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The Peptide Effect
Dosage Guide

MOTS-c Dosage Guide: Metabolic & Exercise Protocol

Educational reference covering MOTS-c dosage protocols, metabolic support applications, reconstitution instructions, and AMPK activation research. Dosing information discussed in published studies for informational purposes only.

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Medical Disclaimer

This guide is for educational and informational purposes only. It is not medical advice. Dosages described reflect ranges discussed in published research and clinical practice literature — they are not recommendations. Always consult a licensed healthcare provider before using any peptide. Legality and availability vary by jurisdiction.

Overview

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino-acid peptide encoded by the mitochondrial genome, first identified by Changhan Lee and colleagues at the University of Southern California in 2015. It is classified as a mitochondria-derived peptide (MDP) and has been discussed in research literature as a key regulator of metabolic homeostasis. MOTS-c activates the AMP-activated protein kinase (AMPK) pathway, a central metabolic sensor that regulates glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. Studies in animal models have reported that MOTS-c administration improved insulin sensitivity, prevented diet-induced obesity, and enhanced exercise capacity. The peptide has attracted significant interest in the aging and metabolism research fields because endogenous MOTS-c levels have been reported to decline with age and in metabolic disease states.

Dosing Protocols

Standard Metabolic Support Protocol

Route: Subcutaneous injection
Dose: 5 mg
Frequency: 3 times per week (e.g., Monday, Wednesday, Friday)
Duration: 4–8 weeks per course

This protocol is the most commonly discussed dosing regimen in research-oriented contexts. The 5 mg dose administered three times weekly provides consistent AMPK pathway activation across the week. Effects on metabolic markers have been discussed as developing over several weeks of consistent use.

Exercise Performance Protocol

Route: Subcutaneous injection
Dose: 5 mg
Frequency: 3–5 times per week, often administered pre-workout or in the morning
Duration: 4–8 weeks

This protocol is discussed in fitness and performance optimization contexts. The rationale for pre-workout timing is based on MOTS-c's effects on AMPK activation and glucose metabolism during exercise. Some protocols discussed in research communities suggest daily dosing during intensive training blocks.

Research / Intensive Protocol

Route: Subcutaneous injection
Dose: 5–10 mg
Frequency: Once daily
Duration: 14-day course

A higher-dose, shorter-duration approach that has been referenced in some research protocols. The 10 mg dose represents the upper end of what is commonly discussed. This protocol may be followed by a transition to the standard 3x/week schedule or a washout period for assessment.

Reconstitution & Storage

Vial sizes5 mg lyophilized powder per vial
Recommended water volume1 mL bacteriostatic water (BAC water) per 5 mg vial, yielding 5 mg/mL
StorageStore unreconstituted vials refrigerated at 2–8 °C (36–46 °F). Protect from light and moisture.
Stability once reconstitutedReconstituted solution should be refrigerated and used within 14 days. MOTS-c may be less stable in solution than some other peptides, so prompt use after reconstitution is recommended.

Use our reconstitution calculator to determine exact syringe units for your dose.

Cycle Guidance

MOTS-c is commonly discussed in 4–8 week courses followed by an assessment period. The rationale for cycling is not based on tolerance development (which has not been a prominent concern in the limited published data) but rather on practical considerations around cost, ongoing assessment of metabolic response, and the observation that MOTS-c's effects on AMPK signaling may have downstream metabolic benefits that persist beyond the active dosing period. Some protocols suggest repeating courses with 4-week breaks, while others discuss seasonal or quarterly use. Individuals with metabolic conditions are generally discussed as potentially benefiting from longer courses. Monitoring metabolic markers such as fasting glucose, insulin sensitivity (HOMA-IR), and lipid panels between courses has been discussed as a useful approach for guiding treatment decisions.

Stacking Considerations

  • MOTS-c is sometimes discussed alongside other mitochondrial-targeted compounds, as its mechanism involves mitochondrial metabolism and biogenesis. Combining with NAD+ precursors (NMN, NR) has been discussed for comprehensive mitochondrial support, though controlled combination data is lacking.
  • Some protocols combine MOTS-c with epithalon in longevity-focused regimens, targeting different aspects of cellular aging (metabolic health via MOTS-c and telomere maintenance via epithalon).
  • Concurrent use with metformin has been discussed, as both compounds activate AMPK, though this overlap raises theoretical questions about additive or redundant effects that have not been resolved in published studies.
  • Exercise is generally discussed as synergistic with MOTS-c, as both activate AMPK. Many protocols emphasize that MOTS-c is intended to complement, not replace, regular physical activity.

