MOTS-c Is an Exercise-Induced Mitochondrial-Encoded Regulator of Age-Dependent Physical Decline and Muscle Homeostasis
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Abstract
Abstract Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.
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In mouse models, MOTS-c administration has been shown to enhance physical performance across various age groups, including when treatment is initiated in older adulthood.
“In mouse models, MOTS-c administration has been shown to enhance physical performance across various age groups, including when treatment is initiated in older adulthood”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [119]
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References 90 · Cited by 199
Research works printed but not linked: 2
- [55]Kim, K. H., Son, J. M., Benayoun, B. A. & Lee, C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab.10.1016/j.cmet.2018.06.008 (2018). PMC6185997 29983246 · DOI
- [56]Li S Laher I Exercise pills: at the starting line Trends Pharmacol. Sci. 2015 36 906 917 10.1016/j.tips.2015.08.014 26439443 · DOI
- Authors
- Reynolds, J. C., Lai, R. W., Woodhead, J. S. T., Joly, J. H., Mitchell, C. J., Cameron-Smith, D., Lu, R., Cohen, P., Graham, N. A., Benayoun, B. A., Merry, T. L., & Lee, C.
- Affiliations
- University of Southern California (US)
- University of Auckland (NZ)
- University of British Columbia (CA)
- Corresponding author
- Lee, Changhan
- ORCID
- Venue
- Nature Communications
- Published
- 2021-01-20
- Volume
- 12
- Issue
- 1
- Pages
- 470-470
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7817689
- OpenAlex
- W2996207293
- Cited by
- 199
- References
- 90
- Citations by year
- 2026: 37 · 2025: 38 · 2024: 30 · 2023: 42 · 2022: 26 · 2021: 23 · 2020: 3
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG052374, P01AG034906, R01AG052258)
- American Federation for Aging Research
- USC Manning Endowment Fellowship
- USC Viterbi School of Engineering
- Marsden Fund Fast Start Grant, Rutherford Discovery Fellowship
- Ellison Medical Foundation, Hanson-Thorell family
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- MOTS-c, physical activity, aging, physical capacity, healthspan, skeletal muscle metabolism, muscle homeostasis, proteostasis, mitochondrial genome
- MeSH terms
- Adult, Aging, Animals, Cell Line, Cell Nucleus, Gene Expression Regulation, Homeostasis, Humans, Male, Mice, Inbred C57BL, Mitochondria, Mitochondria, Muscle, Stress, Physiological, Muscle, Skeletal, Mitochondrial Proteins, Myoblasts, Mice, Metabolomics, Young Adult
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