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Tutak K, Broniarek I, Zielezinski A, Niewiadomska D, Skrzypczak T, Baud A, Sobczak K. Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions. eLife 2025; 13:RP98631. [PMID: 40377206 DOI: 10.7554/elife.98631] [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] [Indexed: 05/18/2025] Open
Abstract
Expansion of CGG repeats (CGGexp) in the 5' untranslated region (5'UTR) of the FMR1 gene underlies the fragile X premutation-associated conditions including tremor/ataxia syndrome, a late-onset neurodegenerative disease and fragile X-associated primary ovarian insufficiency. One common pathomechanism of these conditions is the repeat-associated non-AUG-initiated (RAN) translation of CGG repeats of mutant FMR1 mRNA, resulting in production of FMRpolyG, a toxic protein containing long polyglycine tract. To identify novel modifiers of RAN translation we used an RNA-tagging system and mass spectrometry-based screening. It revealed proteins enriched on CGGexp-containing FMR1 RNA in cellulo, including a ribosomal protein RPS26, a component of the 40 S subunit. We demonstrated that depletion of RPS26 and its chaperone TSR2, modulates FMRpolyG production and its toxicity. We also found that the RPS26 insufficiency impacted translation of limited number of proteins, and 5'UTRs of mRNAs encoding these proteins were short and guanosine and cytosine-rich. Moreover, the silencing of another component of the 40 S subunit, the ribosomal protein RPS25, also induced repression of FMRpolyG biosynthesis. Results of this study suggest that the two 40 S ribosomal proteins and chaperone TSR2 play an important role in noncanonical CGGexp-related RAN translation.
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Affiliation(s)
- Katarzyna Tutak
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, Poznan, Poland
| | - Izabela Broniarek
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, Poznan, Poland
| | - Andrzej Zielezinski
- Department of Computational Biology, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University Uniwersytetu Poznańskiego 6, Poznan, Poland
| | - Daria Niewiadomska
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, Poznan, Poland
| | - Tomasz Skrzypczak
- Center of Advanced Technology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 10, Poznan, Poland
| | - Anna Baud
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, Poznan, Poland
| | - Krzysztof Sobczak
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, Poznan, Poland
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O'Bryan SJ, Critchlow A, Fuchs CJ, Hiam D, Lamon S. The contribution of age and sex hormones to female neuromuscular function across the adult lifespan. J Physiol 2025. [PMID: 40349308 DOI: 10.1113/jp287496] [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: 11/29/2024] [Accepted: 04/04/2025] [Indexed: 05/14/2025] Open
Abstract
Neuromuscular ageing is characterized by neural and/or skeletal muscle degeneration that decreases maximal force and power. Female neuromuscular ageing occurs earlier in life compared to males, potentially due to sex hormone changes during the menopausal transition. We quantified neuromuscular function in 88 females represented equally over each decade from 18 to 80 years of age and investigated the role of decreased ovarian hormone concentrations following menopause. Neuromuscular assessment included quadriceps maximal voluntary and evoked isometric torque and surface electromyography measurements, plus one-repetition maximum leg press. Voluntary and evoked torques and one-repetition maximum decreased non-linearly with age, with accelerated reductions starting during the fourth decade. An absence of changes in volitional recruitment of existing quadriceps motor units and Ia afferent facilitation of spinal motoneurons suggests that functional decline was largely mediated by impairment in intrinsic peripheral muscle function and/or neuromuscular transmission. Maximal muscle compound action potential amplitude decreased with increasing age for rectus femoris muscle only, indicating increased vulnerability to neuromuscular degeneration compared to vastus lateralis and medialis. In postmenopausal females, some variance was explained by inter-individual differences in quadriceps tissue composition and lifestyle factors, but changes in total or free concentrations of oestradiol, progesterone and/or testosterone were included in all correlations with age-related decreases in isometric voluntary and evoked torques. We demonstrate an accelerated onset of neuromuscular degeneration of peripheral muscular origin around menopause onset associated with changes in sex hormone concentrations. Interventions aimed at mitigating declines in ovarian hormones and their subsequent effects on neuromuscular function after menopause should be further explored. KEY POINTS: Neuromuscular deterioration with age is associated with poor physical function and quality of life in older adults, but female-specific trajectories and mechanisms remain unclear. This study is the first to map neuromuscular function across each decade of the adult lifespan in 88 females from 18 to 80 years old and to examine the potential role of hormonal changes after menopause. We show an accelerated reduction in neuromuscular function, primarily of peripheral muscular origin, that occurs during the fourth decade and coincides with menopause onset. In postmenopausal females, age-related reductions in neuromuscular function can in part be explained by quadriceps lean and intramuscular fat composition, physical activity and protein intake, and sex hormone concentrations. These findings help us better understand the factors that contribute to the loss of neuromuscular function with age in females, enabling the identification of potential therapeutic interventions to prolong female health span.
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Affiliation(s)
- Steven J O'Bryan
- Institute for Health and Sport, Victoria University, Melbourne, Australia
| | - Annabel Critchlow
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
| | - Cas J Fuchs
- Department of Human Biology, NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Danielle Hiam
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
| | - Séverine Lamon
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
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Marchese M, Bernardi S, Vivarelli R, Doccini S, Santucci L, Ogi A, Licitra R, Zang J, Soliymani R, Mero S, Neuhauss SC, Ciarmoli L, Signore G, Lalowski MM, Santorelli FM. CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease. Mol Psychiatry 2025:10.1038/s41380-025-03043-8. [PMID: 40346285 DOI: 10.1038/s41380-025-03043-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 04/14/2025] [Accepted: 04/30/2025] [Indexed: 05/11/2025]
Abstract
CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in the CLN5 gene encoding the lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and lysosomal function. Limited knowledge of cellular mechanisms and unclear drug targets hinder translating this to children's treatment, which remains symptomatic. We developed and characterized a new cln5 knock-out zebrafish model that replicates key features and molecular signatures of the human disease. Loss of Cln5 function in vivo altered axonal growth of retinal ON-bipolar cells and disrupted calcium homeostasis in the cerebellum, revealing new disease features. Additionally, multi-omic analyses at different developmental stages revealed an impaired glucose metabolism as an original finding in NCL. A novel biomarker, PHGDH, was validated in zebrafish and human skin fibroblasts harboring pathogenic variants in CLN5, and in CLN7. We also tested metformin which improved the expression of PHGDH in patient-derived cells, and rescued zebrafish behavior. This work demonstrates the profound metabolic impact of CLN5 dysfunction, offering a promising avenue toward targeted therapies for juvenile dementia.
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Affiliation(s)
- Maria Marchese
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy.
| | - Sara Bernardi
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy
| | - Rachele Vivarelli
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy
| | - Stefano Doccini
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy
| | - Lorenzo Santucci
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy
| | - Asahi Ogi
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy
| | - Rosario Licitra
- Department of Veterinary Sciences, University of Pisa, 56124, Pisa, Italy
| | - Jingjing Zang
- University of Zurich, Department of Molecular Life Sciences, 8057, Zurich, Switzerland
| | - Rabah Soliymani
- Meilahti Proteomics Unit, Department of Biochemistry & Developmental Biology, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland
| | - Serena Mero
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy
| | - Stephan Cf Neuhauss
- University of Zurich, Department of Molecular Life Sciences, 8057, Zurich, Switzerland
| | - Lea Ciarmoli
- Department of Biology, University of Pisa, 56126, Pisa, Italy
| | - Giovanni Signore
- Department of Biology, University of Pisa, 56126, Pisa, Italy
- Institute of Clinical Physiology, National Research Council, 56124, Pisa, Italy
| | - Maciej M Lalowski
- Meilahti Proteomics Unit, Department of Biochemistry & Developmental Biology, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland
- Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6 St., 61-614, Poznań, Poland
| | - Filippo M Santorelli
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy.
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MacGregor K, Ellefsen S, Pillon NJ, Hammarström D, Krook A. Sex differences in skeletal muscle metabolism in exercise and type 2 diabetes mellitus. Nat Rev Endocrinol 2025; 21:166-179. [PMID: 39604583 DOI: 10.1038/s41574-024-01058-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 11/29/2024]
Abstract
This Review focuses on currently available literature describing sex differences in skeletal muscle metabolism in humans, as well as highlighting current research gaps within the field. These discussions serve as a call for action to address the current lack of sufficient sex-balanced studies in skeletal muscle research, and the resulting limitations in understanding sex-specific physiological and pathophysiological responses. Although the participation of women in studies has increased, parity between the sexes remains elusive, affecting the validity of conclusions drawn from studies with limited numbers of participants. Changes in skeletal muscle metabolism contribute to the development of metabolic disease (such as type 2 diabetes mellitus), and maintenance of skeletal muscle mass is a key component for health and the ability to maintain an independent life during ageing. Exercise is an important factor in maintaining skeletal muscle health and insulin sensitivity, and offers promise for both prevention and treatment of metabolic disease. With the increased realization of the promise of precision medicine comes the need to increase patient stratification and improve the understanding of responses in different populations. In this context, a better understanding of sex-dependent differences in skeletal muscle metabolism is essential.
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Affiliation(s)
- Kirstin MacGregor
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Stian Ellefsen
- Inland University of Applied Sciences, Lillehammer, Norway
| | - Nicolas J Pillon
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | | | - Anna Krook
- Inland University of Applied Sciences, Lillehammer, Norway.
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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Blondin DP, Haman F, Swibas TM, Hogan-Lamarre S, Dumont L, Guertin J, Richard G, Weissenburger Q, Hildreth KL, Schauer I, Panter S, Wyland L, Carpentier AC, Miao Y, Shi J, Juarez-Colunga E, Kohrt WM, Melanson EL. Brown adipose tissue metabolism in women is dependent on ovarian status. Am J Physiol Endocrinol Metab 2024; 326:E588-E601. [PMID: 38477875 PMCID: PMC11211003 DOI: 10.1152/ajpendo.00077.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/12/2024] [Accepted: 03/12/2024] [Indexed: 03/14/2024]
Abstract
In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min-1) and postmenopausal women (0.63 ± 0.28 min-1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min-1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g-1·min-1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min-1 to 0.91 ± 0.41 min-1) to that observed in postmenopausal women (0.91 ± 0.63 min-1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.NEW & NOTEWORTHY In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.
