1016/j.redox.2022.102374] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/12/2022] [Accepted: 06/14/2022] [Indexed: 12/23/2022] Open
Abstract
Skeletal muscle fibers are malleable and undergo rapid remodeling in response to increased contractile activity (i.e., exercise) or prolonged periods of muscle inactivity (e.g., prolonged bedrest). Exploration of the cell signaling pathways regulating these skeletal muscle adaptations reveal that redox signaling pathways play a key role in the control of muscle remodeling during both exercise and prolonged muscle inactivity. In this regard, muscular exercise results in an acute increase in the production of reactive oxygen species (ROS) in the contracting fibers; however, this contraction-induced rise in ROS production rapidly declines when contractions cease. In contrast, prolonged muscle disuse results in a chronic elevation in ROS production within the inactive fibers. This difference in the temporal pattern of ROS production in muscle during exercise and muscle inactivity stimulates divergent cell-signaling pathways that activate both genomic and nongenomic mechanisms to promote muscle remodeling. This review examines the role that redox signaling plays in skeletal muscle adaptation in response to both prolonged muscle inactivity and endurance exercise training. We begin with a summary of the sites of ROS production in muscle fibers followed by a review of the cellular antioxidants that are responsible for regulation of ROS levels in the cell. We then discuss the specific redox-sensitive signaling pathways that promote skeletal muscle adaptation in response to both prolonged muscle inactivity and exercise. To stimulate future research, we close with a discussion of unanswered questions in this exciting field.
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Affiliation(s)
- Scott K Powers
- Department of Health Sciences, Stetson University, Deland, FL, 32723, USA.
| | - Matthew Schrager
- Department of Health Sciences, Stetson University, Deland, FL, 32723, USA
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32
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Guo CL. Self-Sustained Regulation or Self-Perpetuating Dysregulation: ROS-dependent HIF-YAP-Notch Signaling as a Double-Edged Sword on Stem Cell Physiology and Tumorigenesis. Front Cell Dev Biol 2022; 10:862791. [PMID: 35774228 PMCID: PMC9237464 DOI: 10.3389/fcell.2022.862791] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/29/2022] [Indexed: 12/19/2022] Open
Abstract
Organ development, homeostasis, and repair often rely on bidirectional, self-organized cell-niche interactions, through which cells select cell fate, such as stem cell self-renewal and differentiation. The niche contains multiplexed chemical and mechanical factors. How cells interpret niche structural information such as the 3D topology of organs and integrate with multiplexed mechano-chemical signals is an open and active research field. Among all the niche factors, reactive oxygen species (ROS) have recently gained growing interest. Once considered harmful, ROS are now recognized as an important niche factor in the regulation of tissue mechanics and topology through, for example, the HIF-YAP-Notch signaling pathways. These pathways are not only involved in the regulation of stem cell physiology but also associated with inflammation, neurological disorder, aging, tumorigenesis, and the regulation of the immune checkpoint molecule PD-L1. Positive feedback circuits have been identified in the interplay of ROS and HIF-YAP-Notch signaling, leading to the possibility that under aberrant conditions, self-organized, ROS-dependent physiological regulations can be switched to self-perpetuating dysregulation, making ROS a double-edged sword at the interface of stem cell physiology and tumorigenesis. In this review, we discuss the recent findings on how ROS and tissue mechanics affect YAP-HIF-Notch-PD-L1 signaling, hoping that the knowledge can be used to design strategies for stem cell-based and ROS-targeting therapy and tissue engineering.
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Affiliation(s)
- Chin-Lin Guo
- Institute of Physics, Academia Sinica, Taipei, Taiwan
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33
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Sun Y, Wang Z, Nie C, Xue L, Wang Y, Liu J, Fan M, Zhang D, He R, Zhang X, Qian H, Chow BKC, Li Y, Wang L. Hydroxysafflor yellow A triggered a fast-to-slow muscle fiber-type conversion via regulating FoxO1 in myocytes. Food Funct 2022; 13:6317-6328. [PMID: 35611953 DOI: 10.1039/d1fo03612b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Hydroxysafflor yellow A (HSYA) is the main bioactive component of safflower and has been reported to have significant health-promoting abilities. However, the regulation of HSYA on different types of skeletal myofibers is largely unknown. Here, in vitro experiments found that the water extract of safflower could significantly increase MyHC I, MB and Tnni1 mRNA expression while downregulating MyHC IIb mRNA expression. Furthermore, HSYA triggered fast-to-slow fiber-type switching and increased gene expression related to mitochondrial biosynthesis both in vitro and in vivo. Autodock analyses proved that FoxO1 is a potential target of HSYA, and qRT-PCR and western blotting further showed that HSYA significantly promoted the activation of the FoxO1 signaling pathway. Additionally, the levels of PGC1α, downstream of FoxO1, also significantly increased after HSYA treatment. Together, our findings suggested that HSYA triggered a fast-to-slow myofiber-type shift through the FoxO1 signaling pathway.
