Mitochondrial & Metabolic Peptides (MOTS-c, SS-31, GLP-1) — References

Mirrored Reference Dossier

Parent Topic: Mitochondrial & Metabolic Peptides (MOTS-c, SS-31, GLP-1) | References Hub: 02 - Compounds & Molecules References MOC

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Landmark Peer-Reviewed Studies

1. Lee et al. (2015) — Cell Metabolism

• Citation: Lee, C., Zeng, J., Drew, B. G., Sallam, T., Martin-Montalvo, A., Wan, J., Kim, S. J., Mehta, H., Hevener, A. L., de Cabo, R., & Cohen, P. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 21(3), 443–454.
• Identifiers: PMID: 25738459 (PubMed · Europe PMC) | PMCID: PMC4350682 (PMC Full Text) | DOI: 10.1016/j.cmet.2015.02.009 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Foundational genomic discovery, metabolomic flux analysis, and hyperinsulinemic-euglycemic clamp study in young, high-fat-diet (HFD), and aged C57BL/6 mice.
• Key Quantitative Outcomes: Identified MOTS-c, a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene. Demonstrated that MOTS-c inhibits the folate cycle in skeletal muscle, elevating endogenous AICAR by $+20\text{-fold}$ ($p<0.001$) to activate AMPK and GLUT4. Systemic administration ($5\text{ mg/kg/day}$) increased insulin-stimulated skeletal muscle glucose disposal rate by $+30\%$ on clamps, prevented HFD-induced obesity and hyperinsulinemia, and completely reversed age-dependent insulin resistance in 12-month-old mice.

2. Reynolds et al. (2021) — Nature Communications

• Citation: Reynolds, J. C., Lai, R. W., Woodhead, J. S., Joly, J. H., Mitchell, C. J., Cameron-Smith, D., Lu, R., Cohen, P., Graham, N. A., Benayoun, B. A., Merry, T. L., & Lee, C. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications, 12(1), 470.
• Identifiers: PMID: 33473109 (PubMed · Europe PMC) | PMCID: PMC7817689 (PMC Full Text) | DOI: 10.1038/s41467-020-20790-0 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Translational human acute exercise muscle-biopsy study ($N=10$ healthy men) paired with late-life murine physical capacity and lifespan intervention ($15\text{ mg/kg}$ MOTS-c in 22-month-old mice).
• Key Quantitative Outcomes: Acute cycling exercise in humans increased endogenous skeletal muscle MOTS-c levels by $+11.9\text{-fold}$ ($p<0.01$) and circulating plasma MOTS-c by $+1.5\text{-fold}$. In aged 22-month-old mice (human equivalent $>65\text{ years}$), 2 weeks of MOTS-c treatment doubled treadmill running time and total running distance ($+100\%,p<0.001$), enabled $100\%$ of aged mice to pass the high-speed sprint test (vs. $16.6\%$ in controls), and late-life intermittent dosing ($3\times /\text{week}$ starting at 23.5 months) trended toward $+7\%$ lifespan extension while significantly improving grip strength and stride length.

3. Siegel et al. (2013) — Aging Cell

• Citation: Siegel, M. P., Kruse, S. E., Percival, J. M., Goh, J., White, C. C., Hopkins, H. C., Kavanagh, T. J., Szeto, H. H., Rabinovitch, P. S., & Marcinek, D. J. (2013). Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell, 12(5), 763–771.
• Identifiers: PMID: 23692570 (PubMed · Europe PMC) | PMCID: PMC3772966 (PMC Full Text) | DOI: 10.1111/acel.12102 (DOI · SciDB · Scholar)
• Study Design & Sample Size: In vivo ${}^{31}\text{P}$ Magnetic Resonance Spectroscopy (${}^{31}\text{P-MRS}$) and optical spectroscopy evaluation in young (5 mo) vs. aged (27 mo) mice before and 1 hour after a single dose of SS-31 (Elamipretide, $3\text{ mg/kg}$).
• Key Quantitative Outcomes: Within 1 hour of a single injection, SS-31 completely restored aged skeletal muscle in vivo maximal ATP production (${\text{ATP}}_{\max }$ increased from $0.68$ to $0.96\text{ mM ATP/s}$, $p<0.01$), Coupling Efficiency ($P/O$ ratio increased from $0.095$ to $0.145$, $p<0.001$), and Phosphocreatine-to-ATP ($\text{PCr/ATP}$) ratio to levels indistinguishable from young 5-month-old controls, while increasing intracellular glutathione redox status (GSH:GSSG) and muscle fatigue resistance ($p=0.015$).

4. Jastreboff et al. (2023) — New England Journal of Medicine

• Citation: Jastreboff, A. M., Kaplan, L. M., Frías, J. P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., Haupt, A., Bergman, B. K., & Hartman, M. L. (2023). Triple–hormone-receptor agonist retatrutide for obesity—a phase 2 trial. New England Journal of Medicine, 389(6), 514–526.
• Identifiers: PMID: 37366315 (PubMed · Europe PMC) | DOI: 10.1056/NEJMoa2301972 (DOI · SciDB · Scholar)
• Study Design & Sample Size: 48-week Phase 2, randomized, double-blind, placebo-controlled trial ($N=338$) evaluating weekly subcutaneous Retatrutide (GIP/GLP-1/Glucagon triple receptor agonist) at doses of $1,4,8,\text{and }12\text{ mg}$.
• Key Quantitative Outcomes: At 48 weeks, mean body-weight reductions were $-8.7\%$ ($1\text{ mg}$), $-17.1\%$ ($4\text{ mg}$), $-22.8\%$ ($8\text{ mg}$), and $-24.2\%$ ($12\text{ mg}$) compared to $-2.1\%$ in placebo ($p<0.001$). $100\%$ of participants on $8\text{ mg}$ or $12\text{ mg}$ achieved $\ge 5\%$ weight reduction, $83\%$ on $12\text{ mg}$ achieved $\ge 15\%$ reduction, and in the MASLD sub-study ($n=98$), $8\text{–}12\text{ mg}$ Retatrutide reduced hepatic fat content by $-81.4\%$ to $-86.0\%$, resolving steatosis in $>85\%$ of patients.