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Affiliation(s)
- Denis P Blondin
- Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
- Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - François Haman
- School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Tracy M Swibas
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Sophie Hogan-Lamarre
- Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
- Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Lauralyne Dumont
- Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
- Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Jolan Guertin
- Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
- Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Gabriel Richard
- Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Quentin Weissenburger
- Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Kerry L Hildreth
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Irene Schauer
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Eastern Colorado Veterans Affairs Geriatric Research, Education, and Clinical Center, Denver, Colorado, United States
| | - Shelby Panter
- Anschutz Health and Wellness Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Liza Wyland
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - André C Carpentier
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, Centre de Recherche du Centre Hospitalier, Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Yubin Miao
- Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Jiayuan Shi
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Elizabeth Juarez-Colunga
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Eastern Colorado Veterans Affairs Geriatric Research, Education, and Clinical Center, Denver, Colorado, United States
| | - Wendy M Kohrt
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Eastern Colorado Veterans Affairs Geriatric Research, Education, and Clinical Center, Denver, Colorado, United States
| | - Edward L Melanson
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Eastern Colorado Veterans Affairs Geriatric Research, Education, and Clinical Center, Denver, Colorado, United States
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Jin F, Wang YF, Zhu ZX. Association between serum estradiol level and appendicular lean mass index in middle-aged postmenopausal women. World J Orthop 2024; 15:45-51. [PMID: 38293265 PMCID: PMC10824069 DOI: 10.5312/wjo.v15.i1.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 11/13/2023] [Accepted: 12/13/2023] [Indexed: 01/16/2024] Open
Abstract
BACKGROUND Previous studies investigating the association between loss of estrogen at menopause and skeletal muscle mass came to contradictory conclusions. AIM To evaluate the association between serum estradiol level and appendicular lean mass index in middle-aged postmenopausal women using population-based data. METHODS This study included 673 postmenopausal women, aged 40-59 years, from the National Health and Nutrition Examination Survey between 2013 and 2016. Weighted multivariable linear regression models were used to evaluate the association between serum E2 Level and appendicular lean mass index (ALMI). When non-linear associations were found by using weighted generalized additive model and smooth curve fitting, two-piecewise linear regression models were further applied to examine the threshold effects. RESULTS There was a positive association between serum E2 level and ALMI. Compared to individuals in quartile 1 group, those in other quartiles had higher ALMI levels. An inverted U-shaped curve relationship between serum E2 Level and ALMI was found on performing weighted generalized additive model and smooth curve fitting, and the inflection point was identified as a serum E2 level of 85 pg/mL. CONCLUSION Our results demonstrated an inverted U-shaped curve relationship between serum E2 levels and ALMI in middle-aged postmenopausal women, suggesting that low serum E2 levels play an important in the loss of muscle mass in middle-aged postmenopausal women.
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Affiliation(s)
- Fang Jin
- Department of Osteoporosis Care and Control, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang Province, China
| | - Yan-Fei Wang
- Department of Osteoporosis Care and Control, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang Province, China
| | - Zhong-Xin Zhu
- Department of Osteoporosis Care and Control, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang Province, China
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Critchlow AJ, Hiam D, Williams R, Scott D, Lamon S. The role of estrogen in female skeletal muscle aging: A systematic review. Maturitas 2023; 178:107844. [PMID: 37716136 DOI: 10.1016/j.maturitas.2023.107844] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/14/2023] [Accepted: 08/30/2023] [Indexed: 09/18/2023]
Abstract
Aging is associated with a loss of skeletal muscle mass and function that negatively impacts the independence and quality of life of older individuals. Females demonstrate a distinct pattern of muscle aging compared to males, potentially due to menopause, when the production of endogenous sex hormones declines. This systematic review aims to investigate the current knowledge about the role of estrogen in female skeletal muscle aging. A systematic search of MEDLINE Complete, Global Health, Embase, PubMed, SPORTDiscus, and CINHAL was conducted. Studies were considered eligible if they compared a state of estrogen deficiency (e.g. postmenopausal females) or supplementation (e.g. estrogen therapy) to normal estrogen conditions (e.g. premenopausal females or no supplementation). Outcome variables of interest included measures of skeletal muscle mass, function, damage/repair, and energy metabolism. Quality assessment was completed with the relevant Johanna Briggs critical appraisal tool, and data were synthesized in a narrative manner. Thirty-two studies were included in the review. Compared to premenopausal women, postmenopausal women had reduced muscle mass and strength, but the effect of menopause on markers of muscle damage and expression of the genes involved in metabolic signaling pathways remains unclear. Some studies suggest a beneficial effect of estrogen therapy on muscle size and strength, but evidence is largely conflicting and inconclusive, potentially due to large variations in the reporting and status of exposure and outcomes. The findings from this review point toward a potential negative effect of estrogen deficiency on aging skeletal muscle, but further mechanistic evidence is needed to clarify its role.
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Affiliation(s)
- Annabel J Critchlow
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Australia.
| | - Danielle Hiam
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Australia.
| | - Ross Williams
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Australia.
| | - David Scott
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.
| | - Séverine Lamon
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Australia.
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Lorey MB, Youssef A, Äikäs L, Borrelli M, Hermansson M, Assini JM, Kemppainen A, Ruhanen H, Ruuth M, Matikainen S, Kovanen PT, Käkelä R, Boffa MB, Koschinsky ML, Öörni K. Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages. Front Cardiovasc Med 2023; 10:1130162. [PMID: 37293282 PMCID: PMC10244518 DOI: 10.3389/fcvm.2023.1130162] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 05/02/2023] [Indexed: 06/10/2023] Open
Abstract
Introduction Lipoprotein(a) (Lp(a)) is an LDL-like particle with an additional apolipoprotein (apo)(a) covalently attached. Elevated levels of circulating Lp(a) are a risk factor for atherosclerosis. A proinflammatory role for Lp(a) has been proposed, but its molecular details are incompletely defined. Methods and results To explore the effect of Lp(a) on human macrophages we performed RNA sequencing on THP-1 macrophages treated with Lp(a) or recombinant apo(a), which showed that especially Lp(a) induces potent inflammatory responses. Thus, we stimulated THP-1 macrophages with serum containing various Lp(a) levels to investigate their correlations with cytokines highlighted by the RNAseq, showing significant correlations with caspase-1 activity and secretion of IL-1β and IL-18. We further isolated both Lp(a) and LDL particles from three donors and then compared their atheroinflammatory potentials together with recombinant apo(a) in primary and THP-1 derived macrophages. Compared with LDL, Lp(a) induced a robust and dose-dependent caspase-1 activation and release of IL-1β and IL-18 in both macrophage types. Recombinant apo(a) strongly induced caspase-1 activation and IL-1β release in THP-1 macrophages but yielded weak responses in primary macrophages. Structural analysis of these particles revealed that the Lp(a) proteome was enriched in proteins associated with complement activation and coagulation, and its lipidome was relatively deficient in polyunsaturated fatty acids and had a high n-6/n-3 ratio promoting inflammation. Discussion Our data show that Lp(a) particles induce the expression of inflammatory genes, and Lp(a) and to a lesser extent apo(a) induce caspase-1 activation and IL-1 signaling. Major differences in the molecular profiles between Lp(a) and LDL contribute to Lp(a) being more atheroinflammatory.
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Affiliation(s)
- Martina B. Lorey
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
- Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Amer Youssef
- Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
| | - Lauri Äikäs
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
| | - Matthew Borrelli
- Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
| | - Martin Hermansson
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
| | - Julia M. Assini
- Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
- Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
| | - Aapeli Kemppainen
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
| | - Hanna Ruhanen
- Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
- Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, Helsinki, Finland
| | - Maija Ruuth
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
| | - Sampsa Matikainen
- Helsinki Rheumatic Disease and Inflammation Research Group, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Petri T. Kovanen
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
| | - Reijo Käkelä
- Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
- Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, Helsinki, Finland
| | - Michael B. Boffa
- Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
- Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
| | - Marlys L. Koschinsky
- Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
- Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada
| | - Katariina Öörni
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
- Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
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Le G, Baumann CW, Warren GL, Lowe DA. In vivo potentiation of muscle torque is enhanced in female mice through estradiol-estrogen receptor signaling. J Appl Physiol (1985) 2023; 134:722-730. [PMID: 36735234 PMCID: PMC10027088 DOI: 10.1152/japplphysiol.00731.2022] [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: 12/01/2022] [Revised: 01/13/2023] [Accepted: 02/02/2023] [Indexed: 02/04/2023] Open
Abstract
Estradiol affects several properties of skeletal muscle in females including strength. Here, we developed an approach to measure in vivo posttetanic twitch potentiation (PTP) of the anterior crural muscles of anesthetized mice and tested the hypothesis that 17β-estradiol (E2) enhances PTP through estrogen receptor (ER) signaling. Peak torques of potentiated twitches were ∼40%-60% greater than those of unpotentiated twitches and such PTP was greater in ovary-intact mice, or ovariectomized (Ovx) mice treated with E2, compared with Ovx mice (P ≤ 0.047). PTP did not differ between mice with and without ERα ablated in skeletal muscle fibers (P = 0.347). Treatment of ovary-intact and Ovx mice with ERβ antagonist and agonist (PHTPP and DPN, respectively) did not affect PTP (P ≥ 0.258). Treatment with G1, an agonist of the G protein-coupled estrogen receptor (GPER), significantly increased PTP in Ovx mice from 41 ± 10% to 66 ± 21% (means ± SD; P = 0.034). Collectively, these data indicate that E2 signals through GPER, and not ERα or ERβ, in skeletal muscles of female mice to augment an in vivo parameter of strength, namely, PTP.NEW & NOTEWORTHY A novel in vivo approach was developed to measure potentiation of skeletal muscle torque in female mice and highlight another parameter of strength that is impacted by estradiol. The enhancement of PTP by estradiol is mediated distinctively through the G-protein estrogen receptor, GPER.
