Scientists discovered that physical exercise triggers the production of a molecule called MOTS-c directly within the mitochondria. Now, researchers are investigating what happens when that signal is amplified, or when it fades with age.
There is a question that exercise biologists have carried for decades without fully answering: why does moving the body do good to everything? To the heart, the brain, metabolism, mood, longevity. The answer is obviously not simple, but a discovery made in 2015 by researchers at the University of Southern California (USC) added a surprising piece to the puzzle.
Exercise, beyond everything already known, appears to activate a kind of chemical messenger inside muscle cells. That messenger has a name: MOTS-c. And its origin is as unusual as its function.
A molecule born from the mitochondria
Most of the body’s signaling molecules are produced according to instructions from the DNA in the cell nucleus, the “headquarters” that controls most of the cell’s operations. MOTS-c is different. It is encoded by the mitochondrial genome, a small circuit of DNA that the mitochondria carry independently, an inheritance from a bacterial symbiosis that occurred more than a billion years ago.
This places it in an extremely small class of molecules called Mitochondrial-Derived Peptides. MOTS-c is the only compound in the Axion catalog with this origin. In practical terms, it means that when the mitochondria sense intense energy demand, as happens during physical exercise, they have the capacity to produce their own signal. A voice of their own inside the cell.
“Exercise triggers the endogenous expression of MOTS-c in skeletal muscle and in circulation.”, Reynolds et al., Nature Communications, 2021
What science already knows about MOTS-c and exercise
In 2021, a study published in Nature Communications by Reynolds and colleagues documented something that opened a new research direction: physical exercise increases MOTS-c levels both in skeletal muscle and in the bloodstream of human beings. The data are observational, that is, they measure the behavior of endogenous MOTS-c in response to exercise, not the effect of exogenous administration of the molecule, but the correlation is clear and replicated.
In the same study, researchers tested the effect of intermittent MOTS-c treatment in aged mice (23.5 months, the equivalent of elderly). The treated animals showed greater physical capacity and better-preserved indicators of muscle homeostasis than controls. The study cannot be extrapolated directly to humans, and the authors are the first to emphasize this, but the convergence between what exercise does in the organism and what MOTS-c appears to signal is at the center of current scientific interest.
The hypothesis moving the field
The question researchers are now investigating can be framed directly: if exercise raises MOTS-c levels and those levels have documented metabolic effects in animal models, what happens when this signaling pathway is studied in greater depth?
That question is far from a definitive answer. No clinical trial with native MOTS-c in humans had been completed and published as of April 2026. What exists, beyond the animal models, are observational and mechanistic data that, in the language of biology, build a solid base of hypotheses.
The emerging field of Mitochondrial-Derived Peptides, led by researchers such as Changhan Lee and Pinchas Cohen at USC, is today one of the most active areas of aging biology. MOTS-c is its anchor compound, the most studied, the most cited, the one that opened the doors to an entire new category of signaling molecules of mitochondrial origin.
If the mechanisms observed in animal models are confirmed in human populations, MOTS-c may represent one of the most relevant directions of research in exercise biology and energy metabolism.
What this means for research
For researchers investigating metabolism, muscle aging, or exercise biology, MOTS-c represents an object of study with unusual characteristics: an endogenous molecule, naturally produced in response to physical activity, with a mechanism of action well described in the preclinical literature and a documented decline with age.
This combination, naturally produced, responsive to energy stress, declining with aging, is exactly the kind of profile that draws interest in laboratories of geroscience, exercise physiology, and metabolic endocrinology. It is no accident that the MDP research field has grown consistently over the past decade, with MOTS-c at its center.
