Impaired Mitochondrial Energetics Characterize Poor Early Recovery of Muscle Mass Following Hind Limb Unloading in Old Mice
Open accessPublished version of a preprint
Abstract
The progression of age-related sarcopenia can be accelerated by impaired recovery of muscle mass following periods of disuse due to illness or immobilization. However, the mechanisms underlying poor recovery of aged muscle following disuse remain to be delineated. Recent evidence suggests that mitochondrial energetics play an important role in regulation of muscle mass. Here, we report that 22- to 24-month-old mice with low muscle mass and low glucose clearance rate also display poor early recovery of muscle mass following 10 days of hind limb unloading. We used unbiased and targeted approaches to identify changes in energy metabolism gene expression, metabolite pools and mitochondrial phenotype, and show for the first time that persistent mitochondrial dysfunction, dysregulated fatty acid β-oxidation, and elevated H2O2 emission occur concomitantly with poor early recovery of muscle mass following a period of disuse in old mice. Importantly, this is linked to more severe whole-body insulin resistance, as determined by insulin tolerance test. The findings suggest that muscle fuel metabolism and mitochondrial energetics could be a focus for mining therapeutic targets to improve recovery of muscle mass following periods of disuse in older animals.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Aging muscles lack the metabolic flexibility to process intramyocellular lipids in the way younger muscles do, leading to lipotoxicity and associated impairments.
“we suggest a hypothesis whereby aging muscles lack the metabolic flexibility to process the IMCLs in the way that younger muscles do [62, 65, 66], leading to lipotoxicity and its associated impairments.”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [65]
Impaired metabolic flexibility with regard to both supply and demand perturbations has been reported in old age.
“Impaired metabolic flexibility with regard to both supply and demand perturbations has been reported in old age [65, 80, 89, 92]”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [65]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Sarcopenia: European consensus on definition and diagnosis
Cruz-Jentoft, A. J., Baeyens, J. P., Bauer, J. M., Boirie, Y., Cederholm, T., Landi, F., Martin, F. C., Michel, J.-P., Rolland, Y., Schneider, S. M., et al. (2010) · Age and Ageing · doi:10.1093/ageing/afq034 · Cited by 11,601 · see citing works
DAVID: Database for Annotation, Visualization, and Integrated Discovery
Dennis, G., Sherman, B. T., Hosack, D. A., Yang, J., Gao, W., Lane, H. C., & Lempicki, R. A. (2003) · Genome Biology · doi:10.1186/gb-2003-4-5-p3 · Cited by 9,327 · see citing works
Cellular energy utilization and molecular origin of standard metabolic rate in mammals
Rolfe, D. F., & Brown, G. C. (1997) · Physiological Reviews · doi:10.1152/physrev.1997.77.3.731 · Cited by 2,021 · see citing works
Koves, T. R., Ussher, J. R., Noland, R. C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J. R. B., Newgard, C. B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.013 · Cited by 1,990 · see citing works
Cellular and molecular mechanisms of muscle atrophy
Bonaldo, P., & Sandri, M. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.010389 · Cited by 1,284 · see citing works
Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives
Rolland, Y., Czerwinski, S., van Kan, G. A., Morley, J. E., Cesari, M., Onder, G., Woo, J., Baumgartner, R., Pillard, F., Boirie, Y., et al. (2008) · The Journal of nutrition, health and aging · doi:10.1007/bf02982704 · Cited by 1,071 · see citing works
Hindlimb unloading rodent model: technical aspects
Morey, E. R., & Globus, R. K. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00969.2001 · Cited by 998 · see citing works
Sandri, M., Lin, J., Handschin, C., Yang, W., Arany, Z. P., Lecker, S. H., Goldberg, A. L., & Spiegelman, B. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607795103 · Cited by 974 · see citing works
Greer, E. L., Oskoui, P. R., Banko, M. R., Maniar, J. M., Gygi, M. P., Gygi, S. P., & Brunet, A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705325200 · Cited by 820 · see citing works
Excessive Loss of Skeletal Muscle Mass in Older Adults With Type 2 Diabetes
Park, S. W., Goodpaster, B. H., Lee, J. S., Kuller, L. H., Boudreau, R., de Rekeneire, N., Harris, T. B., Kritchevsky, S., Tylavsky, F. A., Nevitt, M., et al. (2009) · Diabetes Care · doi:10.2337/dc09-0264 · Cited by 778 · see citing works
Self-citationRole of cardiolipin alterations in mitochondrial dysfunction and disease
Chicco, A. J., & Sparagna, G. C. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00243.2006 · Cited by 641 · see citing works
Mitochondrial fission and remodelling contributes to muscle atrophy
Romanello, V., Guadagnin, E., Gomes, L., Roder, I., Sandri, C., Petersen, Y., Milan, G., Masiero, E., Del Piccolo, P., Foretz, M., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.60 · Cited by 596 · see citing works
Signaling pathways controlling skeletal muscle mass
Egerman, M. A., & Glass, D. J. (2014) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.857291 · Cited by 555 · see citing works
Protecting muscle mass and function in older adults during bed rest
English, K. L., & Paddon-Jones, D. (2010) · Current Opinion in Clinical Nutrition and Metabolic Care · doi:10.1097/mco.0b013e328333aa66 · Cited by 477 · see citing works
Selective degradation of oxidatively modified protein substrates by the proteasome
Grune, T., Merker, K., Sandig, G., & Davies, K. J. A. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00809-x · Cited by 471 · see citing works
Mitochondrial quality control and muscle mass maintenance.
