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Gao X, Wang S, Shen S, Wang S, Xie M, Storey KB, Yu C, Lefai E, Song W, Chang H, Yang C. Differential bone remodeling mechanism in hindlimb unloaded and hibernating Daurian ground squirrels: a comparison between artificial and natural disuse within the same species. J Comp Physiol B 2023; 193:329-350. [PMID: 36988658 DOI: 10.1007/s00360-023-01482-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 02/06/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023]
Abstract
Loss of bone mass can occur in mammals after prolonged disuse but the situation for hibernators that are in a state of torpor for many months of the year is not yet fully understood. The present study assesses the bone remodeling mechanisms present in Daurian ground squirrels (Spermophilus dauricus) during hibernation as compared with a model of hindlimb disuse. Differences in microstructure, mechanical properties, bone remodeling-related proteins (Runx2, OCN, ALP, RANKL, CTK and MMP-9) and key proteins of Wnt/β-catenin signaling pathway (GSK-3β and phospho-β-catenin) were evaluated in ground squirrels under 3 conditions: summer active (SA) vs. hibernation (HIB) vs. hindlimb unloaded (HLU). The results indicated that the body weight in HLU ground squirrels was lower than the SA group, and the middle tibia diameter in the HLU group was lower than that in SA and HIB groups. The thickness of cortical and trabecular bone in femurs from HLU ground squirrels was lower than in SA and HIB groups. Most parameters of the tibia in the HLU group were lower than those in SA and HIB groups, which indicated cortical bone loss in ground squirrels. Moreover, our data showed that the changes in microscopic parameters in the femur were more obvious than those in the tibia in HLU and HIB ground squirrels. The levels of Runx2 and ALP were lower in HLU ground squirrels than SA and HIB groups. The protein levels of OCN were unchanged in the three groups, but the protein levels of ALP were lower in the HLU group than in SA and HIB groups. RANKL, CTK and MMP-9 protein levels were significantly decreased in tibia of HLU ground squirrels as compared with SA and HIB groups. In addition, the protein expression levels of RANKL, CTK and MMP-9 showed no statistical difference between SA and HIB ground squirrels. Thus, the mechanisms involved in the balance between bone formation and resorption in hibernating and hindlimb unloading ground squirrels may be different. The present study showed that in femur, the Wnt signaling pathway was inhibited, the protein level of GSK-3β was increased, and the protein expression of phospho-β-catenin was decreased in the HIB group as compared with the SA group, which indicates that the Wnt signaling pathway has a great influence on the femur of the HIB group. In conclusion, the natural anti-osteoporosis properties of Daurian ground squirrels are seasonal. The squirrels do not experience bone loss when they are inactive for a long time during hibernation, but the mechanisms of anti-osteoporosis did not work in HLU summer active squirrels.
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Affiliation(s)
- Xuli Gao
- Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, 229# North Taibai Road, Xi'an, 710069, People's Republic of China
| | - Siqi Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, 229# North Taibai Road, Xi'an, 710069, People's Republic of China
| | - Siqi Shen
- Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, 229# North Taibai Road, Xi'an, 710069, People's Republic of China
| | - Shuyao Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, 229# North Taibai Road, Xi'an, 710069, People's Republic of China
| | - Manjiang Xie
- Department of Aerospace Physiology, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi'an, 710032, China
| | - Kenneth B Storey
- Department of Biology, Carleton University, Ottawa, ON, K1S 5B6, Canada
| | - Caiyong Yu
- Military Medical Innovation Center, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Etienne Lefai
- INRAE, Unité de Nutrition Humaine, UMR 1019, Université Clermont Auvergne, 63000, Clermont-Ferrand, France
| | - Wenqian Song
- Northwest University Hospital, Xi'an, 710069, People's Republic of China
| | - Hui Chang
- Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, 229# North Taibai Road, Xi'an, 710069, People's Republic of China.
| | - Changbin Yang
- Military Medical Innovation Center, Air Force Medical University, Xi'an, 710032, Shaanxi, China.
