Our Powerhouse’s Master Signaling Molecule

Our mitochondria produce energy to feed all of our cells and tissues, but they also produce signaling molecules, so-called mitokines. Perhaps the most important is MOTS-c, a natural molecule that activate’s our body’s energy metabolism and help us fight against aging and obesity.

Let’s review the science of MOTS-c, one of the most important peptides that has been discovered and revolutionized health and biohacking.

1. What is MOTS-c?

MOTS-c is a novel mitochondrial-derived peptide (MDP) discovered at the University of Southern California (USC) in 2015. It is a chain of 16 amino-acids encoded in the mitochondrial DNA.

• Presence: MOTS-c is found within various bodily tissues, primarily in skeletal muscle and fat tissue. It is also found in circulation in humans.
• Classification: Due to its systemic presence and regulatory actions, MOTS-c has been dubbed a “mitochondrial hormone” or a “mitokine” (a mitochondrial-derived signal).

2. What does MOTS-c do?

MOTS-c effects are primarily related to metabolism, physical capacity, and protection against age-related diseases.

Metabolic Homeostasis and Insulin Sensitivity:

• It stimulates glucose utilization and enhances metabolic flexibility.
• It protects against induced insulin resistance.
• It prevents diet-induced obesity and weight gain.
• It enhances fat oxidation/lipid utilization.
• It relieves hyperglycemia and insulin resistance in gestational diabetes mellitus (GDM) animal models.

Muscle and Physical Capacity:

• It is frequently called an exercise mimetic as it provides many of the benefits associated with exercise.
• Significantly improves physical performance.
• It promotes muscle homeostasis and protects against muscle atrophy. It is suggested as a potential therapy for sarcopenia.

Aging and Stress Resistance:

• It promotes cellular resistance against metabolic stress.
• Late-life MOTS-c treatment can improve indicators of healthy lifespan (healthspan) and delay age-related physical disabilities in mice.
• It may prevent skin aging by lowering inflammation, leading to increased dermal collagen.

Anti-inflammatory and Organ Protection:

• It reduces inflammation and suppresses pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) while increasing anti-inflammatory cytokine IL-10.
• It protects against cardiovascular disease, attenuates vascular calcification, and improves cardiac function and myocardial performance.
• It suppresses ovariectomy-induced bone loss via AMPK activation and promotes bone formation.
• It provides protection against chronic pain, such as cancer-induced bone pain (BCP), through peripheral and central synergistic effects on immune cells and osteoclasts.

3. How is MOTS-c used?

MOTS-c is used as an injectable peptide, often administered through subcutaneous injections in the abdominal area.

Research and Therapeutic Applications:

• For research and therapeutic protocols, it is injected daily, every other day, or once a week at various doses, such as 0.5–1.0 mg/day or 5–10 mg/week. Higher doses are associated with injection site reactions.
• MOTS-c levels in human plasma or serum are commonly measured using specialized in-house ELISA assays, which have shown that exercise can increase the natural levels of MOTS-c in some populations.
• One of the most exciting applications is for metabolic optimization, where MOTS-c has been shown to reduce fat and obesity, and is often applied in conjunction with GLP-1 agonists like Semaglutide or Tirzepatide for targeted fat loss without the need for further dosage increases.

Further Therapeutic Development:

• MOTS-c is a promising therapeutic target. Analogs of MOTS-c are currently in Phase 1 clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). These are synthetic forms that are not bio-identical to the naturally occurring form and may carry additional risks.

4. Is MOTS-c a Natural Peptide?

Yes, MOTS-c is a naturally occurring peptide.

• It is naturally encoded by the mitochondrial DNA.
• It is produced endogenously by the body and found in various tissues, notably in the skeletal muscle and fat tissue, and circulates in the plasma.
• Endogenous MOTS-c levels are regulated by physiological factors: they decrease with fasting and aging, and they significantly increase in skeletal muscle and circulation following exercise in certain populations.

MOTS-c in Hispanic Populations

• A recent study involving Hispanic white women who had survived breast cancer showed that, unlike the White population, Hispanic people don’t produce increased levels of MOTS-c as a consequence of exercise, which implies a reduced benefit to exercising for the Hispanic population.
• This seems to indicate that the benefits of MOTS-c using MOTS-c may be even larger in people with hispanic ascendence.

5. Is MOTS-c Safe?

The protective and beneficial effects of MOTS-c, especially concerning metabolic health and chronic pain, are well documented, which result in positive preliminary safety indicators.

Safety in Animal Models and Therapeutic Comparison:

• Chronic intraperitoneal administration of MOTS-c in mice showed little effect on liver, renal, lipid, or cardiac function, with most of the physiological effects concentrating on metabolic and physical capacity improvements.
• In a bone cancer pain model, MOTS-c reduced pain without producing tolerance, contrasting with morphine, which caused tolerance and addiction.
• MOTS-c treatment does not affect cancer cell proliferation in Lewis lung cancer cells or bone cancer.
• MOTS-c may offer an advantage over some metabolic drugs, as it is suggested to avoid hepatotoxicity associated with metformin, AICAR, or methotrexate.

Concerns/Regulation:

• Because MOTS-c affects muscle exercise capacity, doping control authorities have proposed a test to detect it in plasma samples to prevent its use as performance enhancing agent in sports.
• The rapid metabolic clearance of MOTS-c makes it very hard to detect, and detection strategies for microdosing regimes are highly challenging.
• Furthermore, even though analogs are in clinical trials, widespread clinical safety data is not yet available, despite its natural origin and many studies indicating its important physiological effects.
• This gap in large-scale studies may be related to the inability to patent a naturally occurring substance, which may explain why the synthetic analogs are being pursued as pharmacological agents for market introduction.
• MOTS-c is available in research agent quality.

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