MOTS ‐c increases in skeletal muscle following long‐term physical activity and improves acute exercise performance after a single dose

Abstract

Skeletal muscle adapts to aerobic exercise training, in part, through fast‐to‐slow phenotypic shifts and an expansion of mitochondrial networks. Recent research suggests that the local and systemic benefits of exercise training also may be modulated by the mitochondrial‐derived peptide, MOTS‐c. Using a combination of acute and chronic exercise challenges, the goal of the present study was to characterize the interrelationship between MOTS‐c and exercise. Compared to sedentary controls, 4–8 weeks of voluntary running increased MOTS‐c protein expression ~1.5‐5‐fold in rodent plantaris, medial gastrocnemius, and tibialis anterior muscles and is sustained for 4–6 weeks of detraining. This MOTS‐c increase coincides with elevations in mtDNA reflecting an expansion of the mitochondrial genome to aerobic training. In a second experiment, a single dose (15 mg/kg) of MOTS‐c administered to untrained mice improved total running time (12% increase) and distance (15% increase) during an acute exercise test. In a final experiment, MOTS‐c protein translocated from the cytoplasm into the nucleus in two of six mouse soleus muscles 1 h following a 90‐min downhill running challenge; no nuclear translocation was observed in the plantaris muscles from the same animals. These findings indicate that MOTS‐c protein accumulates within trained skeletal muscle likely through a concomitant increase in mtDNA. Furthermore, these data suggest that the systemic benefits of exercise are, in part, mediated by an expansion of the skeletal muscle‐derived MOTS‐c protein pool. The benefits of training may persist into a period of inactivity (e.g., detraining) resulting from a sustained increase in intramuscular MOTS‐c proteins levels.

Circulating levels of mitochondrial oxidative stress-related peptides MOTS-c and Romo1 in stable COPD: A cross-sectional study

“…Lower levels of circulating MOTS-c were associated with shorter distances walked in the 6MWT, specifically with walking < 350 m, a parameter that is associated with the risk of death in COPD ( 6 ) and more profound OD. Exercise induces MOTS-c synthesis in healthy individuals ( 13 , 30 ); MOTS-c in turn activates the synthesis of other enzymes (such as AMP-activated protein kinase) known to be induced by exercise ( 11 , 31 ). On the other hand, it has been reported recently that MOTS-c promotes muscle differentiation of muscle progenitor cells ( 32 ).…”

Small peptides: could they have a big role in metabolism and the response to exercise?

“…In addition to exercise-induced changes in MOTS-c, a few studies have also investigated training-induced changes in MOTS-c in humans and mice. For example, training-induced increases in the skeletal muscle and plasma concentrations of MOTS-c in mice were reported after 4-8 weeks of treadmill running (Guo et al, 2020;Hyatt, 2022;Yang et al, 2021). In breast cancer survivors, Dieli-Conwright et al (2021) reported that 16 weeks of resistance training combined with aerobic training significantly increased (1.6-fold) resting plasma MOTS-c protein levels.…”

“…However, data from various animal models have shown that the administration of exogenous MDPs and analogues improved metabolic function in adipose tissue, liver, brain, pancreas, heart and skeletal muscle (Cobb et al., 2016; Hoang et al., 2010; Xu et al., 2008; Zhong et al., 2022). Furthermore, a few studies have reported increased protein levels of MDPs, both in the circulation and in skeletal muscle, after exercise and exercise training (Hyatt, 2022; von Walden et al., 2021; Woodhead & Merry, 2021; Woodhead et al., 2020). These studies emphasize the potential significance of the release of MDPs from the skeletal muscle, facilitating communication with various tissues and organs.…”

Mitochondrial stress and mitokines in aging

“…Just like for the nuclear mitokines, circulating and muscle mitochondrial derived peptide levels, in particular of humanin (Woodhead et al, 2020 ) and MOTS‐c (Hyatt, 2022 ; Reynolds et al, 2021 ), have been reported to be exercise‐responsive both in mice and in humans (von Walden et al, 2021 ). For instance, circulating HN and MOTS‐c plus muscle MOTS‐c expression were examined in recreationally active adults after an acute bout of endurance and resistance exercise, the two major types of exercise modalities (von Walden et al, 2021 ).…”