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Bone adaptation and osteoporosis prevention in hibernating mammals. Comp Biochem Physiol A Mol Integr Physiol 2023; 280:111411. [PMID: 36871815 DOI: 10.1016/j.cbpa.2023.111411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/26/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023]
Abstract
Hibernating bears and rodents have evolved mechanisms to prevent disuse osteoporosis during the prolonged physical inactivity that occurs during hibernation. Serum markers and histological indices of bone remodeling in bears indicate reduced bone turnover during hibernation, which is consistent with organismal energy conservation. Calcium homeostasis is maintained by balanced bone resorption and formation since hibernating bears do not eat, drink, urinate, or defecate. Reduced and balanced bone remodeling protect bear bone structure and strength during hibernation, unlike the disuse osteoporosis that occurs in humans and other animals during prolonged physical inactivity. Conversely, some hibernating rodents show varying degrees of bone loss such as osteocytic osteolysis, trabecular loss, and cortical thinning. However, no negative effects of hibernation on bone strength in rodents have been found. More than 5000 genes in bear bone tissue are differentially expressed during hibernation, highlighting the complexity of hibernation induced changes in bone. A complete picture of the mechanisms that regulate bone metabolism in hibernators still alludes us, but existing data suggest a role for endocrine and paracrine factors such as cocaine- and amphetamine-regulated transcript (CART) and endocannabinoid ligands like 2-arachidonoyl glycerol (2-AG) in decreasing bone remodeling during hibernation. Hibernating bears and rodents evolved the capacity to preserve bone strength during long periods of physical inactivity, which contributes to their survival and propagation by allowing physically activity (foraging, escaping predators, and mating) without risk of bone fracture following hibernation. Understanding the biological mechanisms regulating bone metabolism in hibernators may inform novel treatment strategies for osteoporosis in humans.
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Jähn-Rickert K, Zimmermann EA. Potential Role of Perilacunar Remodeling in the Progression of Osteoporosis and Implications on Age-Related Decline in Fracture Resistance of Bone. Curr Osteoporos Rep 2021; 19:391-402. [PMID: 34117624 DOI: 10.1007/s11914-021-00686-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/22/2021] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW We took an interdisciplinary view to examine the potential contribution of perilacunar/canalicular remodeling to declines in bone fracture resistance related to age or progression of osteoporosis. RECENT FINDINGS Perilacunar remodeling is most prominent as a result of lactation; recent advances further elucidate the molecular players involved and their effect on bone material properties. Of these, vitamin D and calcitonin could be active during aging or osteoporosis. Menopause-related hormonal changes or osteoporosis therapies affect bone material properties and mechanical behavior. However, investigations of lacunar size or osteocyte TRAP activity with age or osteoporosis do not provide clear evidence for or against perilacunar remodeling. While the occurrence and potential role of perilacunar remodeling in aging and osteoporosis progression are largely under-investigated, widespread changes in bone matrix composition in OVX models and following osteoporosis therapies imply osteocytic maintenance of bone matrix. Perilacunar remodeling-induced changes in bone porosity, bone matrix composition, and bone adaptation could have significant implications for bone fracture resistance.
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Affiliation(s)
- Katharina Jähn-Rickert
- Heisenberg Research Group, Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestr. 55a, 22529, Hamburg, Germany.
- Mildred Scheel Cancer Career Center Hamburg, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Elizabeth A Zimmermann
- Faculty of Dentistry, McGill University, Strathcona Anatomy and Dentistry Building, 3640 Rue University, Montreal, Canada.