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Affiliation(s)
- Gengyun Le
- Division of Rehabilitation Science and Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
| | - Cory W Baumann
- Division of Rehabilitation Science and Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
| | - Gordon L Warren
- Department of Physical Therapy, Georgia State University, Atlanta, Georgia, United States
| | - Dawn A Lowe
- Division of Rehabilitation Science and Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
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10
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Shu H, Huang Y, Zhang W, Ling L, Hua Y, Xiong Z. An integrated study of hormone-related sarcopenia for modeling and comparative transcriptome in rats. Front Endocrinol (Lausanne) 2023; 14:1073587. [PMID: 36817606 PMCID: PMC9929355 DOI: 10.3389/fendo.2023.1073587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023] Open
Abstract
Sarcopenia is a senile disease with high morbidity, serious complications and limited clinical treatments. Menopause increases the risk of sarcopenia in females, while the exact pathogenesis remains unclear. To systematically investigate the development of hormone-related sarcopenia, we established a model of sarcopenia by ovariectomy and recorded successive characteristic changes. Furthermore, we performed the transcriptome RNA sequencing and bioinformatics analysis on this model to explore the underlying mechanism. In our study, we identified an integrated model combining obesity, osteoporosis and sarcopenia. Functional enrichment analyses showed that most of the significantly enriched pathways were down-regulated and closely correlated with endocrine and metabolism, muscle dysfunction, cognitive impairment and multiple important signaling pathways. We finally selected eight candidate genes to verify their expression levels. These findings confirmed the importance of estrogen in the maintenance of skeletal muscle function and homeostasis, and provided potential targets for further study on hormone-related sarcopenia.
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Affiliation(s)
- Han Shu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yubing Huang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenqian Zhang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Ling
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanyuan Hua
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengai Xiong
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Zhengai Xiong,
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11
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Appiah D, Schreiner PJ, Pankow JS, Brock G, Tang W, Norby FL, Michos ED, Ballantyne CM, Folsom AR. Long-term changes in plasma proteomic profiles in premenopausal and postmenopausal Black and White women: the Atherosclerosis Risk in Communities study. Menopause 2022; 29:1150-1160. [PMID: 35969495 PMCID: PMC9509415 DOI: 10.1097/gme.0000000000002031] [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] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The activity, localization, and turnover of proteins within cells and plasma may contribute to physiologic changes during menopause and may influence disease occurrence. We examined cross-sectional differences and long-term changes in plasma proteins between premenopausal and naturally postmenopausal women. METHODS We used data from 4,508 (19% Black) women enrolled in the Atherosclerosis Risk in Communities study. SOMAscan multiplexed aptamer technology was used to measure 4,697 plasma proteins. Linear regression models were used to compare differences in proteins at baseline (1993-1995) and 18-year change in proteins from baseline to 2011-2013. RESULTS At baseline, 472 women reported being premenopausal and 4,036 women reported being postmenopausal, with average ages of 52.3 and 61.4 years, respectively. A greater proportion of postmenopausal women had diabetes (15 vs 9%), used hypertension (38 vs 27%) and lipid-lowering medications (10 vs 3%), and had elevated total cholesterol and waist girth. In multivariable adjusted models, 38 proteins differed significantly between premenopausal and postmenopausal women at baseline, with 29 of the proteins also showing significantly different changes between groups over the 18-year follow-up as the premenopausal women also reached menopause. These proteins were associated with various molecular/cellular functions (cellular development, growth, proliferation and maintenance), physiological system development (skeletal and muscular system development, and cardiovascular system development and function), and diseases/disorders (hematological and metabolic diseases and developmental disorders). CONCLUSIONS We observed significantly different changes between premenopausal and postmenopausal women in several plasma proteins that reflect many biological processes. These processes may help to understand disease development during the postmenopausal period.
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Affiliation(s)
- Duke Appiah
- Department of Public Health, Texas Tech University Health Sciences Center, Lubbock TX
| | - Pamela J. Schreiner
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - James S. Pankow
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - Guy Brock
- Department of Biostatistics, The Ohio State University, Columbus OH
| | - Weihong Tang
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - Faye L. Norby
- Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA
| | - Erin D. Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MA
| | | | - Aaron R. Folsom
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
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12
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Stalmach A, Boehm I, Fernandes M, Rutter A, Skipworth RJE, Husi H. Gene Ontology (GO)-Driven Inference of Candidate Proteomic Markers Associated with Muscle Atrophy Conditions. Molecules 2022; 27:5514. [PMID: 36080280 PMCID: PMC9457532 DOI: 10.3390/molecules27175514] [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: 07/14/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Skeletal muscle homeostasis is essential for the maintenance of a healthy and active lifestyle. Imbalance in muscle homeostasis has significant consequences such as atrophy, loss of muscle mass, and progressive loss of functions. Aging-related muscle wasting, sarcopenia, and atrophy as a consequence of disease, such as cachexia, reduce the quality of life, increase morbidity and result in an overall poor prognosis. Investigating the muscle proteome related to muscle atrophy diseases has a great potential for diagnostic medicine to identify (i) potential protein biomarkers, and (ii) biological processes and functions common or unique to muscle wasting, cachexia, sarcopenia, and aging alone. We conducted a meta-analysis using gene ontology (GO) analysis of 24 human proteomic studies using tissue samples (skeletal muscle and adipose biopsies) and/or biofluids (serum, plasma, urine). Whilst there were few similarities in protein directionality across studies, biological processes common to conditions were identified. Here we demonstrate that the GO analysis of published human proteomics data can identify processes not revealed by single studies. We recommend the integration of proteomics data from tissue samples and biofluids to yield a comprehensive overview of the human skeletal muscle proteome. This will facilitate the identification of biomarkers and potential pathways of muscle-wasting conditions for use in clinics.
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Affiliation(s)
- Angelique Stalmach
- Centre for Health Science, Division of Biomedical Sciences, Institute of Health Research and Innovation, School of Health, Social Care and Life Sciences, University of the Highlands and Islands, Inverness IV2 3JH, UK
| | - Ines Boehm
- Edinburgh Cancer Research UK Tissue Group, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XR, UK
- Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK
- Biozentrum, University of Basel, 4056 Basel, Switzerland
| | - Marco Fernandes
- Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
| | - Alison Rutter
- Centre for Health Science, Division of Biomedical Sciences, Institute of Health Research and Innovation, School of Health, Social Care and Life Sciences, University of the Highlands and Islands, Inverness IV2 3JH, UK
| | - Richard J. E. Skipworth
- Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK
| | - Holger Husi
- Centre for Health Science, Division of Biomedical Sciences, Institute of Health Research and Innovation, School of Health, Social Care and Life Sciences, University of the Highlands and Islands, Inverness IV2 3JH, UK
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK
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13
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Morani F, Doccini S, Galatolo D, Pezzini F, Soliymani R, Simonati A, Lalowski MM, Gemignani F, Santorelli FM. Integrative Organelle-Based Functional Proteomics: In Silico Prediction of Impaired Functional Annotations in SACS KO Cell Model. Biomolecules 2022; 12:biom12081024. [PMID: 35892334 PMCID: PMC9331974 DOI: 10.3390/biom12081024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 02/07/2023] Open
Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure. Our integrated results strengthen the evidence for disease-specific defects related to bioenergetics and protein quality control systems and reinforce the role of dysregulated cytoskeletal organization in the pathogenesis of ARSACS.
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Affiliation(s)
- Federica Morani
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (F.M.); (F.G.)
| | - Stefano Doccini
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit—IRCCS Stella Maris, 56128 Pisa, Italy; (S.D.); (D.G.)
| | - Daniele Galatolo
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit—IRCCS Stella Maris, 56128 Pisa, Italy; (S.D.); (D.G.)
| | - Francesco Pezzini
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37129 Verona, Italy; (F.P.); (A.S.)
| | - Rabah Soliymani
- HiLIFE, Meilahti Clinical Proteomics Core Facility, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland; (R.S.); (M.M.L.)
| | - Alessandro Simonati
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37129 Verona, Italy; (F.P.); (A.S.)
| | - Maciej M. Lalowski
- HiLIFE, Meilahti Clinical Proteomics Core Facility, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland; (R.S.); (M.M.L.)
- Institute of Bioorganic Chemistry, PAS, Department of Biomedical Proteomics, 61-704 Poznań, Poland
| | - Federica Gemignani
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (F.M.); (F.G.)
| | - Filippo M. Santorelli
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit—IRCCS Stella Maris, 56128 Pisa, Italy; (S.D.); (D.G.)
- Correspondence: ; Tel.: +39-050-886311
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14
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García-Sánchez J, Mafla-España MA, Torregrosa MD, Cauli O. Androstenedione and Follicle-Stimulating Hormone Concentration Predict the Progression of Frailty Syndrome at One Year Follow-Up in Patients with Localized Breast Cancer Treated with Aromatase Inhibitors. Biomedicines 2022; 10:biomedicines10071634. [PMID: 35884939 PMCID: PMC9312841 DOI: 10.3390/biomedicines10071634] [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: 05/17/2022] [Revised: 07/05/2022] [Accepted: 07/05/2022] [Indexed: 11/16/2022] Open
Abstract
Background: The standard treatment in postmenopausal women with estrogen- and progesterone-positive localized breast cancer consists of aromatase inhibitors (AROi). The ability of AROi to promote or worsen frailty syndrome over time and the relationship with changes in gonadal hormones concentration in blood have not been investigated. Methods: A prospective study to evaluate the relationship between frailty syndrome and gonadal hormones concentrations in blood at baseline (prior to AROi treatment) and after 6 and 12 months under AROi treatment in post-menopausal women with breast cancer. Frailty syndrome was evaluated by the Fried’ criteria. We evaluated whether hormone concentration at baseline could predict frailty syndrome at follow-up. Results: Multinomial regression analysis showed that of the different hormones, those significantly (p < 0.05) associated to the worsening of frailty syndrome were high androstenedione levels and low follicle-stimulating hormone (FSH) levels in blood. Receiver operating characteristic curve analysis showed both androstenedione and FSH significantly (p < 0.05) discriminate patients who developed or presented worsening of frailty syndrome over time, with acceptable sensitivity (approximately 80% in both cases) but low specificity (40%). Conclusion: Hormonal concentrations before AROi treatment constitute possible biomarkers to predict the progression of frailty syndrome.
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Affiliation(s)
- Javier García-Sánchez
- Medical Oncology Department, Doctor Peset University Hospital, 46017 Valencia, Spain; (J.G.-S.); (M.D.T.)
- Medical Oncology Department, Hospital Center of Wallonie Picardy, 7500 Tournai, Belgium
| | - Mayra Alejandra Mafla-España
- Frailty Research Organized Group, University of Valencia, 46010 Valencia, Spain;
- Department of Nursing, University of Valencia, 46010 Valencia, Spain
| | - María Dolores Torregrosa
- Medical Oncology Department, Doctor Peset University Hospital, 46017 Valencia, Spain; (J.G.-S.); (M.D.T.)
| | - Omar Cauli
- Frailty Research Organized Group, University of Valencia, 46010 Valencia, Spain;
- Department of Nursing, University of Valencia, 46010 Valencia, Spain
- Correspondence:
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15
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Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis. Int J Mol Sci 2022; 23:ijms23126454. [PMID: 35742897 PMCID: PMC9223656 DOI: 10.3390/ijms23126454] [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] [Received: 04/29/2022] [Revised: 05/27/2022] [Accepted: 05/30/2022] [Indexed: 01/27/2023] Open
Abstract
Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.
