Research in plain language
MOTS-c
What it is
MOTS-c is a 16-amino-acid peptide encoded inside the mitochondrial 12S rRNA gene. In animal studies it activates the cellular energy sensor AMPK and is studied mainly for improving insulin sensitivity, reversing diet- and age-related metabolic decline, and boosting exercise/running capacity. In humans it is mostly studied as a naturally circulating peptide that rises with exercise, not yet as an administered drug.
How studies used it
- Model
- Mouse (C57BL/6, young and aged; also high-fat-diet fed)
- Studied for
- Diet-induced obesity and insulin resistance (metabolic)
- Dose
- 5 mg/kg/day for the short glucose/insulin-sensitivity experiments; 0.5 mg/kg/day for the 8-week obesity-prevention experiment
- Dosing
- Once daily
- Route
- Intraperitoneal
- Duration
- 7 days (insulin-sensitivity arm) and 8 weeks (high-fat-diet obesity-prevention arm)
Effects measured: MOTS-c improved glucose tolerance and insulin sensitivity in glucose-tolerance and hyperinsulinemic-euglycemic clamp tests. In the 8-week high-fat-diet arm at 0.5 mg/kg/day, treated mice were protected against diet-induced obesity (lower body weight gain) and against high-fat-diet-induced insulin resistance and hyperinsulinemia. Mechanistically the peptide acted largely in skeletal muscle, inhibiting the folate-purine cycle and activating AMPK.
Side effects: No adverse events reported in this study
- Model
- Mouse (male C57BL/6J, ~17 weeks, high-fat diet since 5 weeks of age)
- Studied for
- High-fat-diet insulin resistance and plasma metabolite profile (metabolic)
- Dose
- 2.5 mg/kg per dose
- Dosing
- Twice daily
- Route
- Intraperitoneal
- Duration
- 3 consecutive days
Effects measured: Treated mice showed a significant reduction in blood glucose versus controls, and insulin and leptin trended lower. Untargeted metabolomics showed MOTS-c reduced plasma metabolites in sphingolipid, monoacylglycerol and dicarboxylate pathways, consistent with improved insulin sensitivity. Effects were seen after only 3 days.
Side effects: No adverse events reported in this study
- Model
- Mouse (C57BL/6 at 2, 12 and 22 months; plus very old >30 months for the late-life arm)
- Studied for
- Age-dependent physical decline and exercise capacity (exercise/metabolic)
- Dose
- 5 mg/kg/day and 15 mg/kg/day
- Dosing
- Once daily for the acute treadmill arms; intermittent 3 times per week for the late-life arm
- Route
- Intraperitoneal
- Duration
- About 2 weeks for the acute treadmill arms; ongoing from ~23.5 months of age for the late-life longevity/healthspan arm
Effects measured: On the high dose (15 mg/kg/day), 100% of young treated mice reached the top sprint speed (23 m/min) versus 16.6% of controls. Old treated mice ran roughly 2-fold longer in time and about 2.16-fold farther in distance than controls. Late-life intermittent dosing (3x/week) in very old mice improved grip strength, stride length and 60-second walking capacity. The paper also reported that in humans acute exercise raised MOTS-c about 11.9-fold in skeletal muscle and roughly 1.5 to 1.6-fold in circulation (this human arm was observational, no peptide given).
Side effects: No adverse events reported in this study
- Model
- Rat (female Sprague-Dawley, ~120 g) and mouse (female C57BL/6J, 10-11 weeks)
- Studied for
- Acute exercise/endurance performance (exercise capacity)
- Dose
- 15 mg/kg
- Dosing
- Single dose given about 10 minutes before the exercise test
- Route
- Intraperitoneal
- Duration
- Single dose (acute test); chronic arm used 4-8 weeks of voluntary running, not peptide dosing
Effects measured: A single 15 mg/kg dose 10 minutes before testing increased total running time by about 12% and running distance by about 15% in untrained mice. No saline-injected mouse finished the 40-minute test, whereas 5 of 6 MOTS-c-treated mice did. Separately, 4-8 weeks of voluntary running (no peptide) raised endogenous skeletal-muscle MOTS-c protein 1.5 to 5-fold, with elevation persisting weeks into detraining.
Side effects: No adverse events reported in this study
- Model
- Human, professional endurance athletes (75 athletes, 63 male/12 female) vs 30 sedentary age- and BMI-matched controls
- Studied for
- Association of habitual endurance exercise with circulating MOTS-c (exercise physiology, observational)
- Dose
- Not applicable: observational study, no MOTS-c was administered. Reported endogenous serum levels were about 2.36 ng/mL (low/moderate endurance) and 2.22 ng/mL (high endurance) versus 3.89 ng/mL in controls
- Dosing
- Not applicable (no dosing; single cross-sectional blood draw)
- Route
- Not applicable (endogenous measurement, no administration)
- Duration
- Cross-sectional (single time point)
Effects measured: Professional athletes had significantly LOWER serum MOTS-c than sedentary controls (p=0.0001), the opposite direction of an acute-exercise spike. This shows the human exercise-MOTS-c relationship is complex (chronic training associated with lower resting levels) and is correlational, not causal.
Side effects: No adverse events reported in this study
How solid the evidence is
Evidence is dominated by ANIMAL work and is mostly from a single research group (Pinchas Cohen / Changhan Lee at USC) plus its collaborators, so it is not yet independently broad. The metabolic and exercise mouse studies (PMID 25738459, 31293078, 33473109) are consistent and use clear per-kg intraperitoneal dosing (0.5 to 15 mg/kg/day), but mouse mg/kg does not translate directly to a human dose, and group sizes in some arms are small. The single-dose performance study (PMID 35808870, 15 mg/kg) is a small rodent study (5-6 mice per group) and partly in rats. There are NO human interventional dosing trials of MOTS-c: humans only appear as observational data. Importantly the human evidence is mixed and partly contradictory: Reynolds (33473109) reports acute exercise transiently RAISES MOTS-c, while the athlete cross-sectional study (39077591) found chronically trained athletes have LOWER resting serum MOTS-c than sedentary controls, which weakens any simple "more MOTS-c is better" narrative. Net: promising and mechanistically coherent in mice, but no human efficacy or safety dosing data, single-lab concentration, and a notable human observational result pointing the opposite way. All five PMIDs and citations were verified against NCBI records.
Sources
- Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015.(PMID 25738459)
- Kim SJ, et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiological Reports. 2019.(PMID 31293078)
- Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021.(PMID 33473109)
- Hyatt JK. MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose. Physiological Reports. 2022.(PMID 35808870)
- Alser M, et al. The Effect of Chronic Endurance Exercise on Serum Levels of MOTS-c and Humanin in Professional Athletes. Reviews in Cardiovascular Medicine. 2022.(PMID 39077591)
Study data, research use only. No established human dosing protocol.