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Yin R, Zhang J, Xu S, Kong Y, Wang H, Gao Y. Resistance to disuse-induced iron overload in Daurian ground squirrels (Spermophilus dauricus) during extended hibernation inactivity. Comp Biochem Physiol B Biochem Mol Biol 2021; 257:110650. [PMID: 34298179 DOI: 10.1016/j.cbpb.2021.110650] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/15/2021] [Accepted: 07/18/2021] [Indexed: 11/30/2022]
Abstract
Iron overload occurs in disuse-induced osteoporosis. Hibernators are a natural animal model of resistance to disuse osteoporosis. We hypothesized that hibernators avoid iron overload to resist disuse-induced osteoporosis. Here, the role of iron metabolism in resistance to disuse osteoporosis was investigated by studying differences in iron content and iron metabolism in the femurs and livers of Daurian ground squirrels (Spermophilus dauricus) between the summer active and torpid states. Results showed that the femurs were generally well-maintained during torpor, with no significant differences observed in most bone microstructural parameters, except for a significantly lower (by 40%) trabecular bone connection density. Femur and liver iron concentrations were significantly lower during torpor (by 59% and 49%, respectively). Based on histological staining, livers were iron-negative and femurs showed a reduction in iron-positive area (by 83%) during torpor; The number of osteoblasts and osteoclasts showed no significant differences between the two groups. Most iron metabolism/homeostasis proteins expression levels in the femur and liver showed no significant differences between the two groups, with their stable expression likely preventing iron overload during inactivity. Higher femoral transferrin receptor 1 (TfR1) expression (by 108%) and lower liver ferritin expression (by 45%) were found in torpid squirrels. Lower liver ferritin may be related to the lower iron content, with the elevation in femoral TfR1 potentially related to restoration of bone iron levels. In conclusion, despite long periods of inactivity, iron levels in the femur and liver of squirrels were lower, bone formation and resorption were balanced and no iron overload was observed, as is found under disuse conditions in non-hibernators. Therefore, avoiding iron overload may be a potential mechanism for hibernators to avoid disuse-induced bone loss.
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Affiliation(s)
- Rongrong Yin
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an 710069, China
| | - Jie Zhang
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an 710069, China
| | - Shenhui Xu
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an 710069, China
| | - Yong Kong
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an 710069, China
| | - Huiping Wang
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an 710069, China.
| | - Yunfang Gao
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an 710069, China.
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Cerri M, Hitrec T, Luppi M, Amici R. Be cool to be far: Exploiting hibernation for space exploration. Neurosci Biobehav Rev 2021; 128:218-232. [PMID: 34144115 DOI: 10.1016/j.neubiorev.2021.03.037] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 01/08/2023]
Abstract
In mammals, torpor/hibernation is a state that is characterized by an active reduction in metabolic rate followed by a progressive decrease in body temperature. Torpor was successfully mimicked in non-hibernators by inhibiting the activity of neurons within the brainstem region of the Raphe Pallidus, or by activating the adenosine A1 receptors in the brain. This state, called synthetic torpor, may be exploited for many medical applications, and for space exploration, providing many benefits for biological adaptation to the space environment, among which an enhanced protection from cosmic rays. As regards the use of synthetic torpor in space, to fully evaluate the degree of physiological advantage provided by this state, it is strongly advisable to move from Earth-based experiments to 'in the field' tests, possibly on board the International Space Station.
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Affiliation(s)
- Matteo Cerri
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum -University of Bologna, Piazza di Porta S.Donato, 2 40126, Bologna, Italy.
| | - Timna Hitrec
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum -University of Bologna, Piazza di Porta S.Donato, 2 40126, Bologna, Italy.
| | - Marco Luppi
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum -University of Bologna, Piazza di Porta S.Donato, 2 40126, Bologna, Italy.
| | - Roberto Amici
- Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum -University of Bologna, Piazza di Porta S.Donato, 2 40126, Bologna, Italy.