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16
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Doccini S, Marchese M, Morani F, Gammaldi N, Mero S, Pezzini F, Soliymani R, Santi M, Signore G, Ogi A, Rocchiccioli S, Kanninen KM, Simonati A, Lalowski MM, Santorelli FM. Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease. Cells 2022; 11:1840. [PMID: 35681535 PMCID: PMC9180748 DOI: 10.3390/cells11111840] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/29/2022] [Accepted: 06/01/2022] [Indexed: 12/01/2022] Open
Abstract
CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5-/- mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments.
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Affiliation(s)
- Stefano Doccini
- Molecular Medicine–IRCCS Stella Maris, 56128 Pisa, Italy; (M.M.); (N.G.); (S.M.); (A.O.)
| | - Maria Marchese
- Molecular Medicine–IRCCS Stella Maris, 56128 Pisa, Italy; (M.M.); (N.G.); (S.M.); (A.O.)
| | - Federica Morani
- Department of Biology, University of Pisa, 56126 Pisa, Italy;
| | - Nicola Gammaldi
- Molecular Medicine–IRCCS Stella Maris, 56128 Pisa, Italy; (M.M.); (N.G.); (S.M.); (A.O.)
- Ph.D. Program in Neuroscience, University of Florence, 50121 Florence, Italy
| | - Serena Mero
- Molecular Medicine–IRCCS Stella Maris, 56128 Pisa, Italy; (M.M.); (N.G.); (S.M.); (A.O.)
| | - Francesco Pezzini
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37129 Verona, Italy; (F.P.); (A.S.)
| | - Rabah Soliymani
- HiLIFE, Meilahti Clinical Proteomics Core Facility, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
| | - Melissa Santi
- NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, 56127 Pisa, Italy;
| | | | - Asahi Ogi
- Molecular Medicine–IRCCS Stella Maris, 56128 Pisa, Italy; (M.M.); (N.G.); (S.M.); (A.O.)
| | | | - Katja M. Kanninen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland;
| | - Alessandro Simonati
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37129 Verona, Italy; (F.P.); (A.S.)
| | - Maciej M. Lalowski
- HiLIFE, Meilahti Clinical Proteomics Core Facility, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
- Institute of Bioorganic Chemistry, PAS, Department of Biomedical Proteomics, 61-704 Poznan, Poland
| | - Filippo M. Santorelli
- Molecular Medicine–IRCCS Stella Maris, 56128 Pisa, Italy; (M.M.); (N.G.); (S.M.); (A.O.)
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17
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Sun Z. Low intensity pulsed ultrasound information technology intervention in diagnosis and prediction of Muscle Atrophy. Pak J Med Sci 2021; 37:1569-1573. [PMID: 34712284 PMCID: PMC8520380 DOI: 10.12669/pjms.37.6-wit.4839] [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] [Received: 04/05/2021] [Revised: 06/08/2021] [Accepted: 07/17/2021] [Indexed: 11/15/2022] Open
Abstract
Objective: To discuss the effects and function of LIPUS on muscle atrophy (MA), analysis from various aspects through the study of low-intensity pulsed ultrasound (LIPUS) information technology intervention (ITI) in diagnosis and the prediction of muscle atrophy.. Method: In this study conducted in our university, 74 healthy female SD rats aged three months, weighing 100-200g were selected. All rats were placed in sterile cages from June 2020 to September 2020. They were divided into three groups. In the OVO group and OVE group, the mice are treated with LIPUS, Finally, the changes of body weight, grasping power, biochemical indexes and glycogen content of gastrocnemius muscle were analyzed and recorded to explore the effect and value of LIPUS ITI combined with intermittent weight-bearing exercise in the treatment of MA Results: After weight-bearing running, the body weight of model (OVO) group, exercise (OVE) group and NC group had significant statistical significance (P<0.01). It was found that the weight of OVE group was much more as compared to OVO group. There was significant difference in body weight between OVO group and NC group (P<0.05). After LIPUS treatment, it was found that the weight of OVO group, OVE group, LIPUS group and OVE +LIPUS group increased. Compared with the NC group, there was significant statistical difference (P<0.01). Conclusion: Low intensity pulsed ultrasound ITI has a good effect on improving MA, so as to effectively improve the weight of gastrocnemius muscle. The combined application of the two is better for the improvement of muscular atrophy.
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Affiliation(s)
- Zhijun Sun
- Zhijun Sun, Master of Degree. Department of Physical Education Teaching, Tianjin University of Commerce, Beichen 300134, Tianjin, China
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18
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Nguyen HH, Milat F, Vincent AJ. New insights into the diagnosis and management of bone health in premature ovarian insufficiency. Climacteric 2021; 24:481-490. [PMID: 33955314 DOI: 10.1080/13697137.2021.1917539] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Premature ovarian insufficiency (POI), defined as a loss of ovarian function before the age of 40 years, is a life-changing diagnosis that has numerous long-term consequences. Musculoskeletal complications, including osteoporosis and fractures, are a key concern for women with POI. The risk of bone loss is influenced by the underlying etiology of POI, and the degree and duration of estrogen deficiency. A decline in muscle mass as a result of estrogen and androgen deficiency may contribute to skeletal fragility, but has not been examined in women with POI. This article aims to review musculoskeletal health in POI; summarize the traditional and novel modalities available to screen for skeletal fragility and muscle dysfunction; and provide updated evidence for available management strategies.
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Affiliation(s)
- H H Nguyen
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.,Department of Endocrinology, Monash Health, Clayton, VIC, Australia.,Department of Endocrinology and Diabetes, Western Health, St. Albans, VIC, Australia
| | - F Milat
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.,Department of Endocrinology, Monash Health, Clayton, VIC, Australia.,Metabolic Bone Research Group, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - A J Vincent
- Department of Endocrinology, Monash Health, Clayton, VIC, Australia.,Monash Centre for Health Research and Implementation, Monash University, Clayton, VIC, Australia
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19
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Estradiol deficiency and skeletal muscle apoptosis: Possible contribution of microRNAs. Exp Gerontol 2021; 147:111267. [PMID: 33548486 PMCID: PMC9897888 DOI: 10.1016/j.exger.2021.111267] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Menopause leads to estradiol (E2) deficiency that is associated with decreases in muscle mass and strength. Here we studied the effect of E2 deficiency on microRNA (miR) signaling that targets apoptotic pathways. METHODS C57BL6 mice were divided into control (normal estrous cycle, n = 8), OVX (E2 deficiency, n = 7) and OVX + E2 groups (E2-pellet, n = 4). Six weeks following the OVX surgery, mice were sacrificed and RNA isolated from gastrocnemius muscles. miR-profiles were studied with Next-Generation Sequencing (NGS) and candidate miRs verified using qPCR. The target proteins of the miRs were found using in silico analysis and measured at mRNA (qPCR) and protein levels (Western blot). RESULTS Of the apoptosis-linked miRs present, eleven (miRs-92a-3p, 122-5p, 133a-3p, 214-3p, 337-3p, 381-3p, 483-3p, 483-5p, 491-5p, 501-5p and 652-3p) indicated differential expression between OVX and OVX + E2 mice in NGS analysis. In qPCR verification, muscle from OVX mice had lower expression of all eleven miRs compared with OVX + E2 (p < 0.050). Accordingly, OVX had higher expression of cytochrome C and caspases 6 and 9 compared with OVX + E2 at the mRNA level (p < 0.050). At the protein level, OVX also had lower anti-apoptotic BCL-W and greater pro-apoptotic cytochrome C and active caspase 9 compared with OVX + E2 (p < 0.050). CONCLUSION E2 deficiency downregulated several miRs related to apoptotic pathways thus releasing their targets from miR-mediated suppression, which may lead to increased apoptosis and contribute to reduced skeletal muscle mass.
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20
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Samad N, Nguyen HH, Scott D, Ebeling PR, Milat F. Musculoskeletal Health in Premature Ovarian Insufficiency. Part One: Muscle. Semin Reprod Med 2021; 38:277-288. [PMID: 33418593 DOI: 10.1055/s-0040-1721797] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Accelerated bone loss and muscle decline coexist in women with premature ovarian insufficiency (POI), but there are significant gaps in our understanding of musculoskeletal health in POI. This article is the first of a two-part review which describes estrogen signaling in muscle and its role in musculoskeletal health and disease. Current evidence regarding the utility of available diagnostic tests and therapeutic options is also discussed. A literature review from January 2000 to March 2020 was conducted to identify relevant studies. Women with POI experience significant deterioration in musculoskeletal health due to the loss of protective effects of estrogen. In addition to bone loss, muscle decay and dysfunction is now increasingly recognized. Nevertheless, there is a paucity of validated tools to assess muscle parameters. There is a growing need to acknowledge bone-muscle codependence to design new therapies which target both muscle and bone, resulting in improved physical performance and reduced morbidity and mortality. More high-quality research and international collaborations are needed to address the deficiencies in our understanding and management of musculoskeletal health in women with POI.