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Affiliation(s)
- Yujie Sun
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Zhijun Wang
- COFCO Aerocean Oils & Grain Industrial Co. Ltd, Shawan, No. 1 West Park Road, West Urumqi Road, Shawan County, Tacheng District, Xinjiang Province 832100, China
| | - Chenzhipeng Nie
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Lamei Xue
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Yu Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Jinxin Liu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Mingcong Fan
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Duo Zhang
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, Georgia, USA
| | - Ruikun He
- BYHEALTH Institute of Nutrition & Health, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Huangpu District, Guangzhou 510663, China
| | - Xuguang Zhang
- BYHEALTH Institute of Nutrition & Health, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Huangpu District, Guangzhou 510663, China
| | - Haifeng Qian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Billy K C Chow
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Yan Li
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Li Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
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34
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The Role of Oxidative Stress in Skeletal Muscle Myogenesis and Muscle Disease. Antioxidants (Basel) 2022; 11:antiox11040755. [PMID: 35453440 PMCID: PMC9026549 DOI: 10.3390/antiox11040755] [Citation(s) in RCA: 95] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023] Open
Abstract
The contractile activity, high oxygen consumption and metabolic rate of skeletal muscle cause it to continuously produce moderate levels of oxidant species, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Under normal physiological conditions, there is a dynamic balance between the production and elimination of ROS/RNS. However, when the oxidation products exceed the antioxidant defense capacity, the body enters a state of oxidative stress. Myogenesis is an important process to maintain muscle homeostasis and the physiological function of skeletal muscle. Accumulating evidence suggests that oxidative stress plays a key role in myogenesis and skeletal muscle physiology and pathology. In this review, we summarize the sources of reactive oxygen species in skeletal muscle and the causes of oxidative stress and analyze the key role of oxidative stress in myogenesis. Then, we discuss the relationship between oxidative stress and muscle homeostasis and physiopathology. This work systematically summarizes the role of oxidative stress in myogenesis and muscle diseases and provides targets for subsequent antioxidant therapy and repair of inflammatory damage in noninflammatory muscle diseases.
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35
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Jîtcă G, Ősz BE, Tero-Vescan A, Miklos AP, Rusz CM, Bătrînu MG, Vari CE. Positive Aspects of Oxidative Stress at Different Levels of the Human Body: A Review. Antioxidants (Basel) 2022; 11:antiox11030572. [PMID: 35326222 PMCID: PMC8944834 DOI: 10.3390/antiox11030572] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/12/2022] [Accepted: 03/14/2022] [Indexed: 02/01/2023] Open
Abstract
Oxidative stress is the subject of numerous studies, most of them focusing on the negative effects exerted at both molecular and cellular levels, ignoring the possible benefits of free radicals. More and more people admit to having heard of the term "oxidative stress", but few of them understand the meaning of it. We summarized and analyzed the published literature data in order to emphasize the importance and adaptation mechanisms of basal oxidative stress. This review aims to provide an overview of the mechanisms underlying the positive effects of oxidative stress, highlighting these effects, as well as the risks for the population consuming higher doses than the recommended daily intake of antioxidants. The biological dose-response curve in oxidative stress is unpredictable as reactive species are clearly responsible for cellular degradation, whereas antioxidant therapies can alleviate senescence by maintaining redox balance; nevertheless, excessive doses of the latter can modify the redox balance of the cell, leading to a negative outcome. It can be stated that the presence of oxidative status or oxidative stress is a physiological condition with well-defined roles, yet these have been insufficiently researched and explored. The involvement of reactive oxygen species in the pathophysiology of some associated diseases is well-known and the involvement of antioxidant therapies in the processes of senescence, apoptosis, autophagy, and the maintenance of cellular homeostasis cannot be denied. All data in this review support the idea that oxidative stress is an undesirable phenomenon in high and long-term concentrations, but regular exposure is consistent with the hormetic theory.
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Affiliation(s)
- George Jîtcă
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (G.J.); (C.E.V.)
| | - Bianca E. Ősz
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (G.J.); (C.E.V.)
- Correspondence:
| | - Amelia Tero-Vescan
- Department of Biochemistry, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (A.T.-V.); (A.P.M.)
| | - Amalia Pușcaș Miklos
- Department of Biochemistry, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (A.T.-V.); (A.P.M.)
| | - Carmen-Maria Rusz
- Doctoral School of Medicine and Pharmacy, I.O.S.U.D, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (C.-M.R.); (M.-G.B.)
| | - Mădălina-Georgiana Bătrînu
- Doctoral School of Medicine and Pharmacy, I.O.S.U.D, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (C.-M.R.); (M.-G.B.)
| | - Camil E. Vari
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (G.J.); (C.E.V.)
