MOTS-c
Mitochondrial Open Reading Frame of the 12S rRNA Type-c
Mechanism of Action
Encoded by a short open reading frame within mitochondrial 12S rRNA and translocates to the nucleus under stress/exercise, regulating antioxidant-response genes. Acts largely through the folate-AICAR-AMPK pathway, activating AMPK and PGC-1α to drive mitochondrial biogenesis and improve insulin sensitivity.
Key Benefits
- AMPK activation and PGC-1α-driven mitochondrial biogenesis
- Improved insulin sensitivity and glucose handling in preclinical models
- Preserved skeletal muscle mass in a mouse cancer-cachexia model
- Reduced oxidative stress and reactive oxygen species damage in skeletal muscle
Dosing Protocol
Human data currently limited to observational studies correlating circulating MOTS-c with exercise/metabolic status (e.g., PCOS, marathon runners) — not therapeutic administration trials.
Ideal Candidates
Research contexts modeling exercise mimetics, mitochondrial dysfunction, insulin resistance, or age-related muscle decline.
Side Effects & Safety
Limited human safety data; preclinical studies report good tolerability at tested doses. No controlled human trials of exogenous administration exist yet.
Regulatory Status
RestrictedResearch compound only. No 503A bulks listing, no FDA review, and no completed trials of exogenous administration in humans — existing human data is observational (circulating/endogenous MOTS-c levels).
Evidence & Citations
- Wan W, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med. 2023;21(1):36.
- Gudiksen A, et al. MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner. Free Radic Biol Med. 2026;246:682-696.
- Yang B, et al. MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway. Biochim Biophys Acta Mol Basis Dis. 2021;1867(6):166126.
- Ramanjaneya M, et al. Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects. Clin Endocrinol (Oxf). 2019;91(2):278-287.
- Jamnick NA, et al. MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia. Front Med (Lausanne). 2026;13:1838178.
Frequently asked
What is MOTS-c?+
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a peptide studied for ampk activation and exercise mimetic. Encoded by a short open reading frame within mitochondrial 12S rRNA and translocates to the nucleus under stress/exercise, regulating antioxidant-response genes. Acts largely through the folate-AICAR-AMPK pathway, activating AMPK and PGC-1α to drive mitochondrial biogenesis and improve insulin sensitivity.
What is the dosing protocol for MOTS-c?+
Literature commonly references 5 mg 2x/wk (low) to 10 mg 3x/wk (maintenance) via SubQ, on a 8–12 weeks cycle. Educational reference only — a licensed Stackhaus Health provider sets any personalized protocol.
What is the regulatory status of MOTS-c?+
Research compound only. No 503A bulks listing, no FDA review, and no completed trials of exogenous administration in humans — existing human data is observational (circulating/endogenous MOTS-c levels).
Where can I access MOTS-c?+
Research-grade MOTS-c is available through Stackhaus Research. For a personalized, provider-reviewed protocol, consult a licensed clinician through Stackhaus Health.
More in Muscle & Performance
Used in these stacks
MOTS-c appears in 1 research protocol in the Stackhaus Academy library.