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Affiliation(s)
- Navira Samad
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria, Australia.,Department of Medicine, School of Clinical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia
| | - Hanh H Nguyen
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria, Australia.,Department of Endocrinology and Diabetes, Western Health, Victoria, Australia
| | - David Scott
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.,Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Peter R Ebeling
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria, Australia
| | - Frances Milat
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria, Australia.,Department of Endocrinology and Diabetes, Western Health, Victoria, Australia
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21
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Huang P, Luo K, Xu J, Huang W, Yin W, Xiao M, Wang Y, Ding M, Huang X. Sarcopenia as a Risk Factor for Future Hip Fracture: A Meta-Analysis of Prospective Cohort Studies. J Nutr Health Aging 2021; 25:183-188. [PMID: 33491032 DOI: 10.1007/s12603-020-1474-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE Our study aims to determine whether sarcopenia is a predictive factor of future hip fractures. DESIGN Systematic review and meta-analysis. Set: We searched for potentially suitable articles in PubMed, Cochrane library, Medline and EMBASE from inception to March 2020. The quality of the research was assessed by the Newcastle-Ottawa Scale (NOS). Finally, a meta-analysis was conducted with the Stata software. PARTICIPANTS Older community-dwelling residents. MEASUREMENTS Hip fracture due to sarcopenia. RESULTS We retrieved 2129 studies through our search strategy, and five studies with 23,359 individuals were analyzed in our pooled analyses. Sarcopenia increases the risk of future hip fractures with a pooled hazard ratio (HR) of 1.42 (95% CI: 1.18-1.71, P <0.001, I2 = 37.7%). In addition, in subgroup analyses based on different definitions of sarcopenia, sarcopenia was associated with the risk of future hip fractures with the Asian Working Group for Sarcopenia (AWGS) criteria with a pooled HR of 2.13(95% CI: 1.33-3.43). When subgroup analyses were conducted by sex, sarcopenia was associated with the risk for future hip fractures in females with pooled HRs of 1.69 (95% CI: 1.18-2.43). Sarcopenia was associated with the risk of future hip fractures in the group with a follow-up period of more than 5 years, with a pooled HR of 1.32 (95% CI: 1.08-1.61), and in the group with a follow-up period of less than 5 years, with a pooled HR of 2.13 (95% CI: 1.33-3.43). CONCLUSIONS Sarcopenia could significantly increase the risk of future hip fracture in old people; thus, it is necessary to prevent hip fractures in individuals with sarcopenia.
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Affiliation(s)
- P Huang
- Mei Ding, Medical College Road, Ganzhou City, Jiangxi Province 341000, China, E-mail address:. Xiaofeng Huang, E-mail address :
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22
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Piasecki J, Inns TB, Bass JJ, Scott R, Stashuk DW, Phillips BE, Atherton PJ, Piasecki M. Influence of sex on the age-related adaptations of neuromuscular function and motor unit properties in elite masters athletes. J Physiol 2021; 599:193-205. [PMID: 33006148 DOI: 10.1113/jp280679] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 09/24/2020] [Indexed: 12/30/2022] Open
Abstract
KEY POINTS Masters athletes maintain high levels of activity into older age and allow an examination of the effects of aging dissociated from the effects of increased sedentary behaviour. Evidence suggests masters athletes are more successful at motor unit remodelling, the reinnervation of denervated fibres acting to preserve muscle fibre number, but little data are available in females. Here we used intramuscular electromyography to demonstrate that motor units sampled from the tibialis anterior show indications of remodelling from middle into older age and which does not differ between males and females. The age-related trajectory of motor unit discharge characteristic differs according to sex, with female athletes progressing to a slower firing pattern that was not observed in males. Our findings indicate motor unit remodelling from middle to older age occurs to a similar extent in male and female athletes, with discharge rates progressively slowing in females only. ABSTRACT Motor unit (MU) remodelling acts to minimise loss of muscle fibres following denervation in older age, which may be more successful in masters athletes. Evidence suggests performance and neuromuscular function decline with age in this population, although the majority of studies have focused on males, with little available data on female athletes. Functional assessments of strength, balance and motor control were performed in 30 masters athletes (16 male) aged 44-83 years. Intramuscular needle electrodes were used to sample individual motor unit potentials (MUPs) and near-fibre MUPs in the tibialis anterior (TA) during isometric contractions at 25% maximum voluntary contraction, and used to determine discharge characteristics (firing rate, variability) and biomarkers of peripheral MU remodelling (MUP size, complexity, stability). Multilevel mixed-effects linear regression models examined effects of age and sex. All aspects of neuromuscular function deteriorated with age (P < 0.05) with no age × sex interactions, although males were stronger (P < 0.001). Indicators of MU remodelling also progressively increased with age to a similar extent in both sexes (P < 0.05), whilst MU firing rate progressively decreased with age in females (p = 0.029), with a non-significant increase in males (p = 0.092). Masters athletes exhibit age-related declines in neuromuscular function that are largely equal across males and females. Notably, they also display features of MU remodelling with advancing age, probably acting to reduce muscle fibre loss. The age trajectory of MU firing rate assessed at a single contraction level differed between sexes, which may reflect a greater tendency for females to develop a slower muscle phenotype.
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Affiliation(s)
- Jessica Piasecki
- Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Thomas B Inns
- Clinical, Metabolic and Molecular Physiology, MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
| | - Joseph J Bass
- Clinical, Metabolic and Molecular Physiology, MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
| | - Reece Scott
- Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Daniel W Stashuk
- Department of Systems Design Engineering, University of Waterloo, Ontario, Canada
| | - Bethan E Phillips
- Clinical, Metabolic and Molecular Physiology, MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
| | - Philip J Atherton
- Clinical, Metabolic and Molecular Physiology, MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
| | - Mathew Piasecki
- Clinical, Metabolic and Molecular Physiology, MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
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23
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Phytoestrogenic effect of fenugreek seed extract helps in ameliorating the leg pain and vasomotor symptoms in postmenopausal women: A randomized, double-blinded, placebo-controlled study. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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24
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Arasu UT, Deen AJ, Pasonen-Seppänen S, Heikkinen S, Lalowski M, Kärnä R, Härkönen K, Mäkinen P, Lázaro-Ibáñez E, Siljander PRM, Oikari S, Levonen AL, Rilla K. HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells. Cell Mol Life Sci 2020; 77:4093-4115. [PMID: 31820036 PMCID: PMC7532973 DOI: 10.1007/s00018-019-03399-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 11/11/2019] [Accepted: 11/26/2019] [Indexed: 12/17/2022]
Abstract
Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3-positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.
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Affiliation(s)
- Uma Thanigai Arasu
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
| | - Ashik Jawahar Deen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | | | - Sami Heikkinen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
- Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Maciej Lalowski
- Faculty of Medicine, Biochemistry and Developmental Biology, Meilahti Clinical Proteomics Core Facility, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Riikka Kärnä
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Kai Härkönen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Petri Mäkinen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Elisa Lázaro-Ibáñez
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Centre for Drug Research, University of Helsinki, Helsinki, Finland
| | - Pia R-M Siljander
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Centre for Drug Research, University of Helsinki, Helsinki, Finland
- EV Group and EV Core, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Sanna Oikari
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Anna-Liisa Levonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Kirsi Rilla
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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25
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Larson AA, Baumann CW, Kyba M, Lowe DA. Oestradiol affects skeletal muscle mass, strength and satellite cells following repeated injuries. Exp Physiol 2020; 105:1700-1707. [PMID: 32851730 DOI: 10.1113/ep088827] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023]
Abstract
NEW FINDINGS What is the central question of this study? Oestradiol (E2 ) plays an important role in regulating skeletal muscle strength in females. To what extent does E2 deficiency affect recovery of strength and satellite cell number when muscle is challenged by multiple injuries? What is the main finding and its importance? E2 deficiency impairs the adaptive potential of skeletal muscle following repeated injuries, as measured by muscle mass and strength. The impairment is likely multifactorial with our data indicating that one mechanism is reduction in satellite cell number. Our findings have implications for ageing, hormone replacement and regenerative medicine in regards to maintaining satellite cell number and ultimately the preservation of skeletal muscle's adaptive potential. ABSTRACT Oestradiol's effects on skeletal muscle are multifactorial including the preservation of mass, contractility and regeneration. Here, we aimed to determine the extent to which oestradiol deficiency affects strength recovery when muscle is challenged by multiple BaCl2 -induced injuries and to assess how satellite cell number is influenced by the combination of oestradiol deficiency and repetitive skeletal muscle injuries. A longitudinal study was designed, using an in vivo anaesthetized mouse approach to precisely and repeatedly measure maximal isometric torque, coupled with endpoint fluorescence-activated cell sorting to quantify satellite cells. Isometric torque and strength gains were lower in ovariectomized mice at several time points after the injuries compared to those treated with 17β-oestradiol. Satellite cell number was 41-43% lower in placebo- than in oestradiol-treated ovariectomized mice, regardless of injury status or number of injuries. Together, these results indicate that the loss of oestradiol blunts adaptive strength gains and that the number of satellite cells likely contributes to the impairment.
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Affiliation(s)
- Alexie A Larson
- Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, MN, USA
| | - Cory W Baumann
- Divisions of Rehabilitation Science and Physical Therapy, Department of Rehabilitation Medicine, Medical School, University of Minnesota, Minneapolis, MN, USA
| | - Michael Kyba
- Lillehei Heart Institute and Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN, USA
| | - Dawn A Lowe
- Divisions of Rehabilitation Science and Physical Therapy, Department of Rehabilitation Medicine, Medical School, University of Minnesota, Minneapolis, MN, USA
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Epidemiological Study on the Dose-Effect Association between Physical Activity Volume and Body Composition of the Elderly in China. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17176365. [PMID: 32882889 PMCID: PMC7504482 DOI: 10.3390/ijerph17176365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/24/2020] [Accepted: 08/27/2020] [Indexed: 11/23/2022]
Abstract
Purpose: The purpose of this study was to investigate Chinese old adults’ different body compositions in response to various levels of physical activity (PA). To the best of our knowledge, this is the first study to demonstrate the dose–response relationship between PA and body composition in old adults. Methods: 2664 participants older than 60 years (males: n = 984, females: n = 1680) were recruited for this cross-sectional health survey. PA was assessed by the short form of the International Physical Activity Questionnaire (IPAQ), and the body composition was measured by bioelectrical impedance analysis (BIA) instruments. The differences of separate body composition indices (lean body mass, LBM; bone mass, BM; and fat mass, FM) of older participants with different PA levels (below PA recommendation and over PA recommendation) were examined using the one-way analysis of variance (ANOVA). To compare the differences of three body composition indices with six different multiples of PA recommendation (0–1 REC, 1–2 REC, 2–4 REC, 4–6 REC, >6 REC), the one-way ANOVA and Turkey’s test was used for the post hoc analysis to identify the upper PA-benefit threshold in different indices of body composition. Results: The LBM and BM are significantly higher and the FM are significantly lower in old adults performing more PA volume than the WHO recommendation, compared with individuals performing less PA volume than the WHO recommendation. There were significant increases in LBM for males in “1–2 REC”, “2–4 REC”, and “>6 REC” groups, compared with the “0–1 REC” group; and there were significant increases in BM for males in “1–2 REC”, “2–4 REC”, compared with the “0–1 REC” group. The best PA volume for LBM and BM in females was the PA volume of “2–4 REC”. Additionally, whether males or females, there was no significant difference in FM between the “0–1 REC” group and other separate groups. Conclusion: The PA volume that causes best benefit for body composition of the elderly occurs at 1 to 2 times the recommended minimum PA for males, while it occurs at 2 to 4 times that recommended for females. No additional harms for old adults’ body composition occurs at six or more times the recommended minimum PA.
