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

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.