Romanello, V., & Sandri, M. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2015.00422 · Cited by 434 · see citing works
Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle
Muoio, D. M., & Neufer, P. D. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.010 · Cited by 343 · see citing works
Mitochondrial Structure and Function Are Disrupted by Standard Isolation Methods
Picard, M. A., Taivassalo, T., Ritchie, D., Wright, K. J., Thomas, M. M., Romestaing, C., & Hepple, R. T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018317 · Cited by 324 · see citing works
Coen, P. M., Jubrias, S. A., Distefano, G., Amati, F., Mackey, D. C., Glynn, N. W., Manini, T. M., Wohlgemuth, S. E., Leeuwenburgh, C., Cummings, S. R., et al. (2013) · The Journals of Gerontology: Series A · doi:10.1093/gerona/gls196 · Cited by 323 · see citing works
Self-citationLi, Y.-P., Chen, Y., Li, A. S., & Reid, M. B. (2003) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00129.2003 · Cited by 313 · see citing works
PROTEIN TURNOVER WITH SPECIAL REFERENCE TO MAN
Waterlow, J. C. (1984) · Quarterly Journal of Experimental Physiology · doi:10.1113/expphysiol.1984.sp002829 · Cited by 301 · see citing works
Jang, Y. C., Lustgarten, M. S., Liu, Y., Müller, F. L., Bhattacharya, A., Liang, H., Salmon, A. B., Brooks, S. V., Larkin, L. M., Hayworth, C. R., et al. (2009) · The FASEB Journal · doi:10.1096/fj.09-146308 · Cited by 290 · see citing works
Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies
Bergouignan, A., Rudwill, F., Simon, C., & Blanc, S. (2011) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00698.2011 · Cited by 272 · see citing works
Min, K., Smuder, A. J., Kwon, O.-S., Kavazis, A. N., Szeto, H. H., & Powers, S. K. (2011) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00591.2011 · Cited by 265 · see citing works
Mitochondrial signaling contributes to disuse muscle atrophy
Powers, S. K., Wiggs, M. P., Duarte, J. A., Zergeroğlu, A. M., & Demirel, H. A. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00609.2011 · Cited by 244 · see citing works
Ayala, J. E., Bracy, D. P., Julien, B. M., Rottman, J. N., Fueger, P. T., & Wasserman, D. H. (2007) · Diabetes · doi:10.2337/db06-0883 · Cited by 237 · see citing works
Self-citationAutophagy inhibition induces atrophy and myopathy in adult skeletal muscles
Masiero, E., & Sandri, M. (2010) · Autophagy · doi:10.4161/auto.6.2.11137 · Cited by 220 · see citing works
Cannavino, J., Brocca, L., Sandri, M., Bottinelli, R., & Pellegrino, M. A. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.275545 · Cited by 220 · see citing works
Oxidation enhances myofibrillar protein degradation via calpain and caspase-3
Smuder, A. J., Kavazis, A. N., Hudson, M. B., Nelson, W. B., & Powers, S. K. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.06.025 · Cited by 217 · see citing works
Brault, J. J., Jespersen, J. G., & Goldberg, A. L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.113092 · Cited by 217 · see citing works
Baehr, L. M., West, D. W. D., Marcotte, G. R., Marshall, A. G., de Sousa, L. G. O., Baar, K., & Bodine, S. C. (2016) · Aging · doi:10.18632/aging.100879 · Cited by 205 · see citing works
Molecular networks in skeletal muscle plasticity
Hoppeler, H. H. (2016) · Journal of Experimental Biology · doi:10.1242/jeb.128207 · Cited by 194 · see citing works
Joseph, A., Adhihetty, P. J., & Leeuwenburgh, C. (2016) · The Journal of Physiology · doi:10.1113/jp270659 · Cited by 186 · see citing works
Shotgun lipidomics of cardiolipin molecular species in lipid extracts of biological samples