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27
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Hulmi JJ, Penna F, Pöllänen N, Nissinen TA, Hentilä J, Euro L, Lautaoja JH, Ballarò R, Soliymani R, Baumann M, Ritvos O, Pirinen E, Lalowski M. Muscle NAD + depletion and Serpina3n as molecular determinants of murine cancer cachexia-the effects of blocking myostatin and activins. Mol Metab 2020; 41:101046. [PMID: 32599075 PMCID: PMC7364159 DOI: 10.1016/j.molmet.2020.101046] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/16/2020] [Accepted: 06/23/2020] [Indexed: 12/26/2022] Open
Abstract
Objective Cancer cachexia and muscle loss are associated with increased morbidity and mortality. In preclinical animal models, blocking activin receptor (ACVR) ligands has improved survival and prevented muscle wasting in cancer cachexia without an effect on tumour growth. However, the underlying mechanisms are poorly understood. This study aimed to identify cancer cachexia and soluble ACVR (sACVR) administration-evoked changes in muscle proteome. Methods Healthy and C26 tumour-bearing (TB) mice were treated with recombinant sACVR. The sACVR or PBS control were administered either prior to the tumour formation or by continued administration before and after tumour formation. Muscles were analysed by quantitative proteomics with further examination of mitochondria and nicotinamide adenine dinucleotide (NAD+) metabolism. To complement the first prophylactic experiment, sACVR (or PBS) was injected as a treatment after tumour cell inoculation. Results Muscle proteomics in TB cachectic mice revealed downregulated signatures for mitochondrial oxidative phosphorylation (OXPHOS) and increased acute phase response (APR). These were accompanied by muscle NAD+ deficiency, alterations in NAD+ biosynthesis including downregulation of nicotinamide riboside kinase 2 (Nrk2), and decreased muscle protein synthesis. The disturbances in NAD+ metabolism and protein synthesis were rescued by treatment with sACVR. Across the whole proteome and APR, in particular, Serpina3n represented the most upregulated protein and the strongest predictor of cachexia. However, the increase in Serpina3n expression was associated with increased inflammation rather than decreased muscle mass and/or protein synthesis. Conclusions We present evidence implicating disturbed muscle mitochondrial OXPHOS proteome and NAD+ homeostasis in experimental cancer cachexia. Treatment of TB mice with a blocker of activin receptor ligands restores depleted muscle NAD+ and Nrk2, as well as decreased muscle protein synthesis. These results indicate putative new treatment therapies for cachexia and that although acute phase protein Serpina3n may serve as a predictor of cachexia, it more likely reflects a condition of elevated inflammation.
Cachectic muscle proteome shows decreased OXPHOS and increased acute phase response. Cancer cachexia is characterized by lowered muscle Nrk2 expression and NAD+ levels. Blocking activin receptor 2B ligands rescues muscle NAD+ homeostasis in cachexia. Blocking activin receptor 2B ligands prevents affected protein synthesis in cachexia. Serpina3n predicts cachexia and cancer-induced APR independently from muscle atrophy.
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Affiliation(s)
- J J Hulmi
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland; Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
| | - F Penna
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - N Pöllänen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - T A Nissinen
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - J Hentilä
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - L Euro
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - J H Lautaoja
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - R Ballarò
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - R Soliymani
- Meilahti Clinical Proteomics Core Facility, HiLIFE, Faculty of Medicine, Biochemistry and Developmental biology, University of Helsinki, Helsinki, Finland
| | - M Baumann
- Meilahti Clinical Proteomics Core Facility, HiLIFE, Faculty of Medicine, Biochemistry and Developmental biology, University of Helsinki, Helsinki, Finland
| | - O Ritvos
- Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - E Pirinen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - M Lalowski
- Meilahti Clinical Proteomics Core Facility, HiLIFE, Faculty of Medicine, Biochemistry and Developmental biology, University of Helsinki, Helsinki, Finland
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Gómez-Rodríguez R, Díaz-Pulido B, Gutiérrez-Ortega C, Sánchez-Sánchez B, Torres-Lacomba M. Prevalence, Disability and Associated Factors of Playing-Related Musculoskeletal Pain among Musicians: A Population-Based Cross-Sectional Descriptive Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E3991. [PMID: 32512798 PMCID: PMC7312771 DOI: 10.3390/ijerph17113991] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/31/2020] [Accepted: 06/02/2020] [Indexed: 11/29/2022]
Abstract
Background: Playing-related musculoskeletal disorders are the most frequent complaints among instrumental musicians. The aims of this study were: to assess the prevalence of musculoskeletal pain; to evaluate neck, shoulder, and lower back disability; and to determine the associated factors with the presence of musculoskeletal pain among musicians. Methods: A population-based, cross-sectional descriptive study was conducted. We selected Spaniard musicians over 16 years old who played a musical instrument for at least five hours per week. They answered the Spanish versions of the Standardised Nordic Questionnaire, the Oswestry Disability Index, Neck Disability Index and Shoulder Pain and Disability Index. Results: We found 94.8% of musicians presented at least one symptomatic region in the last 12 months, and 72.3% in the last seven days. Female musicians (OR 4.38, CI 2.11-9.12), musicians with overweight or obesity (OR 5.32, CI 2.18-12.97), and musicians who play more than 14 h per week (OR 3.86, CI 1.80-8.29)were shown to be a higher risk of suffering musculoskeletal pain. Conclusions: Musculoskeletal disorders symptoms are highly prevalent in musicians. The main risk factors related to musculoskeletal disorders symptoms were gender (being female), overweight, obesity, and spending playing more than 14 h a week practicing. This study highlights the need to provide strategies to prevent occupational disabilities among musicians. Further studies are needed to analyse the prevalence of pain in the musician using other sampling methods.
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Affiliation(s)
| | - Belén Díaz-Pulido
- Physiotherapy Department, University of Alcalá, Alcalá de Henares, 28805 Madrid, Spain
| | - Carlos Gutiérrez-Ortega
- Medical Statistics Unit, Department of Epidemiology, Hospital Central de la Defensa, 28047 Madrid, Spain;
| | - Beatriz Sánchez-Sánchez
- Physiotherapy Department, Physiotherapy in Women’s Health Research Group, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28805 Madrid, Spain; (B.S.-S.); (M.T.-L.)
| | - María Torres-Lacomba
- Physiotherapy Department, Physiotherapy in Women’s Health Research Group, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28805 Madrid, Spain; (B.S.-S.); (M.T.-L.)
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Role of Menopausal Transition and Physical Activity in Loss of Lean and Muscle Mass: A Follow-Up Study in Middle-Aged Finnish Women. J Clin Med 2020; 9:jcm9051588. [PMID: 32456169 PMCID: PMC7290663 DOI: 10.3390/jcm9051588] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 05/15/2020] [Accepted: 05/22/2020] [Indexed: 12/13/2022] Open
Abstract
In midlife, women experience hormonal changes due to menopausal transition. A decrease especially in estradiol has been hypothesized to cause loss of muscle mass. This study investigated the effect of menopausal transition on changes in lean and muscle mass, from the total body to the muscle fiber level, among 47–55-year-old women. Data were used from the Estrogenic Regulation of Muscle Apoptosis (ERMA) study, where 234 women were followed from perimenopause to early postmenopause. Hormone levels (estradiol and follicle stimulating hormone), total and regional body composition (dual-energy X-ray absorptiometry (DXA) and computed tomography (CT) scans), physical activity level (self-reported and accelerometer-measured) and muscle fiber properties (muscle biopsy) were assessed at baseline and at early postmenopause. Significant decreases were seen in lean body mass (LBM), lean body mass index (LBMI), appendicular lean mass (ALM), appendicular lean mass index (ALMI), leg lean mass and thigh muscle cross-sectional area (CSA). Menopausal status was a significant predictor for all tested muscle mass variables, while physical activity was an additional significant contributor for LBM, ALM, ALMI, leg lean mass and relative muscle CSA. Menopausal transition was associated with loss of muscle mass at multiple anatomical levels, while physical activity was beneficial for the maintenance of skeletal muscle mass.
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Validity and Reliability of a Single Question for Leisure-Time Physical Activity Assessment in Middle-Aged Women. J Aging Phys Act 2020; 28:231-241. [PMID: 31585436 DOI: 10.1123/japa.2019-0093] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 06/27/2019] [Accepted: 07/01/2019] [Indexed: 11/18/2022]
Abstract
PURPOSE To investigate the validity and test-retest reliability of a single seven-level scale physical activity assessment question (SR-PA L7) and its three-level categorization (SR-PA C3). METHODS The associations of SR-PA L7 and C3 with accelerometer-measured leisure-time physical activity (ACC-LTPA) and with the results of four different physical performance tests (6-min walk [n = 733], knee extension [n = 695], vertical jump [n = 731], and grip force [n = 780]) were investigated among women aged 47-55 years participating in the Estrogenic Regulation of Muscle Apoptosis study (n = 795). The reliability was studied using Spearman correlations with 4-month test-retest period (n = 152). RESULTS SR-PA L7 and C3 had low correlations with ACC-LTPA (rs = .105-.337). SR-PA L7, SR-PA C3, and ACC-LTPA explained comparable but small amount of variance of the physical performance test results. The reliability analysis provided moderate agreement (rs = .707 and .622 for SR-PA L7 and C3, respectively). CONCLUSIONS SR-PA L7 and C3 demonstrated limited validity and reasonable repeatability.
