MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis

Joseph C. Reynolds, Rochelle W. Lai, Jonathan S. T. Woodhead, James H. Joly, Cameron J. Mitchell, David Cameron-Smith, Ryan Lu, Pinchas Cohen, Nicholas A. Graham, Bérénice A. Benayoun, Troy L. Merry and Changhan Lee ()
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Joseph C. Reynolds: Leonard Davis School of Gerontology, University of Southern California
Rochelle W. Lai: Leonard Davis School of Gerontology, University of Southern California
Jonathan S. T. Woodhead: Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland
James H. Joly: USC Mork Family Department of Chemical Engineering and Materials Science
Cameron J. Mitchell: The University of Auckland
David Cameron-Smith: The University of Auckland
Ryan Lu: Leonard Davis School of Gerontology, University of Southern California
Pinchas Cohen: Leonard Davis School of Gerontology, University of Southern California
Nicholas A. Graham: USC Mork Family Department of Chemical Engineering and Materials Science
Bérénice A. Benayoun: Leonard Davis School of Gerontology, University of Southern California
Troy L. Merry: The University of Auckland
Changhan Lee: Leonard Davis School of Gerontology, University of Southern California

Nature Communications, 2021, vol. 12, issue 1, 1-11

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.

Date: 2021
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DOI: 10.1038/s41467-020-20790-0

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