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

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.

Stress and circulating cell-free mitochondrial DNA: A systematic review of human studies, physiological considerations, and technical recommendations

“…Beyond steroidogenesis in the mitochondrial matrix, mitochondria contain their own genome from which small mtDNA-encoded peptides are synthesized (e.g., MOTS-c, humanin) ( Yen et al, 2020 ; Lee et al, 2015 ; Reynolds et al, 2020a ), and released in the systemic circulation in response to challenges to optimize metabolic regulation. Thus, mitochondria-derived signaling molecules – or mitokines – likely play a significant role in human physiology and stress adaptation ( Reynolds et al, 2020b ).…”

The Role of the Skeletal Muscle Secretome in Mediating Endurance and Resistance Training Adaptations

“…As a new class of circulating signaling molecules, skeletal muscle-produced and -secreted MDPs could potentially be involved in training adaptation. Indeed, both mice and human participants showed increased MOTS-c expression in skeletal muscle as well as increased circulating levels upon acute endurance exercise ( Reynolds et al, 2021 ; Yang et al, 2021 ). Similarly, the MDP humanin increased in muscle and plasma of healthy young men following acute high-intensity cycling.…”

“…However, the intracellular mechanisms regulating MDP production and secretion during exercise are still unknown, even though a responsiveness to signals associated with cellular energy stress occurring in exercised muscles is conceivable ( Merry et al, 2020 ). Moreover, despite the training-like effects of systemic MOTS-c treatment on endurance performance in mice ( Reynolds et al, 2021 ), the role and molecular targets of exercise-induced MDPs as well as their auto-, para- and endocrine relevance in mediating physiological training adaptation has yet to be established. Kumagai et al (2021) suggested that MOTS-c could act as a myostatin inhibitor by increasing Akt activity via activation of mTORC2 and inhibition of phosphatase and tensin homolog (PTEN) through casein kinase 2 (CK2) activation.…”

Mitochondrial nucleoid in cardiac homeostasis: bidirectional signaling of mitochondria and nucleus in cardiac diseases

“…Recent research has reported that MOTS-c translocates from mitochondria into the nucleus in response to glucose restriction, leading to retrograde signaling [ 118 , 184 ]. MOTS-c can bind to nuclear genomic DNA and interact with transcription factor Nrf2 to activate gene transcription, resulting in increased cellular resistance to metabolic stress [ 118 ].…”

“…MOTS-c can bind to nuclear genomic DNA and interact with transcription factor Nrf2 to activate gene transcription, resulting in increased cellular resistance to metabolic stress [ 118 ]. Reynolds et al in 2021 found that MOTS-c is an exercise-induced mitochondrial-encoded regulator of muscle homeostasis which can regulate the nuclear genes involved in metabolism and proteostasis, thereby significantly improving physical performance in young, middle-aged, and old mice [ 184 ]. Moreover, administration of MTOS-c at late-life (23.5 months) can increase the lifespan of old mice.…”