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31
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Klinge CM. Estrogenic control of mitochondrial function. Redox Biol 2020; 31:101435. [PMID: 32001259 PMCID: PMC7212490 DOI: 10.1016/j.redox.2020.101435] [Citation(s) in RCA: 164] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 12/15/2022] Open
Abstract
Sex-based differences in human disease are caused in part by the levels of endogenous sex steroid hormones which regulate mitochondrial metabolism. This review updates a previous review on how estrogens regulate metabolism and mitochondrial function that was published in 2017. Estrogens are produced by ovaries and adrenals, and in lesser amounts by adipose, breast stromal, and brain tissues. At the cellular level, the mechanisms by which estrogens regulate diverse cellular functions including reproduction and behavior is by binding to estrogen receptors α, β (ERα and ERβ) and G-protein coupled ER (GPER1). ERα and ERβ are transcription factors that bind genomic and mitochondrial DNA to regulate gene transcription. A small proportion of ERα and ERβ interact with plasma membrane-associated signaling proteins to activate intracellular signaling cascades that ultimately alter transcriptional responses, including mitochondrial morphology and function. Although the mechanisms and targets by which estrogens act directly and indirectly to regulate mitochondrial function are not fully elucidated, it is clear that estradiol regulates mitochondrial metabolism and morphology via nuclear and mitochondrial-mediated events, including stimulation of nuclear respiratory factor-1 (NRF-1) transcription that will be reviewed here. NRF-1 is a transcription factor that interacts with coactivators including peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) to regulate nuclear-encoded mitochondrial genes. One NRF-1 target is TFAM that binds mtDNA to regulate its transcription. Nuclear-encoded miRNA and lncRNA regulate mtDNA-encoded and nuclear-encoded transcripts that regulate mitochondrial function, thus acting as anterograde signals. Other estrogen-regulated mitochondrial activities including bioenergetics, oxygen consumption rate (OCR), and extracellular acidification (ECAR), are reviewed.
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Affiliation(s)
- Carolyn M Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, 40292, KY, USA.
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Doccini S, Morani F, Nesti C, Pezzini F, Calza G, Soliymani R, Signore G, Rocchiccioli S, Kanninen KM, Huuskonen MT, Baumann MH, Simonati A, Lalowski MM, Santorelli FM. Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction. Cell Death Discov 2020; 6:18. [PMID: 32257390 PMCID: PMC7105465 DOI: 10.1038/s41420-020-0250-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 02/27/2020] [Accepted: 03/04/2020] [Indexed: 12/20/2022] Open
Abstract
CLN5 disease is a rare form of late-infantile neuronal ceroid lipofuscinosis (NCL) caused by mutations in the CLN5 gene that encodes a protein whose primary function and physiological roles remains unresolved. Emerging lines of evidence point to mitochondrial dysfunction in the onset and progression of several forms of NCL, offering new insights into putative biomarkers and shared biological processes. In this work, we employed cellular and murine models of the disease, in an effort to clarify disease pathways associated with CLN5 depletion. A mitochondria-focused quantitative proteomics approach followed by functional validations using cell biology and immunofluorescence assays revealed an impairment of mitochondrial functions in different CLN5 KO cell models and in Cln5 - /- cerebral cortex, which well correlated with disease progression. A visible impairment of autophagy machinery coupled with alterations of key parameters of mitophagy activation process functionally linked CLN5 protein to the process of neuronal injury. The functional link between impaired cellular respiration and activation of mitophagy pathways in the human CLN5 disease condition was corroborated by translating organelle-specific proteome findings to CLN5 patients' fibroblasts. Our study highlights the involvement of CLN5 in activation of mitophagy and mitochondrial homeostasis offering new insights into alternative strategies towards the CLN5 disease treatment.
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Affiliation(s)
- Stefano Doccini
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy
| | - Federica Morani
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy
| | - Claudia Nesti
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy
| | - Francesco Pezzini
- Neurology (Child Neurology and Neuropathology), Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
| | - Giulio Calza
- Medicum, Biochemistry/Developmental Biology and HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Rabah Soliymani
- Medicum, Biochemistry/Developmental Biology and HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Giovanni Signore
- NEST, Scuola Normale Superiore, Pisa, Italy
- Fondazione Pisana per la Scienza, Pisa, Italy
| | | | - Katja M. Kanninen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Mikko T. Huuskonen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Marc H. Baumann
- Medicum, Biochemistry/Developmental Biology and HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Alessandro Simonati
- Neurology (Child Neurology and Neuropathology), Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
| | - Maciej M. Lalowski
- Medicum, Biochemistry/Developmental Biology and HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Filippo M. Santorelli
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy
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Laakkonen EK, Soliymani R, Lalowski M. Estrogen regulates muscle bioenergetic signaling. Aging (Albany NY) 2020; 10:160-161. [PMID: 29410389 PMCID: PMC5842845 DOI: 10.18632/aging.101380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 02/02/2018] [Indexed: 11/25/2022]
Affiliation(s)
- Eija K Laakkonen
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, FIN-40014, Finland
| | - Rabah Soliymani
- Helsinki Institute for Life Science (HiLIFE) and Faculty of Medicine, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, FI-00014, Finland
| | - Maciej Lalowski
- Helsinki Institute for Life Science (HiLIFE) and Faculty of Medicine, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, FI-00014, Finland
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34
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Lacham-Kaplan O, Camera DM, Hawley JA. Divergent Regulation of Myotube Formation and Gene Expression by E2 and EPA during In-Vitro Differentiation of C2C12 Myoblasts. Int J Mol Sci 2020; 21:E745. [PMID: 31979341 PMCID: PMC7037418 DOI: 10.3390/ijms21030745] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/20/2020] [Accepted: 01/21/2020] [Indexed: 12/21/2022] Open
Abstract
Estrogen (E2) and polyunsaturated fatty acids (n-3PUFA) supplements independently support general wellbeing and enhance muscle regeneration in-vivo and myotube formation in-vitro. However, the combined effect of E2 and n-3PUFA on myoblast differentiation is not known. The purpose of the study was to identify whether E2 and n-3PUFA possess a synergistic effect on in-vitro myogenesis. Mouse C2C12 myoblasts, a reliable model to reiterate myogenic events in-vitro, were treated with 10nM E2 and 50μM eicosapentaenoic acid (EPA) independently or combined, for 0-24 h or 0-120 h during differentiation. Immunofluorescence, targeted qPCR and next generation sequencing (NGS) were used to characterize morphological changes and differential expression of key genes involved in the regulation of myogenesis and muscle function pathways. E2 increased estrogen receptor α (Erα) and the expression of the mitogen-activated protein kinase 11 (Mapk11) within 1 h of treatment and improved myoblast differentiation and myotube formation. A significant reduction (p < 0.001) in myotube formation and in the expression of myogenic regulatory factors Mrfs (MyoD, Myog and Myh1) and the myoblast fusion related gene, Tmem8c, was observed in the presence of EPA and the combined E2/EPA treatment. Additionally, EPA treatment at 48 h of differentiation inhibited the majority of genes associated with the myogenic and striated muscle contraction pathways. In conclusion, EPA and E2 had no synergistic effect on myotube formation in-vitro. Independently, EPA inhibited myoblast differentiation and overrides the stimulatory effect of E2 when used in combination with E2.
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Affiliation(s)
- Orly Lacham-Kaplan
- Exercise and Nutrition Research Program, Mary Mackillop Institute for Health Research, Australian Catholic University, Melbourne 3000, Australia;
| | - Donny M. Camera
- Department of Health and Medical Sciences, Swinburne University of Technology, Melbourne 3122, Australia;
| | - John A. Hawley
- Exercise and Nutrition Research Program, Mary Mackillop Institute for Health Research, Australian Catholic University, Melbourne 3000, Australia;
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Li X, Fan L, Zhu M, Jiang H, Bai W, Kang J. Combined intervention of 17β-estradiol and treadmill training ameliorates energy metabolism in skeletal muscle of female ovariectomized mice. Climacteric 2019; 23:192-200. [DOI: 10.1080/13697137.2019.1660639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- X. Li
- Department of Obstetrics and Gynecology, Peking University Ninth School of Clinical Medicine, Beijing, China
| | - L. Fan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - M. Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - H. Jiang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - W. Bai
- Department of Obstetrics and Gynecology, Peking University Ninth School of Clinical Medicine, Beijing, China
| | - J. Kang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Monterrosa-Castro A, Ortiz-Banquéz M, Mercado-Lara M. Prevalence of sarcopenia and associated factors in climacteric women of the Colombian Caribbean. Menopause 2019; 26:1038-1044. [PMID: 31453967 DOI: 10.1097/gme.0000000000001347] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE The aim of the study was to determine the prevalence of sarcopenia and associated factors in climacteric middle-aged women. METHODS This was a cross-sectional study carried out in Colombian Caribbean women (40-59 y, n = 403), who were surveyed with a form that included sociodemographic information and two validated tools (the Menopause Rating Scale and the SF-36 Health questionnaire). Calf circumference, handgrip, and gait speed were measured. Low muscle mass (calf circumference <31 cm), reduced muscle strength (<20 kg in handgrip), and lower physical performance (<0.8 m/s gait speed) were estimated. Criteria of the European Working Group on Sarcopenia in Older People were used to identify sarcopenia. Association between sarcopenia (dependent variable) and menopausal symptoms and health perception (independent variables) was estimated. RESULTS Median age of surveyed women was 48 years, with 44.5% being postmenopausal. 9.6% had low muscle mass, 18.1% had reduced muscle strength, and 6.9% had lower physical performance. Presarcopenia was identified in 9.6% and sarcopenia in 7.9% (nonsevere sarcopenia 7.1% and severe sarcopenia 0.8%). Most important factors associated with sarcopenia were feeling full of life only sometimes, feeling a lot of energy only sometimes, having joint/muscular discomfort, history of hysterectomy, hot flashes, mestizo ethnic group, age 50 or more, being postmenopausal, and sleep problems. CONCLUSIONS Sarcopenia was present in this middle-aged female Colombian Caribbean sample and associated with various factors such as ethnicity, age, and menopausal symptoms and status.
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Affiliation(s)
- Alvaro Monterrosa-Castro
- Grupo de Investigación Salud de la Mujer, Facultad de Medicina, Universidad de Cartagena, Cartagena, Colombia
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Abstract
The older Finnish Twin Cohort (FTC) was established in 1974. The baseline survey was in 1975, with two follow-up health surveys in 1981 and 1990. The fourth wave of assessments was done in three parts, with a questionnaire study of twins born during 1945-1957 in 2011-2012, while older twins were interviewed and screened for dementia in two time periods, between 1999 and 2007 for twins born before 1938 and between 2013 and 2017 for twins born in 1938-1944. The content of these wave 4 assessments is described and some initial results are described. In addition, we have invited twin-pairs, based on response to the cohortwide surveys, to participate in detailed in-person studies; these are described briefly together with key results. We also review other projects based on the older FTC and provide information on the biobanking of biosamples and related phenotypes.