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Lavin KM, Coen PM, Baptista LC, Bell MB, Drummer D, Harper SA, Lixandrão ME, McAdam JS, O’Bryan SM, Ramos S, Roberts LM, Vega RB, Goodpaster BH, Bamman MM, Buford TW. State of Knowledge on Molecular Adaptations to Exercise in Humans: Historical Perspectives and Future Directions. Compr Physiol 2022; 12:3193-3279. [PMID: 35578962 PMCID: PMC9186317 DOI: 10.1002/cphy.c200033] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.
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Affiliation(s)
- Kaleen M. Lavin
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Center for Human Health, Resilience, and Performance, Institute for Human and Machine Cognition, Pensacola, Florida, USA
| | - Paul M. Coen
- Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Liliana C. Baptista
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Margaret B. Bell
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Devin Drummer
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sara A. Harper
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Manoel E. Lixandrão
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jeremy S. McAdam
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Samia M. O’Bryan
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sofhia Ramos
- Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Lisa M. Roberts
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rick B. Vega
- Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Bret H. Goodpaster
- Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
| | - Marcas M. Bamman
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Center for Human Health, Resilience, and Performance, Institute for Human and Machine Cognition, Pensacola, Florida, USA
| | - Thomas W. Buford
- Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
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Christiansen D, Bishop DJ. Aerobic-interval exercise with blood flow restriction potentiates early markers of metabolic health in man. Acta Physiol (Oxf) 2022; 234:e13769. [PMID: 34984835 DOI: 10.1111/apha.13769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/02/2021] [Accepted: 01/01/2022] [Indexed: 12/06/2022]
Abstract
AIM This study examined whether aerobic-interval exercise with blood flow restriction (BFR) potentiates early markers of metabolic health compared to exercise with systemic hypoxia or normoxia in man. METHODS In a randomized-crossover fashion, eight healthy men completed nine 2-minute running bouts at 105% of their lactate threshold on three occasions separated by one week, either with BFR (BFR-trial), systemic hypoxia (HYP-trial) or normoxia (control; CON-trial). Near-infrared spectroscopy was used to assess the muscle level of hypoxia. A muscle biopsy was collected at rest and 3 hours after exercise to quantify genes involved in cholesterol synthesis (PGC-1α2), glucose disposal (GLUT4) and capillary growth (HIF-1α; VEGFA), as well as mitochondrial respiration (PGC-1α2/3), uncoupling (UCP3) and expansion (p53; COXIV-1/2; CS; AMPKα1/2). RESULTS The muscle level of hypoxia was matched between the BFR-trial and HYP-trial (~90%; P > .05), which was greater than the CON-trial (~70%; P < .05). PGC-1α2 increased most in the BFR-trial (16-fold vs CON-trial; 11-fold vs HYP-trial; P < .05). GLUT4 and VEGFA selectively increased by 2.0 and 3.4-fold, respectively in BFR-trial (P < .05), which was greater than CON-trial (1.2 and 1.3 fold) and HYP-trial (1.2 and 1.8 fold; P < .05). UCP3 increased more in BFR-trial than the HYP-trial (4.3 vs 1.6 fold), but was not different between BFR-trial and CON-trial (2.1 fold) or between CON-trial and HYP-trial (P > .05). No trial differences were evident for other genes (P > .05). CONCLUSION Independent of the muscle level of hypoxia, BFR-exercise potentiates early markers of metabolic health associated with the regulation of cholesterol production and glucose homeostasis in man.