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Polisel EEC, Beck WR, Scariot PPM, Pejon TMM, Gobatto CA, Manchado-Gobatto FB. Effects of high-intensity interval training in more or less active mice on biomechanical, biophysical and biochemical bone parameters. Sci Rep 2021; 11:6414. [PMID: 33742012 PMCID: PMC7979708 DOI: 10.1038/s41598-021-85585-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/27/2021] [Indexed: 02/07/2023] Open
Abstract
High-intensity interval training (HIIT) is of scientific interest due its role in improving physical fitness, but the effects of HIIT on bone health need be carefully explored. Further, it is necessary to know whether HIIT effects on bone health are dependent on the physical activity levels. This may be experimentally tested since we have built a large cage (LC) that allows animals to move freely, promoting an increase of spontaneous physical activity (SPA) in comparison to a small cage (SC). Thus, we examined the effects of HIIT on biophysical, biomechanical and biochemical parameters of bone tissue of C57BL/6J mice living in cages of two different sizes: small (SC) or large (LC) cages with 1320 cm2 and 4800 cm2 floor space, respectively. Male mice were subdivided into two groups within each housing type: Control (C) and Trained (T). At the end of the interventions, all mice were euthanized to extract the femur bone for biophysical, biomechanical and biochemical analyses. Based a significant interaction from two-way ANOVA, trained mice kept in large cage (but not for trained mice housed in SC) exhibited a reduction of tenacity and displacement at failure in bone. This suggests that long-term HIIT program, in addition with a more active lifestyle correlates with exerts negative effects on the bone of healthy mice. A caution must also be raised about the excessive adoption of physical training, at least regarding bone tissue. On the other hand, increased calcium was found in femur of mice housed in LC. In line with this, LC-C mice were more active (i.e. SPA) than other groups. This implies that an active lifestyle without long-term high intensity physical training seems to play a role in promoting benefits to bone tissue. Our data provides new insights for treatment of osteo-health related disorders.
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Affiliation(s)
- Emanuel E. C. Polisel
- grid.411087.b0000 0001 0723 2494Laboratory of Applied Sport Physiology, School of Applied Sciences, University of Campinas, Pedro Zaccaria Street, 1.300, Jardim Santa Luíza, Limeira, SP 13484-350 Brazil
| | - Wladimir R. Beck
- grid.411247.50000 0001 2163 588XLaboratory of Endocrine Physiology and Physical Exercise, Department of Physiological Sciences, Federal University of São Carlos, São Carlos, SP Brazil
| | - Pedro P. M. Scariot
- grid.411087.b0000 0001 0723 2494Laboratory of Applied Sport Physiology, School of Applied Sciences, University of Campinas, Pedro Zaccaria Street, 1.300, Jardim Santa Luíza, Limeira, SP 13484-350 Brazil
| | - Taciane M. M. Pejon
- grid.411247.50000 0001 2163 588XLaboratory of Endocrine Physiology and Physical Exercise, Department of Physiological Sciences, Federal University of São Carlos, São Carlos, SP Brazil
| | - Claudio A. Gobatto
- grid.411087.b0000 0001 0723 2494Laboratory of Applied Sport Physiology, School of Applied Sciences, University of Campinas, Pedro Zaccaria Street, 1.300, Jardim Santa Luíza, Limeira, SP 13484-350 Brazil
| | - Fúlvia B. Manchado-Gobatto
- grid.411087.b0000 0001 0723 2494Laboratory of Applied Sport Physiology, School of Applied Sciences, University of Campinas, Pedro Zaccaria Street, 1.300, Jardim Santa Luíza, Limeira, SP 13484-350 Brazil
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Zhang J, Chang H, Yin R, Xu S, Wang H, Gao Y. A temporal study on musculoskeletal morphology and metabolism in hibernating Daurian ground squirrels (Spermophilus dauricus). Bone 2021; 144:115826. [PMID: 33348129 DOI: 10.1016/j.bone.2020.115826] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 12/14/2022]
Abstract
Hibernators provide a natural model to study the mechanisms underlying the prevention of disuse-induced musculoskeletal deterioration. Currently, however, these mechanisms remain poorly understood. Here, we investigated changes in morphology and metabolic indices in the hindlimb skeletal muscle and bone of Daurian ground squirrels (Spermophilus dauricus) during different periods of hibernation, and further explored the possible mechanisms involved in the musculoskeletal maintenance of hibernators after prolonged inactivity. Results showed that, compared with levels in the summer active group (SA), almost all morphological indices of skeletal muscle and bone, including muscle mass, muscle fiber cross-sectional area, bone mass, bone length, and bone mechanical properties, were unchanged in the different periods of hibernation. Only a few microstructural parameters