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38
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Ünsal P, Ayçiçek GŞ, Şendur A, Deniz O, Koca M, Boğa İ, Bürkük S, Cankurtaran M, Yavuz BB, Halil M. Effects of Hormone Replacement Therapy on Sarcopenia: Is It Real? J Am Geriatr Soc 2019; 67:1297. [DOI: 10.1111/jgs.15807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 12/10/2018] [Accepted: 12/10/2018] [Indexed: 11/28/2022]
Affiliation(s)
- Pelin Ünsal
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - Gözde Şengül Ayçiçek
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - Ayşe Şendur
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - Olgun Deniz
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - Meltem Koca
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - İlker Boğa
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - Suna Bürkük
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - Mustafa Cankurtaran
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - Burcu Balam Yavuz
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
| | - Meltem Halil
- Department of Internal Medicine, Division of Geriatric Medicine Ankara; Hacettepe University, Faculty of Medicine; Ankara Turkey
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39
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Collins BC, Laakkonen EK, Lowe DA. Aging of the musculoskeletal system: How the loss of estrogen impacts muscle strength. Bone 2019; 123:137-144. [PMID: 30930293 PMCID: PMC6491229 DOI: 10.1016/j.bone.2019.03.033] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 03/21/2019] [Accepted: 03/26/2019] [Indexed: 02/06/2023]
Abstract
Skeletal muscle weakness occurs with aging and in females this is compounded by the loss of estrogen with ovarian failure. Estrogen deficiency mediates decrements in muscle strength from both inadequate preservation of skeletal muscle mass and decrements in the quality of the remaining skeletal muscle. Processes and components of skeletal muscle that are affected by estrogens are beginning to be identified. This review focuses on mechanisms that contribute to the loss of muscle force generation when estrogen is low in females, and conversely the maintenance of strength by estrogen. Evidence is accumulating that estrogen deficiency induces apoptosis in skeletal muscle contributing to loss of mass and thus strength. Estrogen sensitive processes that affect quality, i.e., force generating capacity of muscle, include myosin phosphorylation and satellite cell function. Further detailing these mechanisms and identifying additional mechanisms that underlie estrogenic effects on skeletal muscle is important foundation for the design of therapeutic strategies to minimize skeletal muscle pathologies, such as sarcopenia and dynapenia.
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Affiliation(s)
- Brittany C Collins
- Department of Human Genetics, Medical School, University of Utah, United States of America
| | - Eija K Laakkonen
- Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, Finland
| | - Dawn A Lowe
- Divisions of Rehabilitation Science and Physical Therapy, Department of Rehabilitation Medicine, Medical School, University of Minnesota, United States of America.
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Vignozzi L, Malavolta N, Villa P, Mangili G, Migliaccio S, Lello S. Consensus statement on the use of HRT in postmenopausal women in the management of osteoporosis by SIE, SIOMMMS and SIGO. J Endocrinol Invest 2019; 42:609-618. [PMID: 30456623 DOI: 10.1007/s40618-018-0978-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 11/04/2018] [Indexed: 01/04/2023]
Affiliation(s)
- L Vignozzi
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - N Malavolta
- St Orsola-Malpighi Hospital, Cardio-Thoracic -Vascular Department, Program of Rheumatic and Connective Tissue Disordes and Bone Metabolic Diseases, Bologna, University of Bologna, Bologna, Italy
| | - P Villa
- Department of Obstetrics and Gynecology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - G Mangili
- Department of Obstetrics and Gynecology, IRCCS San Raffaele Hospital, Milan, Italy
| | - S Migliaccio
- Department of Movement, Human and Health Sciences, Unit of Endocrinology, University of "Foro Italico" of Rome, Largo Lauro De Bosis 6, 00195, Rome, Italy.
| | - S Lello
- Department of Woman and Child Health, Policlinico Gemelli Foundation, Rome, Italy
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Lirio-Romero C, Anders C, De La Villa-Polo P, Torres-Lacomba M. Implications on older women of age- and sex-related differences in activation patterns of shoulder muscles: A cross-sectional study. J Women Aging 2018; 31:492-512. [PMID: 30252611 DOI: 10.1080/08952841.2018.1521654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
We conducted a cross-sectional study to assess differences in neuromotor attributes of shoulder muscles between age groups in both sexes and to better understand functional disorders in older women. Twenty young (20-42 years old), 20 middle-aged (43-67), and 20 older (> 68) adults participated in a comparative surface-electromyography study of five muscles. We identified age-related differences in women, especially in scapula stabilizer muscles. There was a tendency for both sexes of delayed onset times with increasing age, excepting the upper trapezius muscle in females. The results highlight the importance of understanding musculoskeletal aging in women to adequately guide physical therapeutic approaches.
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Affiliation(s)
- Cristina Lirio-Romero
- Department of Physical Therapy, State Center of Attention to Brain Injury, Madrid, Spain
| | - Christoph Anders
- Division of Motor Research, Pathophysiology and Biomechanics, Clinic for Trauma, Hand and Reconstructive Surgery, Jena University Hospital, Jena, Germany
| | | | - María Torres-Lacomba
- Physiotherapy in Women´s Health Research Group, Department of Physical Therapy, University of Alcalá, Madrid, Spain
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Purhonen J, Rajendran J, Tegelberg S, Smolander OP, Pirinen E, Kallijärvi J, Fellman V. NAD + repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation. FASEB J 2018; 32:fj201800090R. [PMID: 29782205 DOI: 10.1096/fj.201800090r] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Biosynthetic precursors of NAD+ can replenish a decreased cellular NAD+ pool and, supposedly via sirtuin (SIRT) deacetylases, improve mitochondrial function. We found decreased hepatic NAD+ concentration and downregulated biosynthesis in Bcs1lp.S78G knock-in mice with respiratory chain complex III deficiency and mitochondrial hepatopathy. Aiming at ameliorating disease progression via NAD+ repletion and improved mitochondrial function, we fed these mice nicotinamide riboside (NR), a NAD+ precursor. A targeted metabolomics verified successful administration and suggested enhanced NAD+ biosynthesis in the treated mice, although hepatic NAD+ concentration was unchanged at the end point. In contrast to our expectations, NR did not improve the hepatopathy, hepatic mitochondrial respiration, or survival of Bcs1lp.S78G mice. We linked this lack of therapeutic effect to NAD+-independent activation of SIRT-1 and -3 via AMPK and cAMP signaling related to the starvation-like metabolic state of Bcs1lp.S78G mice. In summary, we describe an unusual metabolic state with NAD+ depletion accompanied by energy deprivation signals, uncompromised SIRT function, and upregulated oxidative metabolism. Our study highlights that the knowledge of the underlying complex metabolic alterations is critical when designing therapies for mitochondrial dysfunction.-Purhonen, J., Rajendran, J., Tegelberg, S., Smolander, O.-P., Pirinen, E., Kallijärvi, J., Fellman, V. NAD+ repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation.
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Affiliation(s)
- Janne Purhonen
- Folkhälsan Research Center, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jayasimman Rajendran
- Folkhälsan Research Center, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Saara Tegelberg
- Folkhälsan Research Center, Helsinki, Finland
- Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden
| | | | - Eija Pirinen
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jukka Kallijärvi
- Folkhälsan Research Center, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Vineta Fellman
- Folkhälsan Research Center, Helsinki, Finland
- Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden
- Children's Hospital, University of Helsinki, Finland
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43
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Lalowski MM, Björk S, Finckenberg P, Soliymani R, Tarkia M, Calza G, Blokhina D, Tulokas S, Kankainen M, Lakkisto P, Baumann M, Kankuri E, Mervaala E. Characterizing the Key Metabolic Pathways of the Neonatal Mouse Heart Using a Quantitative Combinatorial Omics Approach. Front Physiol 2018; 9:365. [PMID: 29695975 PMCID: PMC5904546 DOI: 10.3389/fphys.2018.00365] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 03/26/2018] [Indexed: 01/19/2023] Open
Abstract
The heart of a newborn mouse has an exceptional capacity to regenerate from myocardial injury that is lost within the first week of its life. In order to elucidate the molecular mechanisms taking place in the mouse heart during this critical period we applied an untargeted combinatory multiomics approach using large-scale mass spectrometry-based quantitative proteomics, metabolomics and mRNA sequencing on hearts from 1-day-old and 7-day-old mice. As a result, we quantified 1.937 proteins (366 differentially expressed), 612 metabolites (263 differentially regulated) and revealed 2.586 differentially expressed gene loci (2.175 annotated genes). The analyses pinpointed the fructose-induced glycolysis-pathway to be markedly active in 1-day-old neonatal mice. Integrated analysis of the data convincingly demonstrated cardiac metabolic reprogramming from glycolysis to oxidative phosphorylation in 7-days old mice, with increases of key enzymes and metabolites in fatty acid transport (acylcarnitines) and β-oxidation. An upsurge in the formation of reactive oxygen species and an increase in oxidative stress markers, e.g., lipid peroxidation, altered sphingolipid and plasmalogen metabolism were also evident in 7-days mice. In vitro maintenance of physiological fetal hypoxic conditions retained the proliferative capacity of cardiomyocytes isolated from newborn mice hearts. In summary, we provide here a holistic, multiomics view toward early postnatal changes associated with loss of a tissue regenerative capacity in the neonatal mouse heart. These results may provide insight into mechanisms of human cardiac diseases associated with tissue regenerative incapacity at the molecular level, and offer a prospect to discovery of novel therapeutic targets.
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Affiliation(s)
- Maciej M Lalowski
- Department of Biochemistry, Department of Developmental Biology, Faculty of Medicine, Helsinki Institute of Life Science (HiLIFE) and Medicum, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Susann Björk
- Medicum, Department of Pharmacology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland
| | - Piet Finckenberg
- Medicum, Department of Pharmacology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland
| | - Rabah Soliymani
- Department of Biochemistry, Department of Developmental Biology, Faculty of Medicine, Helsinki Institute of Life Science (HiLIFE) and Medicum, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Miikka Tarkia
- Medicum, Department of Pharmacology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland
| | - Giulio Calza
- Department of Biochemistry, Department of Developmental Biology, Faculty of Medicine, Helsinki Institute of Life Science (HiLIFE) and Medicum, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Daria Blokhina
- Medicum, Department of Pharmacology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland
| | - Sari Tulokas
- Medicum, Department of Pharmacology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland
| | - Matti Kankainen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.,Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Päivi Lakkisto
- Medicum, Department of Clinical Chemistry and Hematology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland
| | - Marc Baumann
- Department of Biochemistry, Department of Developmental Biology, Faculty of Medicine, Helsinki Institute of Life Science (HiLIFE) and Medicum, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Esko Kankuri
- Medicum, Department of Pharmacology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland
| | - Eero Mervaala
- Medicum, Department of Pharmacology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland
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