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MOTS-c

Tags: MOTS-c, Mitochondrial Peptide, Metabolic Health, AMPK

Quick Summary

MOTS-c is a 16-amino-acid mitochondrial-derived peptide that regulates metabolic homeostasis through AICAR-AMPK signaling. Enhances insulin sensitivity, promotes mitochondrial function, and improves exercise performance with limited but promising human safety data.

Quick Facts

  • Typical Dose: 5–15 mg (common ranges: 5–10 mg daily; anti‑aging protocols up to 15 mg 3× weekly)
  • Route: Injectable — Subcutaneous (abdomen, thigh, upper arm); rotate sites
  • Cycle: 4–12 weeks (continuous or intermittent protocols)
  • Storage: Lyophilized: room temp (short term) or freezer; reconstituted: 2–8°C (use within 14 days)

Overview

MOTS‑c is a 16‑amino‑acid mitochondrial‑derived peptide encoded within the 12S rRNA (MT‑RNR1). It acts as a mitohormone that regulates metabolic homeostasis, enhances insulin sensitivity, and promotes mitochondrial function. MOTS‑c signals through the folate‑AICAR‑AMPK pathway and can translocate to the nucleus under metabolic stress to regulate gene expression.

Key Benefits

  • Enhanced insulin sensitivity and improved glucose metabolism
  • Activation of AMPK pathway and mitochondrial function optimization
  • Exercise performance enhancement and potential anti‑aging benefits
  • Potential protection against diet‑induced obesity in preclinical models

Mechanism of action

MOTS‑c inhibits aspects of the folate cycle and activates AICAR‑AMPK signalling. Under metabolic stress it can translocate to the nucleus and interact with stress‑response transcription factors (e.g., NRF2, ATF1/7) to regulate genes involved in metabolism and antioxidant response.

Molecular information

  • Weight: 2,174.6 Da
  • Length: 16 amino acids
  • Type: Mitochondrial‑derived peptide (MDP)

Amino acid sequence:

MRWQEMGYIFYPRKLR

(Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg) — encoded by mitochondrial DNA (MT‑RNR1).

Research Indications

  • Metabolic health: insulin resistance, glucose tolerance
  • Type 2 diabetes: improved glucose homeostasis in clinical and preclinical studies
  • Obesity prevention (preclinical models)
  • Exercise performance and age‑related physical decline

Research Protocols

Goal Dose Frequency Route
Metabolic health 5–10 mg Once daily Subcutaneous
Anti‑aging protocol 15 mg 3× weekly Subcutaneous
Exercise performance 10–15 mg Pre‑workout (as needed) Subcutaneous
Conservative start 5 mg Once daily Subcutaneous

Timing: Morning dosing before exercise is common; exercise increases endogenous MOTS-c production and may synergize with administration.

Interactions

Compatible / Complementary

  • Exercise/physical activity — Synergistic; exercise increases endogenous MOTS-c
  • Glucose-lowering agents — Compatible; monitor glucose closely
  • Antioxidant agents — Compatible; MOTS-c enhances antioxidant response

Monitor

  • Insulin and sulfonylureas — Monitor glucose closely; may require dose adjustment
  • Metformin — Monitor; both enhance insulin sensitivity
  • Beta-blockers — Monitor exercise response

Avoid

  • Competitive athletes subject to WADA testing — Prohibited (metabolic modulator)
  • Pregnancy and breastfeeding — Not recommended; limited human data

How to Reconstitute

  1. Allow lyophilized vial to reach room temperature (~15–20 minutes).
  2. Calculate required BAC volume using a concentration calculator.
  3. Draw bacteriostatic water into syringe and inject slowly down vial side (not directly onto powder).
  4. Gently swirl until dissolved; do not shake vigorously.
  5. Store reconstituted solution at 2–8°C and use within 14 days.

Quality Indicators

Positive Signs

  • White to off-white lyophilized powder with uniform appearance
  • Proper storage maintained (room temp short-term, freezer long-term)
  • Sequence verification: MRWQEMGYIFYPRKLR confirmed
  • Certificate of Analysis (CoA) showing purity >95% by RP-HPLC
  • Clear solution after reconstitution without particles or foam

Warning Signs

  • Discolored or non-uniform lyophilized powder
  • Purity <95% or no CoA provided
  • Cloudiness or particles in reconstituted solution
  • Sequence mismatch or amino acid analysis inconsistencies
  • Improper storage history

What to expect

  • Week 1–2: AMPK activation and early improvements in glucose tolerance
  • Week 2–4: Enhanced exercise capacity and insulin sensitivity
  • Week 4–8: Sustained metabolic benefits and potential body composition improvements
  • Week 8–12: Maximum mitochondrial function enhancement and metabolic flexibility

Side effects & safety

  • Generally well tolerated in animal studies; human long‑term safety data limited
  • Monitor blood glucose when combined with diabetes medications (may require dose adjustments)
  • Possible injection site reactions (redness, swelling)
  • Not recommended during pregnancy or breastfeeding
  • Prohibited by WADA for competitive athletes (metabolic modulator)

References

Metabolic Homeostasis and Obesity Prevention (2015)

  • Lee et al. | Animal model | High-fat diet mice | Obesity prevention, insulin sensitivity improvement

Foundational study demonstrating MOTS-c prevents obesity and improves insulin sensitivity in high-fat diet mice.

View Study → https://doi.org/10.1016/j.cmet.2015.02.009

Exercise Performance and Age-Dependent Physical Decline (2021)

  • Reynolds et al. | Human + Animal model | Muscle MOTS-c measurement | Exercise performance enhancement

Exercise induced a large increase in muscle MOTS-c in humans and improved performance in animal models.

View Study → https://doi.org/10.1038/s41467-020-20790-0

Acute Exercise Enhancement (2022)

  • Hyatt et al. | Animal model | Single-dose studies | Improved running time/distance

Single-dose studies show acute improvements in running time and distance in rodents.

View Study → https://doi.org/10.14814/phy2.15377