of bone showed deterioration in the post-hibernation group (POST), including increased specific bone surface (+71%), decreased trabecular thickness (-43%), and decreased average cortical thickness (-51%) in the tibia, and increased trabecular separation (+60%) in the femur. Furthermore, most examined metabolic indices involved in muscle protein turnover and bone remodeling were unchanged, except for several indices in the inter-bout arousal group (IBA), i.e., increase in the phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1) (IBA vs. SA, +80%) in the vastus medialis muscle, increase in chymotrypsin-like activity (IBA vs. SA, +62%) in the tibialis anterior muscle, increase in osteoblast number (IBA vs. SA, +110%; IBA vs. torpor (TOR), +68%) and osteoclast number (IBA vs. TOR, +105%) per bone surface in the tibia, and increase in osteoclast surface per bone surface (IBA vs. TOR, +128%) in the femur. The above evidence demonstrates that the musculoskeletal morphology of squirrels was largely preserved, and musculoskeletal metabolism was generally maintained after prolonged hibernation inactivity. These findings suggest that the well-maintained musculoskeletal metabolism may be a vital mechanism underlying the preservation of the musculoskeletal system during hibernation. The coincident up-regulation of several metabolic indicators during IBA indicates that musculoskeletal metabolism may be relatively active during this period; however, its role in musculoskeletal maintenance during hibernation needs further clarification.
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Affiliation(s)
- Jie Zhang
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, Xi'an 710069, China
| | - Hui Chang
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, Xi'an 710069, China
| | - Rongrong Yin
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, Xi'an 710069, China
| | - Shenhui Xu
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, Xi'an 710069, China
| | - Huiping Wang
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, Xi'an 710069, China
| | - Yunfang Gao
- Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi'an 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Ministry of Education, Xi'an 710069, China.
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Arfat Y, Rani A, Jingping W, Hocart CH. Calcium homeostasis during hibernation and in mechanical environments disrupting calcium homeostasis. J Comp Physiol B 2020; 190:1-16. [DOI: 10.1007/s00360-019-01255-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/21/2019] [Accepted: 12/16/2019] [Indexed: 12/22/2022]
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Cravens EM, Kirkwood JS, Wolfe LM, Packer RA, Whalen LR, Wojda SJ, Prenni JE, Florant GL, Donahue SW. The effects of neurectomy and hibernation on bone properties and the endocannabinoid system in marmots (Marmota flaviventris). Comp Biochem Physiol A Mol Integr Physiol 2019; 241:110621. [PMID: 31783174 DOI: 10.1016/j.cbpa.2019.110621] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 10/15/2019] [Accepted: 11/21/2019] [Indexed: 01/26/2023]
Abstract
Hibernators have adapted a physiological mechanism allowing them to undergo long periods of inactivity without experiencing bone loss. However, the biological mechanisms that prevent bone loss are unknown. Previous studies found meaningful changes, between active and hibernating marmots, in the endocannabinoid system of many tissues, including bone. Cannabinoid receptors (CB1 and CB2) have divergent localization in bone. CB1 is predominately found on sympathetic nerve terminals, while CB2 is more abundant on bone cells and their progenitors. This study aimed to determine the contribution of innervation on endocannabinoid regulation of bone properties in hibernating (during torpor) and non-hibernating yellow-bellied marmots. Neurectomy, a model for disuse osteoporosis, was performed unilaterally in both hibernating and active marmots. Endocannabinoid concentrations were measured in bone marrow, cortical, and trabecular regions from fourth metatarsals of both hindlimbs using microflow chromatography-tandem quadrupole mass spectrometry. Trabecular bone architectural properties of fifth metatarsals were evaluated using micro-computed tomography. There were ligand-specific increases with neurectomy in active, but not hibernating, marmots. Trabecular bone architectural properties were not affected by neurectomy during hibernation, but did show some minor negative changes in active marmots. These findings suggest protection from bone loss in hibernating rodents is peripherally rather than centrally regulated. Furthermore, findings suggest even active marmots with normal metabolism are partially protected from disuse induced bone loss compared to laboratory rodents. Understanding the mechanism hibernators use to maintain bone density may guide development for novel bone loss prevention therapies.
