MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.
Level 5 - mechanism / opinion, no new human data
Oxford CEBM Level 5 based on preclinical transgenic animal models and basic human physiological mechanistic testing.
PubMed 41520850 · doi:10.1016/j.freeradbiomed.2026.01.002
What was done
Researchers investigated how the mitochondrial-derived peptide MOTS-c regulates skeletal muscle mitochondrial function. They administered MOTS-c to two transgenic mouse strains to evaluate dependency on PGC-1α and AMPK, measuring mitochondrial bioenergetics, respiratory protein content, reactive oxygen species (ROS) emission, ROS-related protein damage, and transcriptional profiles via RNA sequencing. They also measured human interstitial MOTS-c levels and arterio-venous concentration differences during one-legged knee extensor exercise.
What was found
The abstract reports no numerical values, effect sizes, or confidence intervals. MOTS-c administration augmented muscle mitochondrial bioenergetic performance dependent on both PGC-1α and AMPK, without apparent changes in mitochondrial respiratory protein content. MOTS-c treatment decreased mitochondrial ROS emission and ROS-related protein damage. In humans, one-legged knee extensor exercise increased interstitial MOTS-c levels without altering the arterio-venous difference.
Why it matters
This work identifies MOTS-c as an intrinsic regulator of skeletal muscle mitochondrial efficiency and oxidative stress via AMPK and PGC-1α pathways. It also provides physiological evidence that exercising skeletal muscle may not be the primary source of circulating MOTS-c in humans.
Limits
The abstract omits sample sizes for both the mouse models and human participants, as well as specific peptide doses, quantitative effect sizes, and statistical metrics. Functional bioenergetic improvements were established in animal models and may not translate to humans, and the human arm was limited to observational exercise physiology rather than an interventional trial of MOTS-c administration.
Cited by
- partial MOTS-c improves VO2 max and exercise tolerance by upregulating energy pathways and increasing ATP production.