Therapeutic Potential of MOTS-c in Metabolic Health, Physical Endurance, and Osteoporosis Prevention

by Dr. James Ross

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MOTS-c Treatment Enhances Physical Performance and Longevity in Aging Mice

Researchers investigated the effects of the exercise-related protein MOTS-c on physical performance and aging in mice. In this study, animals of different ages were given MOTS-c injections: young (2 months), middle-aged (12 months), and old (22 months). The mice were then assessed with physical tests such as balancing on a rotating rod and running on a progressively faster treadmill. Treated mice in all age groups showed significantly better performance compared to untreated controls.

Mice maintained on a high-fat diet also demonstrated improved physical capacity after receiving MOTS-c, along with reduced weight gain relative to untreated animals. These findings support earlier research indicating that MOTS-c can counteract obesity as well as insulin resistance associated with both diet and age.

Older mice nearing the end of life experienced notable improvements in grip strength, stride length, and walking ability following treatment. In treadmill tests, animals comparable in age to humans over 65 were able to double their running capacity. In several cases their performance even exceeded that of younger untreated mice.

Exercise Induces MOTS-c Expression in Human Skeletal Muscle and Plasma

To evaluate the role of MOTS-c in humans, researchers examined skeletal muscle and blood plasma samples from healthy young men who performed stationary cycling. Samples were collected before exercise, during the activity, immediately afterward, and following a four-hour recovery period.

MOTS-c levels in skeletal muscle increased nearly 12-fold during exercise and remained partially elevated after the rest period. Plasma MOTS-c also rose by about 50% during and after exercise, but returned to baseline after recovery. These results indicate that physical activity stimulates the production of mitochondrial-encoded regulatory factors.

The combined findings from human and mouse studies suggest that both mitochondrial and nuclear genes contribute to the regulation of aging. While additional investigation is necessary, the data indicate that MOTS-c may help extend the period of life spent in good health by counteracting frailty and other age-related conditions. Importantly, the improvements seen in older mice imply that interventions introduced later in life could still provide significant benefits.

Measures of human physical decline, including shorter stride length and reduced walking ability, are known predictors of morbidity and mortality. Thus, late-life therapies that restore mobility may offer a more practical path toward improving health in aging populations.

MOTS-c Promotes Osteogenesis and Bone Regeneration

Emerging evidence suggests that MOTS-c functions as a potent modulator of bone regeneration by enhancing the osteogenic potential of bone marrow mesenchymal stem cells (BMSCs). Treatment with MOTS-c upregulates osteogenesis-related markers, including ALP, Bglap, and Runx2, and markedly increases mineralization capacity. Mechanistically, these effects are mediated through the upregulation of FOXF1, which positively regulates TGF-β signaling. Silencing of FOXF1 attenuates both osteogenic differentiation and TGF-β expression, whereas restoration of TGF-β reverses these inhibitory outcomes, underscoring the critical role of the FOXF1–TGF-β axis.

In addition to accelerating fracture repair, MOTS-c has demonstrated therapeutic potential in osteoporosis. Specifically, MOTS-c promotes calcified nodule formation and significantly enhances the expression of genes associated with the TGF-β/Smad pathway, thereby driving BMSC differentiation into osteoblasts. Functional inhibition of TGF-β1 abrogates these effects, confirming the indispensability of this pathway in MOTS-c–mediated osteogenesis.

Collectively, these findings position MOTS-c as a promising regulator of skeletal homeostasis, exerting its effects through FOXF1-dependent activation of TGF-β/Smad signaling. This mechanistic framework highlights MOTS-c as a potential therapeutic candidate for both fracture healing and the treatment of osteoporosis.

MOTS-c as a Therapeutic Mediator of Mitochondrial and Systemic Health

Within both the nuclear and mitochondrial genomes, there are numerous sites containing open reading frames (ORFs) capable of encoding short peptides, typically fewer than 100 codons in length. Many peptides in eukaryotic cells are derived from larger proteins and undergo post-translational processing; however, the human genome harbors hundreds to thousands of loci with the potential to generate small peptides.

Importantly, the mitochondrial genome also contains such ORFs, some of which produce biologically active transcripts known as mitochondrial-derived peptides (MDPs). Among these, Humanin and MOTS-c are the most well-studied examples. These peptides exert systemic effects, functioning as cytoprotective agents that support mitochondrial function and preserve cellular viability under stress conditions. Experimental treatment with MOTS-c in mice has been shown to prevent age-related insulin resistance and to counteract diet-induced obesity.

Mitochondria, traditionally regarded as energy-producing organelles, are now increasingly recognized as regulators of systemic signaling. Recent discoveries reveal that they encode a broader genetic repertoire than previously appreciated. The identification of Humanin and MOTS-c, both derived from mitochondrial DNA, highlights their role in redefining the functional scope of mitochondria beyond intracellular energy metabolism.

Given their central role, mitochondria are also highly responsive to both intrinsic stressors, such as nuclear or mitochondrial DNA mutations and deletions, fluctuations in energy substrate availability, and elevated reactive oxygen species (ROS), and extrinsic stressors, including toxins, pathogens, and ultraviolet radiation. These factors can disrupt mitochondrial function and dynamics, which are essential for coordinating multiple cellular pathways and ensuring sufficient energy supply for adaptive responses to stress.