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Affiliation(s)
- Danny Christiansen
- Institute for Health & Sport Victoria University Melbourne Victoria Australia
| | - David J. Bishop
- Institute for Health & Sport Victoria University Melbourne Victoria Australia
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McClean C, Davison GW. Circadian Clocks, Redox Homeostasis, and Exercise: Time to Connect the Dots? Antioxidants (Basel) 2022; 11:antiox11020256. [PMID: 35204138 PMCID: PMC8868136 DOI: 10.3390/antiox11020256] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/11/2022] [Accepted: 01/18/2022] [Indexed: 12/14/2022] Open
Abstract
Compelling research has documented how the circadian system is essential for the maintenance of several key biological processes including homeostasis, cardiovascular control, and glucose metabolism. Circadian clock disruptions, or losses of rhythmicity, have been implicated in the development of several diseases, premature ageing, and are regarded as health risks. Redox reactions involving reactive oxygen and nitrogen species (RONS) regulate several physiological functions such as cell signalling and the immune response. However, oxidative stress is associated with the pathological effects of RONS, resulting in a loss of cell signalling and damaging modifications to important molecules such as DNA. Direct connections have been established between circadian rhythms and oxidative stress on the basis that disruptions to circadian rhythms can affect redox biology, and vice versa, in a bi-directional relationship. For instance, the expression and activity of several key antioxidant enzymes (SOD, GPx, and CAT) appear to follow circadian patterns. Consequently, the ability to unravel these interactions has opened an exciting area of redox biology. Exercise exerts numerous benefits to health and, as a potent environmental cue, has the capacity to adjust disrupted circadian systems. In fact, the response to a given exercise stimulus may also exhibit circadian variation. At the same time, the relationship between exercise, RONS, and oxidative stress has also been scrutinised, whereby it is clear that exercise-induced RONS can elicit both helpful and potentially harmful health effects that are dependent on the type, intensity, and duration of exercise. To date, it appears that the emerging interface between circadian rhythmicity and oxidative stress/redox metabolism has not been explored in relation to exercise. This review aims to summarise the evidence supporting the conceptual link between the circadian clock, oxidative stress/redox homeostasis, and exercise stimuli. We believe carefully designed investigations of this nexus are required, which could be harnessed to tackle theories concerned with, for example, the existence of an optimal time to exercise to accrue physiological benefits.
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Jordan AC, Perry CGR, Cheng AJ. Promoting a pro-oxidant state in skeletal muscle: Potential dietary, environmental, and exercise interventions for enhancing endurance-training adaptations. Free Radic Biol Med 2021; 176:189-202. [PMID: 34560246 DOI: 10.1016/j.freeradbiomed.2021.09.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/06/2021] [Accepted: 09/16/2021] [Indexed: 12/17/2022]
Abstract
Accumulating evidence now shows that supplemental antioxidants including vitamin C, vitamin E and N-Acetylcysteine consumption can suppress adaptations to endurance-type exercise by attenuating reactive oxygen and nitrogen species (RONS) formation within skeletal muscle. This emerging evidence points to the importance of pro-oxidation as an important stimulus for endurance-training adaptations, including mitochondrial biogenesis, endogenous antioxidant production, insulin signalling, angiogenesis and growth factor signaling. Although sustained oxidative distress is associated with many chronic diseases, athletes have, on average, elevated levels of certain endogenous antioxidants to maintain redox homeostasis. As a result, trained athletes may have a better capacity to buffer oxidants during and after exercise, resulting in a reduced oxidative eustress stimulus for adaptations. Thus, higher levels of RONS input and exercise-induced oxidative stress may benefit athletes in the pursuit of continuous endurance training redox adaptations. This review addresses why athletes should be looking to enhance exercise-induced oxidative stress and how it can be accomplished. Methods covered include high-intensity interval training, hyperthermia and heat stress, dietary antioxidant restriction and modified antioxidant timing, dietary antioxidants and polyphenols as adjuncts to exercise, and vitamin C as a pro-oxidant.
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Affiliation(s)
- Adam C Jordan
- Muscle Health Research Centre, School of Kinesiology and Health Sciences, Faculty of Health, York University, M3J 1P3, Toronto, Canada
| | - Christopher G R Perry
- Muscle Health Research Centre, School of Kinesiology and Health Sciences, Faculty of Health, York University, M3J 1P3, Toronto, Canada
| | - Arthur J Cheng
- Muscle Health Research Centre, School of Kinesiology and Health Sciences, Faculty of Health, York University, M3J 1P3, Toronto, Canada.
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Hyttinen J, Blasiak J, Tavi P, Kaarniranta K. Therapeutic potential of PGC-1α in age-related macular degeneration (AMD) - the involvement of mitochondrial quality control, autophagy, and antioxidant response. Expert Opin Ther Targets 2021; 25:773-785. [PMID: 34637373 DOI: 10.1080/14728222.2021.1991913] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Age-related macular degeneration (AMD) is the leading, cause of sight loss in the elderly in the Western world. Most patients remain still without any treatment options. The targeting of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a transcription co-factor, is a putative therapy against AMD. AREAS COVERED The characteristics of AMD and their possible connection with PGC-1α as well as the transcriptional and post-transcriptional control of PGC-1α are discussed. The PGC-1α-driven control of mitochondrial functions, and its involvement in autophagy and antioxidant responses are also examined. Therapeutic possibilities via drugs and epigenetic approaches to enhance PGC-1α expression are discussed. Authors conducted a search of literature mainly from the recent decade from the PubMed database. EXPERT OPINION Therapy options in AMD could include PGC-1α activation or stabilization. This could be achieved by a direct elevation of PGC-1α activity, a stabilization or modification of its upstream activators and inhibitors by chemical compounds, like 5-Aminoimidazole-4-carboxamide riboside, metformin, and resveratrol. Furthermore, manipulations with epigenetic modifiers of PGC-1α expression, including miRNAs, e.g. miR-204, are considered. A therapy aimed at PGC-1α up-regulation may be possible in other disorders besides AMD, if they are associated with disturbances in the mitochondria-antioxidant response-autophagy axis.
