Mitochondrial-Derived Peptide MOTS-c Enhances Exercise Performance and Promotes Healthy Aging Through Improved Metabolic Regulation

by Dr. James Ross

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Metabolic Regulation by MOTS-c: Linking Plasma Biomarkers to Insulin Sensitivity

MOTS-c, a mitochondrial‐derived peptide, functions as an exercise mimetic and has been shown to improve insulin sensitivity in aged and diet-induced obese (DIO) mice. To determine its impact on circulating metabolic markers, we conducted an unbiased metabolomics analysis in DIO mice treated with MOTS-c. Our results revealed that sphingolipid, monoacylglycerol, and dicarboxylate metabolic pathways were significantly downregulated, pathways that are otherwise elevated in obesity and type 2 diabetes. Suppression of these routes was associated with reduced plasma sphingosine-1-phosphate (S1P), decreased fat accumulation in skeletal muscle, and diminished hepatic omega-oxidation. Collectively, these effects promoted enhanced fatty acid β-oxidation, lowered hepatic fat deposition, improved insulin sensitivity, and reduced blood glucose within days of treatment. These findings provide mechanistic insight into how MOTS-c regulates systemic metabolism and highlight its therapeutic potential for obesity-related insulin resistance and fatty liver disease.

MOTS-c Treatment Restores and Enhances Exercise Capacity in Aging Mice

Aging is closely linked to a gradual decline in mitochondrial function and disruption of metabolic balance, processes in which MOTS-c appears to play a regulatory role. Levels of MOTS-c are reduced in certain tissues, such as skeletal muscle, as well as in circulation during aging. Previous work demonstrated that a short, one-week administration of MOTS-c restored insulin sensitivity in aged skeletal muscle. Building on this, we examined whether MOTS-c treatment could also counteract age-related declines in physical performance by promoting metabolic homeostasis.

Middle-aged (12 months) and old (22 months) C57BL/6N mice received daily intraperitoneal MOTS-c injections (15 mg/kg/day) for two weeks before undergoing treadmill endurance testing. Both groups exhibited significantly longer running times and higher power output (joules) after treatment. In particular, treated old mice ran farther and endured longer than untreated controls. Remarkably, MOTS-c enabled 17% of old mice to complete the final high-speed stage of the treadmill test, compared to none in the untreated group. Strikingly, treated old mice even outperformed untreated middle-aged mice, indicating that MOTS-c induces broad physiological reprogramming beyond simple age-related restoration.

MOTS-c Restores Circadian Metabolic Flexibility: Implications for Age-Related Insulin Resistance

Metabolic flexibility, defined as the ability to adapt fuel utilization in response to changing energy demands such as exercise, diminishes with advancing age. In our study, respiratory exchange ratio (RER) measurements revealed a reduced day–night shift in aged mice compared to middle-aged mice, with a stronger trend toward statistical significance observed in the latter group (P = 0.076). Daytime RER, but not nighttime values, differed significantly between middle-aged and old mice, with aged animals showing a stronger reliance on carbohydrate metabolism. Remarkably, treatment with MOTS-c restored this circadian pattern in old mice, aligning their RER profile with that of middle-aged animals. These circadian-dependent effects may be partially influenced by feeding behavior, as mice predominantly consume food during the night.

To further investigate, we performed metabolomic profiling on skeletal muscle collected immediately after a 30-minute moderate-intensity treadmill run. MOTS-c treatment (two weeks) significantly altered glycolytic and amino acid metabolism in exercised mice, whereas sedentary controls showed no meaningful changes. These results suggest that MOTS-c promotes an adaptive metabolic response specifically in the context of exercise, enhancing skeletal muscle plasticity.
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Late-onset MOTS-c administration enhances healthspan in mice.

Starting interventions later in life is generally more practical for real-world application than treatments requiring lifelong use. To test this, we examined whether a late-life, intermittent regimen (initiated at about 24 months of age; administered three times per week at 15 mg/kg/day) could improve health and extend lifespan. Healthspan was assessed in very old mice, over 30 months of age, through a series of physical performance tests. The treatment led to notable improvements in grip strength, stride length, and overall mobility as measured by a timed walking test, since running was no longer feasible at this advanced stage. Taken together, the results show that late-life intermittent treatment enhances physical function in aging mice.

MOTS-c modulates gene expression in myoblasts and promotes resilience to metabolic stress.

Skeletal muscle is required to adapt to different exercise-related challenges, including imbalances in nutrient supply and demand, oxidative stress, and heat stress, with mitochondria playing a central role in these processes. Since MOTS-c has been shown to enhance cellular resistance to metabolic and oxidative stress, we examined whether it could also improve skeletal muscle adaptation under metabolic stress using C2C12 mouse myoblast cells. Cell viability was assessed through crystal violet staining, and MOTS-c treatment (10 µM) was found to significantly protect C2C12 cells from 48 hours of glucose restriction (0.5 g/L) and serum deprivation (1% FBS), providing approximately a two-fold improvement in survival.

To further evaluate functional protection, we tested the ability of C2C12 cells to replicate after prolonged metabolic stress. Cells were exposed to one week of glucose restriction and serum deprivation with daily MOTS-c treatment, followed by replenishment with complete medium for two days before staining. MOTS-c-treated cells demonstrated a markedly enhanced capacity to proliferate during recovery, showing about a six-fold increase. Because MOTS-c is linked to promoting fat utilization and supporting metabolic flexibility, we also tested whether treated C2C12 cells could survive in conditions where glucose was absent and only lipids were available. As anticipated, most untreated cells failed to survive, whereas MOTS-c treatment provided significant protection, roughly doubling survival. Metabolic flux analysis further confirmed that MOTS-c substantially increased the ability of cells to utilize lipids as an energy source.

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REFERENCES

1. Reynolds, J.C., Lai, R.W., Woodhead, J.S.T. et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 12, 470 (2021). https://doi.org/10.1038/s41467-020-20790-0
2. Kim SJ, Miller B, Mehta HH, Xiao J, Wan J, Arpawong TE, Yen K, Cohen P. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol Rep. 2019 Jul;7(13):e14171. doi: 10.14814/phy2.14171. PMID: 31293078; PMCID: PMC6640593.

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