Thermogenic and Lipid-Regulating Effects of MOTS-c: Implications for Obesity and Metabolic Health

MOTS-c indirectly inhibits purine biosynthesis, leading to an accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an intermediate in this pathway. Elevated AICAR levels activate AMP-activated protein kinase (AMPK), which promotes fatty acid oxidation. AMPK also suppresses acetyl-CoA carboxylase, an enzyme that converts acetyl-CoA to malonyl-CoA. Since malonyl-CoA normally exerts an allosteric inhibitory effect on carnitine palmitoyltransferase 1 (CPT1), its reduction permits greater fatty acid transport into mitochondria for β-oxidation. Collectively, these catabolic effects enhance lipolysis, diminish lipogenesis, and increase glucose uptake.

Beyond these metabolic effects, AMPK stimulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a transcriptional coactivator. PGC-1α regulates nuclear genes involved in mitochondrial biogenesis, including nuclear respiratory factors NRF-1 and NRF-2 as well as members of the peroxisome proliferator-activated receptor (PPAR) family. Among the downstream targets of NRF-1 is mitochondrial transcription factor A (TFAM), which localizes to mitochondria and enhances transcription of mitochondrial genes, thereby supporting mitochondrial biogenesis and function.

Animal studies provide further insight into the systemic effects of MOTS-c. Rodents receiving MOTS-c treatment exhibited increased energy expenditure and heat production, paralleling the activity of uncoupling proteins (UCPs). These proteins are typically upregulated by adrenergic stimulation of brown adipose tissue, which elevates cyclic AMP (cAMP) signaling. This cascade activates AMPK, stimulates lipolysis, and upregulates UCP-1 transcription. The resulting non-shivering thermogenesis involves the dissipation of heat through proton leakage across the inner mitochondrial membrane, uncoupling oxidative phosphorylation from ATP production. This mechanism explains the observed rise in both heat generation and energy expenditure.

If MOTS-c indeed enhances the expression and activity of UCPs, it represents a potentially novel mechanism for regulating thermogenesis and systemic energy balance, warranting further investigation.

A Systems Approach to Enhance Catabolism While Safeguarding Bone and Glucose Metabolism

Previous work from our group has demonstrated that ovariectomy induces dyslipidemia and increased body mass, both of which are associated with a higher risk of developing metabolic syndrome. In these studies, a resistance training (RT) protocol was effective in reducing such risks. Similarly, Lu et al. reported that ovariectomized rats treated with MOTS-c were protected against body mass gain. In addition, the OVX-MOTS-c group exhibited enhanced activity of brown adipose tissue (BAT), as indicated by elevated mitochondrial markers, including increased expression of PGC-1α, UCP-1, and greater mitochondrial crista density. Interestingly, our own investigations have also shown that RT increased PGC-1α expression in skeletal muscle of ovariectomized animals, paralleling the effects of MOTS-c, though observed in different tissues.

Another well-established effect of RT is its ability to prevent and mitigate osteoporosis and osteopenia commonly observed under low-estrogen conditions, both in ovariectomized animal models and in human studies. In this context, MOTS-c displayed exercise-mimicking properties by significantly preventing ovariectomy-induced bone loss, as assessed by micro-CT. This bone-protective effect was associated with suppression of RANKL-induced osteoclast formation through AMPK activation. Furthermore, MOTS-c reduced osteoclast differentiation and lowered proinflammatory cytokine production in animal models, effects comparable to those induced by physical exercise.

A further mechanism warranting attention is the ability of MOTS-c to elevate intracellular levels of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide). As highlighted in studies by Lee et al., cultured cells exposed to MOTS-c exhibited reduced levels of active folate (5Me-THF), a cofactor in nucleotide biosynthesis. This reduction in 5Me-THF led to increased AICAR accumulation, a key intermediate in de novo nucleotide synthesis with broad metabolic functions.

AICAR is a known AMPK agonist, extensively studied in animal models. AMPK activity typically rises when ATP availability declines. Downstream targets of AMPK include PPAR-α, PPAR-δ, and PGC-1α, which together promote catabolic processes that increase energy production, resembling the adaptations observed with exercise. In fact, AICAR administration enhanced treadmill performance in mice by 44% compared to controls, mimicking endurance adaptations.

Physical exercise activates similar signaling cascades by increasing energy demand, which elevates the AMP/ATP ratio, thereby activating AMPK, PGC-1α, and PPAR-γ.

These shared pathways may represent the connection between MOTS-c signaling and mitochondrial adaptations that facilitate cellular energy supply while promoting beneficial metabolic remodeling. Both MOTS-c and physical exercise have been shown to improve glucose tolerance, enhance metabolic health under high-fat diets, and elevate AICAR levels, ultimately leading to AMPK activation. Taken together, these findings suggest that MOTS-c and physical exercise engage interconnected molecular pathways. Whether MOTS-c should be considered a signaling mediator of exercise remains an open question and a promising direction for future research.

References

1. Weng FB, Zhu LF, Zhou JX, Shan Y, Tian ZG, Yang LW. MOTS-c accelerates bone fracture healing by stimulating osteogenesis of bone marrow mesenchymal stem cells via positively regulating FOXF1 to activate the TGF-β pathway. Eur Rev Med Pharmacol Sci. 2019 Dec;23(24):10623-10630. doi: 10.26355/eurrev_201912_19759. Retraction in: Eur Rev Med Pharmacol Sci. 2021 Mar;25(6):2459. doi: 10.26355/eurrev_202103_25396. PMID: 31858528.
2. Hu BT, Chen WZ. MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway. Eur Rev Med Pharmacol Sci. 2018 Nov;22(21):7156-7163. doi: 10.26355/eurrev_201811_16247. PMID: 30468456.
3. Humanin, MOTS-c and physical exercise: A new perspective

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