MOTS-c is an Exercise-Induced Mitochondrial-Encoded Regulator of Age-Dependent Physical Decline and Muscle Homeostasis

Aging is the leading risk factor for multiple non-communicable chronic diseases. Age-related physiological deterioration is underlined by a progressive loss of cellular homeostasis and physical capacity. Healthy aging can be promoted by preemptively enhancing physical capacity and metabolic fitness. Mitochondria are chief metabolic organelles with strong implications in aging. In addition to their prominent role in bioenergetics, mitochondria also coordinate broad physiological functions by communicating to other cellular compartments or distal cells, using multiple factors including peptides that are encoded within their own independent genome. However, it is unknown if aging is actively regulated by factors encoded in the mitochondrial genome. MOTS-c is a mitochondrial-encoded peptide that regulates metabolic homeostasis, in part, by translocating to the nucleus to regulate adaptive nuclear gene expression in response to cellular stress. Here, we report that MOTS-c is an exercise-induced mitochondrial-encoded peptide that significantly enhanced physical performance when administered to young (2 mo.), middle-aged (12 mo.), and old (22 mo.) mice. In humans, we found that endogenous MOTS-c levels significantly increased in response to exercise in skeletal muscle (5-fold) and in circulation (1.5-fold). Systemic MOTS-c treatment in mice significantly enhanced the performance on a treadmill of all age groups (~2-fold). MOTS-c regulated (i) nuclear genes, including those related to metabolism and protein homeostasis, (ii) glucose and amino acid metabolism in skeletal muscle, and (iii) myoblast adaptation to metabolic stress. Notably, a statistical enrichment analysis on our RNA-seq data, from both mouse skeletal muscle and myoblasts, revealed heat shock factor 1 (HSF1) as a putative transcriptional factor that could regulate gene expression upon MOTS-c treatment. Indeed, siRNA-mediated HSF1 knockdown reversed MOTS-c-dependent stress resistance against glucose restriction/serum deprivation. Ultimately, late-life initiated intermittent MOTS-c treatment (23.5 months; 3x/week) improved overall physical capacity and trended towards increasing lifespan. Our data indicate that aging is regulated by genes that are encoded not only in the nuclear genome, but also in the mitochondrial genome. Considering that aging is the major risk factor for multiple chronic diseases, our study provides new grounds for further investigation into mitochondrial-encoded regulators of healthy lifespan that could also provide novel therapeutic targets of mitochondrial basis.