Potential Side Effects

  • Injection site reactions (redness, minor discomfort) — the most commonly reported adverse effect
  • Transient flushing or warmth — reported by some users shortly after injection
  • Mild gastrointestinal discomfort — reported infrequently
  • Hypoglycemia (low blood sugar) — a theoretical concern given MOTS-c's effects on glucose metabolism, particularly in individuals using insulin or other glucose-lowering medications
  • Fatigue — occasionally reported, possibly related to metabolic shifts during the initial adaptation period
  • The human safety profile is not well established in large controlled trials, as most published MOTS-c research has been conducted in animal models and cell cultures

Contraindications & Cautions

  • Known hypersensitivity to MOTS-c or any formulation component
  • Type 1 diabetes or insulin-dependent diabetes — MOTS-c's glucose-lowering effects could increase hypoglycemia risk, particularly when combined with insulin
  • Concurrent use of insulin or sulfonylureas — monitoring is recommended due to potential additive effects on blood glucose
  • Pregnancy and breastfeeding — no safety data available
  • Active malignancy — the effects of AMPK activation on tumor metabolism are complex and not fully characterized, warranting caution
  • Severe hepatic or renal impairment — metabolism and clearance have not been studied in these populations

Related

MOTS-c Profileenergy metabolismfat losslongevitymuscle growthepithalon dosageaod-9604 dosage

References

  1. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance (2015) — PubMed
  2. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis (2019) — PubMed
  3. Mitochondrial-derived peptides in energy metabolism (2020) — PubMed

Frequently Asked Questions

What is MOTS-c and how does it work?
MOTS-c is a 16-amino-acid peptide encoded by the mitochondrial genome, discovered in 2015 at USC. Its primary mechanism discussed in research literature involves activation of the AMPK pathway, a master metabolic sensor that regulates glucose uptake, fatty acid oxidation, and mitochondrial function. MOTS-c essentially acts as a signaling molecule from the mitochondria to the nucleus, influencing whole-body metabolic homeostasis.
When is the best time to administer MOTS-c?
For exercise performance protocols, pre-workout administration (30–60 minutes before exercise) is commonly discussed to align AMPK activation with exercise-induced metabolic stress. For general metabolic support, morning administration on an empty stomach is frequently referenced. The optimal timing has not been established in controlled human trials, and recommendations are largely based on pharmacological rationale.
Does MOTS-c help with weight loss?
In animal studies, MOTS-c administration prevented diet-induced obesity and improved insulin sensitivity in mouse models (Lee et al., 2015). The peptide's activation of AMPK promotes fatty acid oxidation and glucose metabolism. However, controlled human clinical trials specifically evaluating MOTS-c for weight loss have not been published, so the weight loss effects in humans remain an area of active research interest rather than established evidence.
How does MOTS-c differ from other metabolic peptides?
MOTS-c is unique in that it is encoded by the mitochondrial genome rather than the nuclear genome, making it one of the few known mitochondria-derived peptides with hormonal activity. Unlike GLP-1 agonists (such as semaglutide or tirzepatide), which work through receptor binding to reduce appetite and slow gastric emptying, MOTS-c acts primarily through AMPK activation to enhance cellular energy metabolism. This mechanistic distinction means it targets a fundamentally different metabolic pathway.
Do endogenous MOTS-c levels change with age?
Published research has reported that circulating MOTS-c levels decline with age in humans. A study by Lee et al. also found that physically active individuals tend to have higher circulating MOTS-c levels, and that exercise can acutely increase MOTS-c levels in skeletal muscle. This age-related decline has been cited as a rationale for exogenous MOTS-c supplementation in aging and metabolic health contexts.
Is MOTS-c safe to use with metformin?
Both MOTS-c and metformin activate the AMPK pathway, which raises theoretical questions about additive effects. No controlled studies have evaluated this combination in humans. Individuals using metformin should be aware of the potential for enhanced glucose-lowering effects and the associated risk of hypoglycemia. Monitoring blood glucose levels when using both compounds concurrently is generally recommended.