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Affiliation(s)
- Emily M Cravens
- School of Bioengineering, Colorado State University, Fort Collins, CO, USA
| | - Jay S Kirkwood
- Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, CO, USA
| | - Lisa M Wolfe
- Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, CO, USA
| | - Rebecca A Packer
- Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Lawrence R Whalen
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Samantha J Wojda
- Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA
| | - Jessica E Prenni
- Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, CO, USA
| | - Gregory L Florant
- Department of Biology, Colorado State University, Fort Collins, CO, USA
| | - Seth W Donahue
- School of Bioengineering, Colorado State University, Fort Collins, CO, USA.
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Affiliation(s)
- Thomas E Tomasi
- Department of Biology, Missouri State University, Springfield, MO, USA
| | - Briana N Anderson
- Department of Biology, Missouri State University, Springfield, MO, USA
| | - Theodore Garland
- Department of Evolution, Ecology, and Organismal Biology, University of California – Riverside, Riverside, CA, USA
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Pineda N, Owen M, Tucker C, Wojda S, Kitchen S, Black H, Donahue S. Hibernating Little Pocket Mice Show Few Seasonal Changes in Bone Properties. Anat Rec (Hoboken) 2017; 300:2175-2183. [PMID: 28806499 DOI: 10.1002/ar.23676] [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] [Received: 12/07/2016] [Revised: 05/11/2017] [Accepted: 05/31/2017] [Indexed: 11/09/2022]
Abstract
Periods of disuse or physical inactivity increases bone porosity and decreases bone mineral density, resulting in a loss of bone mechanical competence in many animals. Although large hibernators like bears and marmots prevent bone loss during hibernation, despite long periods of physical inactivity, some small hibernators do lose bone during hibernation. Little pocket mice (Perognathus longimembris) remain underground during winter hibernation and undergo bouts of torpor and interbout arousals, but the torpor bout duration is shorter than other rodent hibernators. Additionally, little pocket mice may enter torpor during summer estivation. In this study, cortical and trabecular bone architectural, mineral, and mechanical properties were analyzed for femurs from little pocket mice captured during 8 different months (March to October) to determine seasonal effects on bone. There were no differences in any bone properties between the pre-hibernation month of October and the post-hibernation month of March, suggesting winter hibernation did not adversely affect bone properties. However, cortical area was higher in March than April, May, and June. Bone mechanical and osteocyte lacunar properties were not different between any months. Trabecular bone in the distal femoral epiphysis showed no changes between months. The distal femoral metaphyseal region showed higher trabecular spacing and lower trabecular number in May than August, otherwise, there were no differences in trabecular parameters. The few monthly differences in bone properties may be due to physical inactivity from periodic summer estivation or from the timing of birth and growth in spring and summer months. Anat Rec, 300:2175-2183, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Noellyn Pineda
- School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado.,Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado
| | - Marjorie Owen
- Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado
| | - Claire Tucker
- Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado
| | - Samantha Wojda
- Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado
| | - Stanley Kitchen
- US Forest Service, Rocky Mountain Research Station, Provo, Utah
| | - Hal Black
- Department of Plant and Wildlife Sciences, Brigham Young University, Provo, Utah
| | - Seth Donahue
- School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado.,Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado
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Sisa C, Turroni S, Amici R, Brigidi P, Candela M, Cerri M. Potential role of the gut microbiota in synthetic torpor and therapeutic hypothermia. World J Gastroenterol 2017; 23:406-413. [PMID: 28210076 PMCID: PMC5291845 DOI: 10.3748/wjg.v23.i3.406] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 11/18/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
