Peptides Released by Mitochondria During Exercise May Explain Some of Its Health Benefits

Acute high-intensity exercise increases concentrations of the mitochondrial-derived peptides (MDPs) humanin and MOTS-c in human skeletal muscle and plasma. MOTS-c treatment in mice improved exercise capacity and performance in both young and aged animals, producing adaptations similar to physical activity — including weight loss, increased antioxidant capacity, and improved insulin sensitivity. However, studies using a MOTS-c inactivating genetic variant and combination exercise + MOTS-c treatment suggest distinct and overlapping pathways between exercise and MOTS-c benefits. Evidence for chronic training effects on MDP expression is conflicting and appears to depend on exercise mode, duration, intensity, and participant characteristics.

Narrative review synthesizing evidence from human exercise studies (acute and chronic) and mouse models examining the effects of exercise on mitochondrial-derived peptide expression and the effects of exogenous MOTS-c treatment on exercise capacity and metabolic parameters.

This review reveals that mitochondria communicate their status during exercise stress by releasing small peptides encoded in mitochondrial DNA — a newly recognized signaling mechanism. The finding that MOTS-c can mimic some exercise benefits in mice (including in aged animals) raises the possibility of developing peptide-based therapies that could provide exercise-like metabolic benefits for people who cannot exercise due to age, disability, or illness.

The discovery of mitochondrial-derived peptides as exercise-responsive signaling molecules adds a new dimension to our understanding of how exercise produces health benefits. It also opens the door to 'exercise mimetics' — molecules that could provide some exercise benefits to people unable to be physically active. MOTS-c in particular has attracted attention as a potential therapeutic for age-related metabolic decline, and this review establishes its connection to the exercise response.

This is a review article, not a primary study. The evidence for chronic training effects on MDPs is conflicting. Most MOTS-c treatment studies are in mice, and human clinical data is limited. The review notes that MDPs beyond MOTS-c have not been well-studied for exercise-mimetic properties, leaving much of the landscape unexplored.