MOTS-C 10 mg

MOTS-C — 10 mg

Purity: ≥98% (HPLC)
Form: lyophilized powder, 3 mL vial
Storage: −20 °C (before opening), +2…+8 °C (after reconstitution, no more than 28 days)
Verification: Janoshik Analytical (Czech Republic) — independent blind test of each batch
Synonyms: MOTS-c, Mitochondrial ORF of the 12S rRNA type-c, mitochondrial peptide MOTS-C

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Contents

1. What is MOTS-C?
2. Why MOTS-C is called the "exercise peptide"
3. Peptide structure
4. AMPK — the cell's energy sensor, in plain terms
5. MOTS-C and metabolism
6. MOTS-C and physical activity
7. MOTS-C, stress, and nuclear translocation
8. Age-related decline of MOTS-C
9. Sources

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1. What is MOTS-C?

MOTS-C is a 16-amino-acid peptide encoded in mitochondrial DNA. This is a fundamentally important detail: the overwhelming majority of known peptides are encoded in nuclear DNA. MOTS-C is one of the few whose "blueprint" resides in the mitochondria — the cellular structures that produce energy.

The peptide was first described in 2015 by the group of Changhan David Lee at the University of Southern California (USC) and published in the journal Cell Metabolism [1]. This discovery changed the understanding of mitochondria: it turned out that they are not merely the "power plants" of the cell, but active signaling centers capable of influencing the metabolism of the entire organism.

MOTS-C has been detected in blood plasma, skeletal muscle, the brain, and the liver. Its level declines with age — and this is precisely what makes it a subject of research in the field of metabolism and cellular aging.

For research use only. Not a medicinal product. Not intended for use in humans or animals.

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2. Why MOTS-C is called the "exercise peptide"

Physical exercise is one of the most powerful metabolic interventions: it improves insulin sensitivity, activates AMPK, increases energy expenditure, and stimulates glucose utilization by muscles. In animal experiments, MOTS-C activates the very same intracellular cascades [1][2]:

• AMPK activation. The main energy sensor of the cell. MOTS-C raises the level of endogenous AICAR — a natural activator of AMPK [1]. This is the same pathway through which physical exercise works.

• Improved insulin sensitivity. In mouse models of diet-induced obesity and age-related insulin resistance, MOTS-C improved glucose utilization by skeletal muscle [1][3].

• Reduced weight gain. In mice on a high-fat diet, administration of MOTS-C significantly reduced body weight gain and prevented fatty degeneration of the liver [1][4].

• Works only under metabolic challenge. A noteworthy detail: MOTS-C had no significant effect on healthy, metabolically sound rodents [4]. The effect appeared only in the presence of a metabolic load — obesity, insulin resistance, or age-related changes.

All data are preclinical. No clinical studies of MOTS-C in humans have yet been conducted.

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3. Peptide structure

Parameter	Value
Amino acid sequence	MRWQEMGYIFYPRKLR
Number of amino acids	16
Encoding gene	Mitochondrial 12S rRNA (MT-RNR1)
Type	Mitochondrially encoded peptide (MDP)
Detected in	Blood plasma, skeletal muscle, brain, liver
Key cascade	Folate → AICAR → AMPK
Year of discovery	2015
Group	Changhan David Lee, USC

MOTS-C belongs to a relatively new class of molecules — mitochondrially encoded peptides (MDPs). Before 2015, it was believed that mitochondrial DNA encoded only 13 proteins of the respiratory chain. The discovery of MOTS-C (and earlier — Humanin) showed that the mitochondrial genome also contains "hidden" open reading frames that encode signaling peptides.

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4. AMPK — the cell's energy sensor, in plain terms

To understand how MOTS-C works, one needs to understand its main target.

AMPK (AMP-activated protein kinase) is the cell's molecular "fuel gauge." When energy is sufficient (ATP is high), AMPK is dormant. When energy drops (ATP falls, AMP rises — during exercise, fasting, or stress), AMPK switches on and triggers a cascade of reactions:

• Switches the cell from "storage" to "expenditure"
• Enhances fat oxidation
• Increases glucose uptake by muscles
• Stimulates mitochondrial biogenesis — the creation of new mitochondria
• Suppresses energy-demanding anabolic processes

It is AMPK that is the switch through which physical exercise, metformin (one of the most studied metabolic drugs), and — as studies have shown — MOTS-C all work [1][5].