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Affiliation(s)
- Juha Hyttinen
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Janusz Blasiak
- Department of Molecular Genetics, Faculty of Biology and Environmental Sciences, University of Lodz, Lodz, Poland
| | - Pasi Tavi
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.,Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
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Gire D, Acharya J, Malik S, Inamdar S, Ghaskadbi S. Molecular mechanism of anti-adipogenic effect of vitexin in differentiating hMSCs. Phytother Res 2021; 35:6462-6471. [PMID: 34612537 DOI: 10.1002/ptr.7300] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 08/28/2021] [Accepted: 09/14/2021] [Indexed: 12/20/2022]
Abstract
In this study, we evaluated a detailed molecular mechanism of anti-adipogenic activity of vitexin, apigenin flavone glucoside, present in germinated fenugreek seeds, in differentiating human mesenchymal stem cells (hMSCs). The lipid content of differentiated adipocytes was estimated by ORO staining. Effect on mitotic clonal expansion was checked by cell cycle analysis. Expression of early and terminal adipocyte differentiation markers, anti- and pro-adipogenic transcription factors and signalling intermediates regulating them was evaluated at RNA and protein level. We found vitexin to be non-cytotoxic up to 20 μM at which intracellular lipid accumulation was significantly decreased. Cell cycle analysis suggested that vitexin does not affect mitotic clonal expansion. Expression of early and late differentiation markers, such as CEBPα, CEBPβ, PPARγ, FABP4, perilipin, adiponectin and Glut4 was significantly reduced in the presence of vitexin. Expression of KLF4 and KLF15, positive regulators of PPARγ, was decreased, whereas that of negative regulators, namely KLF2, GATA2, miR20a, miR27a, miR27b, miR128, miR130a, miR130b, miR182 and miR548 increased with vitexin treatment. This effect was mediated by the activation of the AMP-activated protein kinase (AMPK) pathway via the activation of LepR and additionally by inhibiting ROS. Thus, our results showed that vitexin regulates the expression of PPARγ and inhibits adipogenesis of hMSCs at an early stage of differentiation.
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Affiliation(s)
- Dhananjay Gire
- Department of Zoology, Savitribai Phule Pune University, Pune, India
| | - Jhankar Acharya
- Department of Zoology, Savitribai Phule Pune University, Pune, India
| | - Sajad Malik
- Department of Zoology, Savitribai Phule Pune University, Pune, India
| | - Shrirang Inamdar
- Department of Zoology, Savitribai Phule Pune University, Pune, India
| | - Saroj Ghaskadbi
- Department of Zoology, Savitribai Phule Pune University, Pune, India
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Redox Signaling and Sarcopenia: Searching for the Primary Suspect. Int J Mol Sci 2021; 22:ijms22169045. [PMID: 34445751 PMCID: PMC8396474 DOI: 10.3390/ijms22169045] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/17/2021] [Accepted: 08/19/2021] [Indexed: 12/16/2022] Open
Abstract
Sarcopenia, the age-related decline in muscle mass and function, derives from multiple etiological mechanisms. Accumulative research suggests that reactive oxygen species (ROS) generation plays a critical role in the development of this pathophysiological disorder. In this communication, we review the various signaling pathways that control muscle metabolic and functional integrity such as protein turnover, cell death and regeneration, inflammation, organismic damage, and metabolic functions. Although no single pathway can be identified as the most crucial factor that causes sarcopenia, age-associated dysregulation of redox signaling appears to underlie many deteriorations at physiological, subcellular, and molecular levels. Furthermore, discord of mitochondrial homeostasis with aging affects most observed problems and requires our attention. The search for the primary suspect of the fundamental mechanism for sarcopenia will likely take more intense research for the secret of this health hazard to the elderly to be unlocked.
