MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, +4 more
Nature Communications (2021)
Acute exercise raised skeletal-muscle MOTS-c expression nearly 12-fold and circulating MOTS-c by approximately 50% in human volunteers; exogenous MOTS-c administered to mice approximately doubled treadmill running capacity at young, middle-aged, and old time points — the strongest single-paper integration of MOTS-c human physiology and mouse pharmacology to date.
This 2021 Nature Communications paper from the Cohen and Lee laboratories (the same group as the original 2015 discovery paper, Lee 2015) is the most consequential MOTS-c follow-up to date and the foundation for the "exercise mimetic" framing of the molecule in contemporary metabolic and longevity discourse. The authors integrate human exercise physiology with mouse pharmacology across three age cohorts. In human volunteers, an acute exercise bout increased MOTS-c expression in skeletal muscle approximately 12-fold and elevated circulating MOTS-c by approximately 50% during and shortly after exercise, with partial elevation persisting at four hours of rest. In mice, exogenous MOTS-c administration approximately doubled treadmill running capacity in young (2 months), middle-aged (12 months), and old (22 months) cohorts — a striking finding given that the typical age-dependent performance decline in mice is what most longevity interventions target. The paper also demonstrates that endogenous skeletal-muscle and circulating MOTS-c levels decline with age in mice, that MOTS-c regulates a subset of nuclear genes related to metabolism and proteostasis after nuclear translocation, and that late-life MOTS-c treatment improved both performance and healthspan markers in old mice. Together with Lee 2015, this paper is the foundation for nearly every current claim that MOTS-c is meaningfully exercise-related.
The human findings are descriptive — they establish that exercise induces endogenous MOTS-c, but they do not establish that exogenous MOTS-c administration improves human exercise capacity. The mouse running-capacity findings are striking but rodent treadmill performance is influenced by training paradigm, motivation, and handling variability; replication in independent laboratories at the same effect-size magnitudes is the next step the field has not yet fully delivered. The "exercise-mimetic" framing — that taking MOTS-c could substitute for exercise — is a substantial inferential leap from what the paper shows, which is that exercise raises MOTS-c and that MOTS-c improves rodent performance. The paper does not address chronic-administration safety, interaction with cancer biology (an open question for any AMPK-activating intervention), or interaction with anti-diabetic pharmacotherapy in humans. Pinchas Cohen has commercial interests in MOTS-c development through CohBar Inc., which is appropriately disclosed but which readers should note. Like the rest of the MOTS-c literature, the paper has zero direct evidence that the rodent effect sizes translate to humans through exogenous dosing.
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