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5. MOTS-C and metabolism

In the original work by Lee and colleagues (2015), MOTS-C was administered to mice on a high-fat diet. Results [1]:

• Significant reduction in body weight gain compared with the control group
• Prevention of fatty degeneration of the liver
• Increased glucose utilization by skeletal muscle
• Increased AMPK activation in muscle tissue
• Increased expression of glucose transporters

In a 2019 metabolomic study (Kim and colleagues), MOTS-C was shown to lower three metabolic pathways characteristically elevated in obesity and type 2 diabetes: sphingolipid metabolism, monoacylglycerol metabolism, and dicarboxylate metabolism [3]. The authors describe an improvement in fatty acid beta-oxidation in the liver.

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6. MOTS-C and physical activity

The relationship works in both directions: physical exercise raises the expression of MOTS-C, and MOTS-C reproduces part of the metabolic effects of exercise.

In a study by Hyatt (2022), it was described that the level of MOTS-C in skeletal muscle increases after prolonged, regular physical activity. Moreover, a single administration of MOTS-C improved acute exercise performance in mice [6].

Yang and colleagues (2021) described a synergy of MOTS-C with physical exercise: combined exposure enhanced the expression of PGC-1α (a key regulator of mitochondrial biogenesis), reduced insulin resistance, and improved glucose metabolism via the AMPK pathway [7].

This makes MOTS-C interesting not as a "replacement for physical exercise," but as a molecule that may possibly work within the same cascade as it — enhancing the metabolic response to exercise.

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7. MOTS-C, stress, and nuclear translocation

One of the most unusual properties of MOTS-C: it is able to move from the cytoplasm into the cell nucleus.

Under conditions of cellular stress (oxidative stress, metabolic imbalance), MOTS-C translocates into the nucleus, where it interacts with the transcription factor NRF2 and regulates the expression of genes with antioxidant response elements (ARE) [5][8]. In effect, the mitochondrial peptide "sends a message" to the cell nucleus — this is a rare example of retrograde signaling from mitochondria to the nucleus.

This mechanism links MOTS-C not only to energy metabolism, but also to stress resistance at the cellular level — yet another reason for interest in it in the context of aging research.

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8. Age-related decline of MOTS-C

The circulating level of MOTS-C in blood plasma declines with age. This observation has been described in several works and correlates with the age-related decline in:

• Insulin sensitivity
• Muscle mass (sarcopenia)
• Mitochondrial function
• Physical endurance

In a 2021 review, MOTS-C was classified among candidate biomarkers of metabolic health: its level correlates with insulin resistance in lean (but not in obese) individuals, and in children and adolescents with obesity a decrease in circulating MOTS-C was observed [3][4].

The question of whether the decline of MOTS-C is a cause or a consequence of age-related metabolic changes remains open.

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Sources

1. Lee C., Zeng J., Drew B.G. et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab., 21(3): 443–454, 2015. PubMed

2. Lee C., Kim K.H., Cohen P. MOTS-c: a novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic. Biol. Med., 100: 182–187, 2016. PMC

3. Kim S.J. et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol. Rep., 7(13): e14171, 2019. PMC

4. Lu H. et al. MOTS-c: an equal opportunity insulin sensitizer. J. Mol. Med., 97: 487–490, 2019. PMC

5. Li H. et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Transl. Med. Aging, 7: 13–21, 2023. PMC

6. Hyatt J.K. MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose. Physiol. Rep., 10: e15377, 2022.

7. 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., 1867: 166126, 2021.

8. Kim K.H., Son J.M., Benayoun B.A., Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab., 28(3): 516–524, 2018. PubMed

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This material was prepared by the LONGIVIYA editorial team on the basis of published scientific research. The information is for educational purposes only and is not a medical recommendation.

For research use only. Not a medicinal product. Not intended for use in humans or animals. Independent verification of each batch: Janoshik Analytical (Czech Republic).