Therapeutic hypothermia is today used in several clinical settings, among them the gut related diseases that are influenced by ischemia/reperfusion injury. This perspective paved the way to the study of hibernation physiology, in natural hibernators, highlighting an unexpected importance of the gut microbial ecosystem in hibernation and torpor. In natural hibernators, intestinal microbes adaptively reorganize their structural configuration during torpor, and maintain a mutualistic configuration regardless of long periods of fasting and cold temperatures. This allows the gut microbiome to provide the host with metabolites, which are essential to keep the host immunological and metabolic homeostasis during hibernation. The emerging role of the gut microbiota in the hibernation process suggests the importance of maintaining a mutualistic gut microbiota configuration in the application of therapeutic hypothermia as well as in the development of new strategy such as the use of synthetic torpor in humans. The possible utilization of tailored probiotics to mold the gut ecosystem during therapeutic hypothermia can also be taken into consideration as new therapeutic strategy.
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Bogren LK, Johnston EL, Barati Z, Martin PA, Wojda SJ, Van Tets IG, LeBlanc AD, Donahue SW, Drew KL. The effects of hibernation and forced disuse (neurectomy) on bone properties in arctic ground squirrels. Physiol Rep 2016; 4:4/10/e12771. [PMID: 27225624 PMCID: PMC4886160 DOI: 10.14814/phy2.12771] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 03/22/2016] [Indexed: 12/11/2022] Open
Abstract
Bone loss is a well‐known medical consequence of disuse such as in long‐term space flight. Immobilization in many animals mimics the effects of space flight on bone mineral density. Decreases in metabolism are also thought to contribute to a loss of skeletal mass. Hibernating mammals provide a natural model of disuse and metabolic suppression. Hibernating ground squirrels have been shown to maintain bone strength despite long periods of disuse and decreased metabolism during torpor. This study examined if the lack of bone loss during torpor was a result of the decrease in metabolic rate during torpor or an evolutionary change in these animals affording protection against disuse. We delineated changes in bone density during natural disuse (torpor) and forced disuse (sciatic neurectomy) in the hind limbs of the arctic ground squirrel (AGS) over an entire year. We hypothesized that the animals would be resistant to bone loss due to immobilization and disuse during the winter hibernation season when metabolism is depressed but not the summer active season. This hypothesis was not supported. The animals maintained bone density (dual‐energy X‐ray absorptiometry) and most bone structural and mechanical properties in both seasons. This was observed in both natural and forced disuse, regardless of the known metabolic rate increase during the summer. However, trabecular bone volume fraction (microcomputed tomography) in the distal femur was lower in neurectomized AGS at the study endpoint. These results demonstrate a need to better understand the relationship between skeletal load (use) and bone density that may lead to therapeutics or strategies to maintain bone density in disuse conditions.
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Affiliation(s)
- Lori K Bogren
- Chemistry and Biochemistry Department, Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska
| | - Erin L Johnston
- Chemistry and Biochemistry Department, Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska
| | - Zeinab Barati
- Chemistry and Biochemistry Department, Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska
| | - Paula A Martin
- Chemistry and Biochemistry Department, Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska
| | - Samantha J Wojda
- Mechanical Engineering Department, Colorado State University, Fort Collins, Colorado
| | - Ian G Van Tets
- Department of Biological Sciences, University of Alaska Anchorage, Anchorage, Alaska
| | | | - Seth W Donahue
- Mechanical Engineering Department, Colorado State University, Fort Collins, Colorado
| | - Kelly L Drew
- Chemistry and Biochemistry Department, Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska
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