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Ostrom EL, Valencia AP, Marcinek DJ, Traustadóttir T. High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response. Free Radic Biol Med 2021; 172:82-89. [PMID: 34089788 PMCID: PMC8355059 DOI: 10.1016/j.freeradbiomed.2021.05.039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/19/2021] [Accepted: 05/30/2021] [Indexed: 12/21/2022]
Abstract
High intensity exercise is a popular mode of exercise to elicit similar or greater adaptive responses compared to traditional moderate intensity continuous exercise. However, the molecular mechanisms underlying these adaptive responses are still unclear. The purpose of this pilot study was to compare high and low intensity contractile stimulus on the Nrf2-mediated redox stress response in mouse skeletal muscle. An intra-animal design was used to control for variations in individual responses to muscle stimulation by comparing a stimulated limb (STIM) to the contralateral unstimulated control limb (CON). High Intensity (HI - 100Hz), Low Intensity (LI - 50Hz), and Naïve Control (NC - Mock stimulation vs CON) groups were used to compare these effects on Nrf2-ARE binding, Keap1 protein, and downstream gene and protein expression of Nrf2 target genes. Muscle stimulation significantly increased Nrf2-ARE binding in LI-STIM compared to LI-CON (p = 0.0098), while Nrf2-ARE binding was elevated in both HI-CON and HI-STIM compared to NC (p = 0.0007). The Nrf2-ARE results were mirrored in the downregulation of Keap1, where Keap1 expression in HI-CON and HI-STIM were both significantly lower than NC (p = 0.008) and decreased in LI-STIM compared to LI-CON (p = 0.015). In addition, stimulation increased NQO1 protein compared to contralateral control regardless of stimulation intensity (p = 0.019), and HO1 protein was significantly higher in high intensity compared to the Naïve control group (p = 0.002). Taken together, these data suggest a systemic redox signaling exerkine is activating Nrf2-ARE binding and is intensity gated, where Nrf2-ARE activation in contralateral control limbs were only seen in the HI group. Other research in exercise induced Nrf2 signaling support the general finding that Nrf2 is activated in peripheral tissues in response to exercise, however the specific exerkine responsible for the systemic signaling effects is not known. Future work should aim to delineate these redox sensitive systemic signaling mechanisms.
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Affiliation(s)
- Ethan L Ostrom
- Department of Biological Sciences, Northern Arizona University, United States
| | - Ana P Valencia
- Department of Radiology, University of Washington School of Medicine, United States
| | - David J Marcinek
- Department of Radiology, University of Washington School of Medicine, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, United States
| | - Tinna Traustadóttir
- Department of Biological Sciences, Northern Arizona University, United States.
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Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases. Biomolecules 2021; 11:biom11081144. [PMID: 34439810 PMCID: PMC8391472 DOI: 10.3390/biom11081144] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/31/2021] [Accepted: 08/01/2021] [Indexed: 12/12/2022] Open
Abstract
Mitochondria are essential organelles in physiology and kidney diseases, because they produce cellular energy required to perform their function. During mitochondrial metabolism, reactive oxygen species (ROS) are produced. ROS function as secondary messengers, inducing redox-sensitive post-translational modifications (PTM) in proteins and activating or deactivating different cell signaling pathways. However, in kidney diseases, ROS overproduction causes oxidative stress (OS), inducing mitochondrial dysfunction and altering its metabolism and dynamics. The latter processes are closely related to changes in the cell redox-sensitive signaling pathways, causing inflammation and apoptosis cell death. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in mitochondria has not been addressed. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases.
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Aoi W, Iwasa M, Marunaka Y. Metabolic functions of flavonoids: From human epidemiology to molecular mechanism. Neuropeptides 2021; 88:102163. [PMID: 34098453 DOI: 10.1016/j.npep.2021.102163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/11/2021] [Accepted: 05/19/2021] [Indexed: 12/12/2022]
Abstract
Dietary flavonoid intake is associated with the regulation of nutrient metabolism in the living body. Observational and cohort studies have reported a negative association between flavonoid intake and the risk of metabolic and cardiovascular diseases. Several intervention trials in humans have also supported the benefits of dietary flavonoids. In experimental studies using animal models, a daily diet rich in typical flavonoids such as catechins, anthocyanin, isoflavone, and quercetin was shown to improve whole-body energy expenditure, mitochondrial activity, and glucose tolerance. For some flavonoids, molecular targets for the metabolic modulations have been suggested. Although the effect of flavonoids on neurons has been unclear, several flavonoids have been shown to regulate thermogenesis and feeding behavior through modulating autonomic and central nervous systems. Based on epidemiological and experimental studies, this review summarizes the evidence on the metabolic benefits of flavonoids and their potential mechanism of action in metabolic regulation.