Han, X., Yang, K., Yang, J., Cheng, H., & Gross, R. W. (2006) · Journal of Lipid Research · doi:10.1194/jlr.d500044-jlr200 · Cited by 184 · see citing works
Self-citationSuetta, C., Frandsen, U., Mackey, A. L., Jensen, L., Hvid, L. G., Bayer, M. L., Petersson, S. J., Schrøder, H. D., Andersen, J. L., Aagaard, P., et al. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.257121 · Cited by 182 · see citing works
Dardevet, D. P., Sornet, C., Taillandier, D., Savary‐Auzeloux, I., Attaix, D., & Grizard, J. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118264 · Cited by 174 · see citing works
Han, X., Yang, K., Cheng, H., Fikes, K. N., & Gross, R. W. (2005) · Journal of Lipid Research · doi:10.1194/jlr.d500007-jlr200 · Cited by 164 · see citing works
Self-citationWang, M., Han, R. H., & Han, X. (2013) · Analytical Chemistry · doi:10.1021/ac402078p · Cited by 162 · see citing works
Self-citationCoen, P. M., Menshikova, E. V., Distéfano, G., Zheng, D., Tanner, C., Standley, R., Helbling, N., Dubis, G. S., Ritov, V., Xie, H., et al. (2015) · Diabetes · doi:10.2337/db15-0809 · Cited by 155 · see citing works
Self-citationTalbert, E. E., Smuder, A. J., Min, K., Kwon, O. S., Szeto, H. H., & Powers, S. K. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00471.2013 · Cited by 138 · see citing works
Cardiolipin and Mitochondrial Function in Health and Disease
Paradies, G., Paradies, V., Ruggiero, F. M., & Petrosillo, G. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5280 · Cited by 131 · see citing works
Skeletal muscle function and hypertrophy are diminished in old age
Degens, H., & Alway, S. E. (2003) · Muscle & Nerve · doi:10.1002/mus.10314 · Cited by 125 · see citing works
Hao, Y., Jackson, J. R., Wang, Y., Edens, N., Pereira, S. L., & Alway, S. E. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00840.2010 · Cited by 124 · see citing works
Mitochondrial Biogenesis and Fragmentation as Regulators of Muscle Protein Degradation
Romanello, V., & Sandri, M. (2010) · Current Hypertension Reports · doi:10.1007/s11906-010-0157-8 · Cited by 117 · see citing works
Temporal alterations in protein signaling cascades during recovery from muscle atrophy
Childs, T. E., Spangenburg, E. E., Vyas, D. R., & Booth, F. W. (2003) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00478.2002 · Cited by 112 · see citing works
Multidimensional Mass Spectrometry-Based Shotgun Lipidomics
Wang, M., & Han, X. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-1258-2_13 · Cited by 104 · see citing works
Self-citationStephens, F. B., Chee, C., Wall, B. T., Murton, A. J., Shannon, C. E., van Loon, L. J. C., & Tsintzas, K. (2015) · Diabetes · doi:10.2337/db14-0961 · Cited by 102 · see citing works
Murton, A. J., Marimuthu, K., Mallinson, J. E., Selby, A. L., Smith, K., Rennie, M. J., & Greenhaff, P. L. (2015) · Diabetes · doi:10.2337/db15-0021 · Cited by 97 · see citing works
Aucello, M., Dobrowolny, G., & Musarò, A. (2009) · Autophagy · doi:10.4161/auto.5.4.7962 · Cited by 73 · see citing works
Wang, M., Hayakawa, J., Yang, K., & Han, X. (2014) · Analytical Chemistry · doi:10.1021/ac403798q · Cited by 67 · see citing works
Self-citationWang, M., Fang, H., & Han, X. (2012) · Analytical Chemistry · doi:10.1021/ac300695p · Cited by 63 · see citing works
Self-citationZarzhevsky, N., Carmeli, E., Fuchs, D., Coleman, R., Stein, H. J., & Reznick, A. Z. (2001) · Experimental Gerontology · doi:10.1016/s0531-5565(00)00189-3 · Cited by 57 · see citing works
Mitochondrial and skeletal muscle health with advancing age
