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

The takeaway

Mitochondrial-derived peptides like MOTS-c and humanin are released during exercise and may act as signaling molecules that help coordinate the body's adaptive response, with MOTS-c showing exercise-mimicking benefits in mice.

MOTS-c improved exercise capacity in aged mice
Producing exercise-like benefits including weight loss, enhanced antioxidant capacity, and improved insulin sensitivity — through both shared and distinct pathways compared to actual exercise

What the researchers found

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.

Why it matters

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 numbers in context

2 key MDPs studied (humanin, MOTS-c) · Benefits in both young and aged mice · Weight loss + antioxidant capacity + insulin sensitivity with MOTS-c · Distinct + overlapping pathways with exercise

How the study worked

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.

Who was studied

Review covering human exercise studies and mouse models examining mitochondrial-derived peptides

What this study cannot tell us

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.

How to read the evidence

This is a narrative review synthesizing findings from human exercise studies and animal experiments. The human data on MDP responses to exercise is relatively new and sometimes conflicting, while the most compelling MOTS-c treatment data comes from mouse models. No clinical trials of MDP therapy in humans are discussed.

When this study was published

Published in 2021, this review captures the early stages of research into mitochondrial-derived peptides as exercise-responsive molecules. The field has continued to develop, with ongoing interest in MOTS-c as a potential therapeutic.

The bigger picture

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.

Questions still open

Could MOTS-c or other mitochondrial-derived peptides be developed as therapies for people who cannot exercise due to aging, disability, or chronic illness?
Do mitochondrial-derived peptides beyond humanin and MOTS-c also respond to exercise and have exercise-mimetic properties?
What determines whether chronic exercise training increases or decreases MDP levels — is it the type, intensity, or duration of training?

Common questions

What are mitochondrial-derived peptides and why are they important?

Mitochondrial-derived peptides (MDPs) are small peptides encoded by short genes within mitochondrial DNA — separate from the cell's main nuclear DNA. They act as signaling molecules that communicate the mitochondria's status to the rest of the cell and to other tissues. The best-studied MDPs are humanin (linked to cell protection and longevity) and MOTS-c (linked to metabolism and exercise response).

Could a peptide pill ever replace exercise?

Not likely as a complete replacement — exercise affects virtually every organ system through hundreds of mechanisms. However, MOTS-c and similar peptides could potentially provide some exercise-like metabolic benefits for people who are unable to exercise. This review shows that MOTS-c and exercise share some pathways but also work through distinct mechanisms, suggesting peptides could complement rather than substitute for physical activity.

Read the original research

Mitochondrial-derived peptides and exercise.

Biochimica et biophysica acta. General subjects, 1865(12), 130011

View on PubMed ↗Publisher’s paper ↗

Citation

Woodhead, Jonathan S T; Merry, Troy L. (2021). Mitochondrial-derived peptides and exercise.. Biochimica et biophysica acta. General subjects, 1865(12), 130011. https://doi.org/10.1016/j.bbagen.2021.130011