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Affiliation(s)
- Wataru Aoi
- Laboratory of Nutrition Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan.
| | - Masayo Iwasa
- Laboratory of Nutrition Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan
| | - Yoshinori Marunaka
- Medical Research Institute, Kyoto Industrial Health Association, Kyoto 604-8472, Japan; Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu 525-8577, Japan; Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; International Research Center for Food Nutrition and Safety, College of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
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Asano T, Tsujii M, Iino T, Odake K, Sudo A. Pathological features of reinnervated skeletal muscles after crush injury of the sciatic nerve in ob/ob mice. Muscle Nerve 2021; 64:365-373. [PMID: 34212392 DOI: 10.1002/mus.27365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 06/21/2021] [Accepted: 06/27/2021] [Indexed: 11/11/2022]
Abstract
INTRODUCTION/AIMS Obesity is a factor contributing to suboptimal improvement of motor function in peripheral nerve disorders. In this study we aimed to evaluate the skeletal muscles during denervation and reinnervation after nerve crush injury in leptin-deficient (ob/ob) mice. METHODS Experiments were performed on the skeletal muscles of the hindlimbs in 20 male ob/ob mice and controls. Characteristics of the gastrocnemius muscles were evaluated by histological analysis, immunohistological analysis, and Sircol-collagen assay after measurement of body weight and wet weight of the skeletal muscles, and by walking track analysis. The sciatic nerve was denervated by crushing with smooth forceps and reinnervation was evaluated. RESULTS Gastrocnemius wet weight was significantly lower in the ob/ob mice than in the control mice. A smaller cross-sectional area of type II fibers and increase of type I fiber grouping of the skeletal muscles was demonstrated in the ob/ob mice. After nerve injury, motor function recovery was equal between the groups but the cross-sectional area of type II fibers was significantly smaller in the ob/ob mice than in control mice at 4 weeks. The denervated muscles showed an increase in collagen deposition in the interstitial space; predominant in the ob/ob mice after nerve injury. DISCUSSION The results of this study suggest that fibrosis in the skeletal muscle of obese patients after nerve injury is prominent, which may impair improvement of muscle function after treatment of peripheral nerve disorders.
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Affiliation(s)
- Takahiro Asano
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Masaya Tsujii
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Takahiro Iino
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Kazuya Odake
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
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Rubilar T, Barbieri ES, Gazquez A, Avaro M. Sea Urchin Pigments: Echinochrome A and Its Potential Implication in the Cytokine Storm Syndrome. Mar Drugs 2021; 19:267. [PMID: 34064550 PMCID: PMC8151293 DOI: 10.3390/md19050267] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/14/2021] [Accepted: 04/23/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Echinochrome A (EchA) is a pigment from sea urchins. EchA is a polyhydroxylated 1,4-naphthoquinone that contains several hydroxyl groups appropriate for free-radical scavenging and preventing redox imbalance. EchA is the most studied molecule of this family and is an active principle approved to be used in humans, usually for cardiopathies and glaucoma. EchA is used as a pharmaceutical drug. Methods: A comprehensive literature and patent search review was undertaken using PubMed, as well as Google Scholar and Espacenet search engines to review these areas. Conclusions: In the bloodstream, EchA can mediate cellular responses, act as a radical scavenger, and activate the glutathione pathway. It decreases ROS imbalance, prevents and limits lipid peroxidation, and enhances mitochondrial functions. Most importantly, EchA contributes to the modulation of the immune system. EchA can regulate the generation of regulatory T cells, inhibit pro-inflammatory IL-1β and IL-6 cytokine production, while slightly reducing IL-8, TNF-α, INF-α, and NKT, thus correcting immune imbalance. These characteristics suggest that EchA is a candidate drug to alleviate the cytokine storm syndrome (CSS).
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Affiliation(s)
- Tamara Rubilar
- Laboratorio de Química de Organismos Marinos, Instituto Patagónico del Mar, Universidad Nacional de la Patagonia San Juan Bosco (UNPSJB), Puerto Madryn 9120, Chubut, Argentina;
- Laboratorio de Oceanografía Biológica, Centro Para el Estudio de Sistemas Marinos (CESIMAR), CONICET, Puerto Madryn 9120, Chubut, Argentina;
| | - Elena S. Barbieri
- Laboratorio de Oceanografía Biológica, Centro Para el Estudio de Sistemas Marinos (CESIMAR), CONICET, Puerto Madryn 9120, Chubut, Argentina;
- Laboratorio de Virología, Instituto Patagónico del Mar, Universidad Nacional de la Patagonia San Juan Bosco (UNPSJB), Puerto Madryn 9120, Chubut, Argentina
| | - Ayelén Gazquez
- Instituto Tecnológico de Chascomús, The Chascomús Technological Institute (INTECH), CONICET-UNSAM, Chascomús 7130, Buenos Aires, Argentina;
| | - Marisa Avaro
- Laboratorio de Química de Organismos Marinos, Instituto Patagónico del Mar, Universidad Nacional de la Patagonia San Juan Bosco (UNPSJB), Puerto Madryn 9120, Chubut, Argentina;
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Triolo M, Hood DA. Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle. Cells 2021; 10:cells10051054. [PMID: 33946883 PMCID: PMC8146406 DOI: 10.3390/cells10051054] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/24/2021] [Accepted: 04/27/2021] [Indexed: 01/18/2023] Open
Abstract
Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss.
