Preclinical Research & Case Studies

Mechanism: A 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene. Proposed to act largely on skeletal muscle, inhibiting the folate one-carbon cycle to activate AMPK, with downstream effects on glucose uptake and lipid handling.

• Lee, Zeng, Drew et al. (2015), Cell Metabolism (21:443–454): The foundational MOTS-c paper: intraperitoneal MOTS-c improved insulin sensitivity in diet-induced obese mice, reduced age-related insulin resistance in older mice, and increased skeletal-muscle glucose uptake, with AMPK activation identified as the mechanism.
  Model: Diet-induced obese and aged mice + myocytes | Source →
• Kim et al. (2019), Physiological Reports: An unbiased metabolomics approach found MOTS-c reduced sphingolipid, monoacylglycerol, and dicarboxylate pathways (elevated in obesity/T2D models) and increased beta-oxidation, improving insulin sensitivity in diet-induced obese mice.
  Model: Diet-induced obese mice (metabolomics) | Source →
• Reynolds et al. (2021), Nature Communications (12:470): MOTS-c significantly enhanced physical performance in young (2-mo), middle-aged (12-mo), and old (22-mo) mice; late-life (23.5-mo) intermittent treatment increased physical capacity and healthspan, alongside regulation of nuclear metabolism/proteostasis genes.
  Model: Young, middle-aged, and aged mice | Source →
• Muscle-atrophy signaling study (2021): Found MOTS-c reduced myostatin and muscle-atrophy signaling in skeletal muscle, complementing reports that MOTS-c improves muscle strength and exercise capacity in high-fat-diet-fed and aged mice.
  Model: High-fat-diet-fed and aged mice | Source →
• Pancreatic-islet senescence study (2025), Experimental & Molecular Medicine: MOTS-c levels fell with aging in islet cells; treating aged mouse islets with MOTS-c reduced β-cell senescence and improved glucose intolerance in diabetic-mouse models.
  Model: Aged and diabetic mouse islet models | Source →

Research stage: Mechanism replicated across rodent and cell-line studies; circulating MOTS-c declines with age in humans, but no administered-MOTS-c human study has read out.