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    MOTS-C Research Update: What Mitochondrial Derived Peptide Studies Show So Far

    12 May 202611 min readBy the Peptx research team

    MOTS-C is a 16 amino acid peptide encoded within the mitochondrial 12S rRNA gene. Since its discovery in 2015, studies have linked it to insulin sensitivity, exercise capacity, and mitochondrial function. Here is the current evidence base.

    MOTS-C (Mitochondrial Open Reading Frame of the 12S rRNA type-c) is one of a small group of mitochondrial derived peptides (MDPs) encoded by short open reading frames within mitochondrial DNA. First characterised by Lee and colleagues at USC in 2015, it has become one of the most actively studied peptides in metabolic and cellular senescence research [1].

    Mechanism of Action

    MOTS-C functions as a metabolic regulator that signals from the mitochondrion to the nucleus. Kim and colleagues (2018) showed that under metabolic stress it translocates to the nucleus in an AMPK-dependent manner and regulates a broad range of nuclear genes, including antioxidant response genes. AMP activated protein kinase (AMPK) is also a central downstream effector of its insulin sensitising and metabolic effects in vivo [1,2].

    Insulin Sensitivity and Glucose Homeostasis

    The original 2015 study in Cell Metabolism demonstrated that MOTS-C treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance as well as diet-induced obesity, with improved glucose disposal and reduced fat accumulation in the liver. The same study identified skeletal muscle as the main target tissue, with increased AMPK activation and GLUT4 expression in muscle [1].

    Human observational studies have reported lower circulating MOTS-C concentrations in adults with type 2 diabetes than in controls [3], and in obese boys and adolescent males, where concentrations correlated inversely with HOMA-IR [4].

    Exercise Capacity and Skeletal Muscle

    A 2021 study in Nature Communications reported that MOTS-C treatment significantly improved physical performance, including treadmill running, in young, middle aged, and old mice. The authors linked the effect in part to improved metabolic flexibility, and MOTS-C increased fatty acid-driven respiration in cultured muscle cells. Endogenous MOTS-C also rises in human skeletal muscle and plasma in response to exercise, suggesting it acts as an exercise responsive myokine [5].

    Cardiovascular and Endothelial Findings

    Preclinical work has reported endothelial protective effects: pretreating rodent arteries with MOTS-C improved their response to acetylcholine, and in a study of 40 patients, lower circulating MOTS-C was associated with coronary endothelial dysfunction [6]. In a rat model, MOTS-C reduced experimentally induced vascular calcification, alongside increased AMPK activation [7].

    Cellular Senescence Markers

    Circulating MOTS-C declines with chronological age in humans, although a study of healthy men found higher MOTS-C levels in the skeletal muscle of older participants [8]. A specific mitochondrial DNA variant (m.1382A>C) that alters the MOTS-C peptide sequence, found in Northeast Asian populations, has been linked to reaching exceptional old age (100 years or more) in Japanese genetic studies; Fuku and colleagues (2015) proposed MOTS-C as a possible mechanism but stressed that more research is needed [9]. Animal studies have shown that late life MOTS-C treatment improves grip strength, gait, and walking performance in old mice [5].

    Bone, Inflammation, and Other Emerging Areas

    Smaller studies have reported MOTS-C effects on osteoblast differentiation of rat bone marrow stem cells [10], suppression of osteoclast formation and bone loss in ovariectomised mice, a model of postmenopausal bone loss [11], and lower pro-inflammatory cytokine levels in mice with bacterial infection, alongside effects on macrophage signalling [12]. These findings remain at preclinical stage.

    Human Trials: Where the Evidence Currently Stands

    To date, robust randomised controlled trials of exogenous MOTS-C in humans have not been published. The current human evidence base is observational, focused on circulating endogenous concentrations and their associations with metabolic disease, exercise, and ageing. Researchers should treat all therapeutic claims for exogenous administration in humans as unsupported by Phase 2 or Phase 3 clinical data.

    Research Procurement Considerations

    For in vitro and preclinical work, the relevant quality parameters for MOTS-C are:

    • HPLC purity not less than 99%
    • Mass spectrometry confirmation of the 16 residue sequence
    • Endotoxin below 0.5 EU/mg for cell culture
    • Documentation of synthesis route, since the methionine residues are oxidation prone

    References

    1. [1] Lee C, et al. "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance." Cell Metab. 2015;21(3):443-454. PubMed 25738459
    2. [2] Kim KH, et al. "The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress." Cell Metab. 2018;28(3):516-524. PubMed 29983246
    3. [3] Ramanjaneya M, et al. "Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects." Front Endocrinol (Lausanne). 2019;10:331. PubMed 31214116
    4. [4] Du C, et al. "Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance." Pediatr Diabetes. 2018. PubMed 29691953
    5. [5] Reynolds JC, et al. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nat Commun. 2021;12(1):470. PubMed 33473109
    6. [6] Qin Q, et al. "Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction." Int J Cardiol. 2018;254:23-27. PubMed 29242099
    7. [7] Wei M, et al. "Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway." Cardiorenal Med. 2020;10(1):42-50. PubMed 31694019
    8. [8] D'Souza RF, et al. "Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition." Aging (Albany NY). 2020;12(6):5244-5258. PubMed 32182209
    9. [9] Fuku N, et al. "The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity?" Aging Cell. 2015;14(6):921-923. PubMed 26289118
    10. [10] 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;22(21):7156-7163. PubMed 30468456
    11. [11] Ming W, et al. "Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation." Biochem Biophys Res Commun. 2016;476(4):412-419. PubMed 27237975
    12. [12] Zhai D, et al. "MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA." Mol Immunol. 2017;92:151-160. PubMed 29096170

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