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Affiliation(s)
- Matthew Triolo
- Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada;
- School of Kinesiology and Health Science, York University, Toronto, ON M3J 1P3, Canada
| | - David A. Hood
- Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada;
- School of Kinesiology and Health Science, York University, Toronto, ON M3J 1P3, Canada
- Correspondence: ; Tel.: +(416)-736-2100 (ext. 66640)
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Bouviere J, Fortunato RS, Dupuy C, Werneck-de-Castro JP, Carvalho DP, Louzada RA. Exercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle. Antioxidants (Basel) 2021; 10:antiox10040537. [PMID: 33808211 PMCID: PMC8066165 DOI: 10.3390/antiox10040537] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/16/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022] Open
Abstract
Physical exercise represents a major challenge to whole-body homeostasis, provoking acute and adaptative responses at the cellular and systemic levels. Different sources of reactive oxygen species (ROS) have been described in skeletal muscle (e.g., NADPH oxidases, xanthine oxidase, and mitochondria) and are closely related to the physiological changes induced by physical exercise through the modulation of several signaling pathways. Many signaling pathways that are regulated by exercise-induced ROS generation, such as adenosine monophosphate-activated protein kinase (AMPK), mitogen activated protein kinase (MAPK), nuclear respiratory factor2 (NRF2), and PGC-1α are involved in skeletal muscle responses to physical exercise, such as increased glucose uptake, mitochondriogenesis, and hypertrophy, among others. Most of these adaptations are blunted by antioxidants, revealing the crucial role played by ROS during and after physical exercise. When ROS generation is either insufficient or exacerbated, ROS-mediated signaling is disrupted, as well as physical exercise adaptations. Thus, an understanding the limit between "ROS that can promote beneficial effects" and "ROS that can promote harmful effects" is a challenging question in exercise biology. The identification of new mediators that cause reductive stress and thereby disrupt exercise-stimulated ROS signaling is a trending on this topic and are covered in this current review.
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Affiliation(s)
- Jessica Bouviere
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Rodrigo S. Fortunato
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Corinne Dupuy
- Université Paris-Saclay, UMR 9019CNRS, Gustave Roussy, 94800 Villejuif, France;
| | - Joao Pedro Werneck-de-Castro
- Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Denise P. Carvalho
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Ruy A. Louzada
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
- Université Paris-Saclay, UMR 9019CNRS, Gustave Roussy, 94800 Villejuif, France;
- Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- Correspondence:
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Exopolysaccharides isolated from Rhizopus nigricans induced colon cancer cell apoptosis in vitro and in vivo via activating the AMPK pathway. Biosci Rep 2021; 40:221749. [PMID: 31894839 PMCID: PMC6960068 DOI: 10.1042/bsr20192774] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 12/30/2019] [Accepted: 12/31/2019] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related human deaths. The exopolysaccharide (EPS1-1), isolated from Rhizopus nigricans, has been described as exhibiting anti-tumor and pro-apoptotic activity against CRC, although the underlying mechanism is poorly understood. Herein, we investigate how EPS1-1 induces apoptosis of CRC cells in vitro and in vivo. Our results show that, in vitro, EPS1-1 suppressed cell growth and facilitated apoptosis in a dose- and time-dependent manner by activating the AMP-activated protein kinase (AMPK) pathway in mouse colon cancer CT26 cells. However, treatment with small interfering RNAs (siRNAs) targeting AMPKα or with compound C, an AMPK inhibitor, interfered with the pro-apoptosis effects of EPS1-1. We also show that EPS1-1 initiated the release of reactive oxygen species (ROS) and liver kinase B1 (LKB1), both of which are necessary signals for AMPK activation. Furthermore, EPS1-1-mediated apoptosis is regulated by inactivation of mammalian target of rapamycin complex 1 (mTORC1) and activation of the jun-NH2 kinase (JNK)-p53 signaling axis dependent on AMPK activation. In vivo, azoxymethane/dextran sulfate sodium (AOM/DSS)-treated CRC mice, when administered EPS1-1, exhibited activation of the AMPK pathway, inhibition of mTORC1, and accumulation of p53 in tumor tissues. Collectively, these findings suggest that EPS1-1-induced apoptosis relies on the activation of the AMPK pathway. The present study provides evidence suggesting that EPS1-1 may be an effective target for development of novel CRC therapeutic agents.
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