Konopka, A. R., & Nair, K. S. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.05.008 · Cited by 54 · see citing works
Magne, H., Savary‐Auzeloux, I., Vazeille, E., Claustre, A., Attaix, D., Listrat, A., Santé-Lhoutellier, V., Gatellier, P., Dardevet, D. P., & Combaret, L. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.201707 · Cited by 42 · see citing works
Targeting mitochondrial function and proteostasis to mitigate dynapenia
Musci, R. V., Hamilton, K. L., & Miller, B. F. (2017) · European Journal of Applied Physiology · doi:10.1007/s00421-017-3730-x · Cited by 38 · see citing works
The effects of chronic muscle use and disuse on cardiolipin metabolism
Ostojić, O., O′Leary, M. F. N., Singh, K., Menzies, K. J., Vainshtein, A., & Hood, D. A. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01312.2012 · Cited by 30 · see citing works
Lee, S., Leone, T. C., Rogosa, L., Rumsey, J. W., Ayala, J. E., Coen, P. M., Fitts, R. H., Vega, R. B., & Kelly, D. P. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00380.2016 · Cited by 16 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Protective Effects of Ghrelin on Fasting-Induced Muscle Atrophy in Aging Mice
Wu, C.-S., Wei, Q., Wang, H., Kim, D. M., Balderas, M., Wu, G., Lawler, J., Safe, S., Guo, S., Devaraj, S., et al. (2020) · The Journals of Gerontology: Series A · doi:10.1093/gerona/gly256 · Cited by 81 · see citing works
Cadena, S. M., Zhang, Y., Fang, J., Brachat, S., Kuss, P., Giorgetti, E., Stodieck, L. S., Kneissel, M., & Glass, D. J. (2019) · Scientific Reports · doi:10.1038/s41598-019-45821-9 · Cited by 61 · see citing works
Targeting Intramyocellular Lipids to Improve Aging Muscle Function
Russ, D. W., Manickam, R., & Tipparaju, S. M. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02622-6 · Cited by 15 · see citing works
“Impaired metabolic flexibility with regard to both supply and demand perturbations has been reported in old age [65, 80, 89, 92] and ectopic lipid accumulation with aging, diabetes and obesity is associated with a blunted adaptation to exercise, all conditions that are associated with mitochondrial…”
- Authors
- Zhang, X., Trevino, M. B., Wang, M., Gardell, S. J., Ayala, J. E., Han, X., Kelly, D. P., Goodpaster, B. H., Vega, R. B., & Coen, P. M.
- Affiliations
- Translational Research Institute for Metabolism and Diabetes (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Coen, Paul M
- ORCID
- Venue
- The Journals of Gerontology: Series A
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03-19
- Volume
- 73
- Issue
- 10
- Pages
- 1313-1322
- ISSN
- 1079-5006 (ISSN-L)
- 1758-535X
- PMC
- PMC6132115
- OpenAlex
- W2793419639
- Cited by
- 58
- References
- 57
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 6 · 2023: 7 · 2022: 5 · 2021: 9 · 2020: 7 · 2019: 8 · 2018: 1
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journals of Gerontology Series A (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (K01 AG044437)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- sarcopenia, mitochondrial dysfunction, hindlimb unloading, disuse, muscle mass recovery, aging, insulin resistance, fatty acid beta-oxidation, hydrogen peroxide, glucose clearance, muscle energy metabolism, gene expression, metabolite pools, aged mice
- MeSH terms
- Aging, Animals, Energy Metabolism, Fatty Acids, Insulin Resistance, Male, Mice, Inbred C57BL, Mitochondria, Muscle, Muscular Atrophy, Muscle, Skeletal, Hindlimb Suspension, Mice, Metabolome, Sarcopenia, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
