MOTS-C 40mg

MOTS-c is a 16-amino acid peptide encoded within the mitochondrial DNA. It plays a crucial role in regulating cellular metabolism by influencing pathways related to glucose utilization, insulin sensitivity, and cellular stress responses. Under conditions of metabolic stress, MOTS-c translocates to the nucleus, where it modulates the expression of genes associated with mitochondrial biogenesis and metabolic regulation .

Mechanism of Action

MOTS-c operates by entering the cell nucleus and interacting with transcription factors that govern the expression of genes involved in energy metabolism and mitochondrial function. This interaction helps maintain cellular homeostasis, particularly during periods of metabolic stress, by enhancing the cell's ability to adapt to changing energy demands .

MOTS-c Research

Muscle Metabolism

Research in mice indicates that MOTS-c can reverse age-related insulin resistance in muscles by enhancing glucose uptake. It achieves this by improving the skeletal muscle response to AMPK activation, which increases the expression of glucose transporters. Importantly, this activation occurs independently of the insulin pathway, providing an alternative method to boost muscle glucose uptake when insulin is insufficient or ineffective. The overall effect is improved muscle function, enhanced muscle growth, and reduced functional insulin resistance.

Fat Metabolism

Studies in mice have shown that low estrogen levels lead to increased fat mass and dysfunction in normal adipose tissue, which raises the risk of insulin resistance and diabetes. Supplementing with MOTS-c increases brown fat activity and reduces adipose tissue accumulation. The peptide also appears to prevent adipose dysfunction and the inflammation that often precedes insulin resistance.

MOTS-c’s influence on fat metabolism is partly mediated through activation of the AMPK pathway, a critical energy sensor that promotes glucose and fatty acid uptake for metabolism. This is the same pathway activated by ketogenic diets, such as the Atkins diet, which encourage fat metabolism while preserving lean body mass. MOTS-c targets the methionine-folate cycle, increases AICAR levels, and activates AMPK.

New research suggests MOTS-c can translocate from mitochondria to the nucleus, where it regulates gene expression involved in glucose restriction and antioxidant responses following metabolic stress.

Evidence also indicates that MOTS-c regulates lipid metabolism by downregulating sphingolipid, monoacylglycerol, and dicarboxylate pathways while increasing beta-oxidation. This action helps prevent fat accumulation and may offer new strategies to combat obesity and diabetes by addressing mitochondrial fat metabolism dysfunction, which contributes to insulin resistance and excessive fat storage.

Insulin Sensitivity

Research measuring MOTS-c levels in insulin-sensitive and insulin-resistant individuals shows the peptide correlates with insulin sensitivity primarily in lean subjects. This suggests MOTS-c plays a role in the development of insulin insensitivity rather than its maintenance. Scientists believe MOTS-c could serve as a biomarker for pre-diabetic lean individuals, potentially acting as an early warning sign. Supplementation might help delay insulin resistance and diabetes onset. While mouse studies are promising, further research is needed to fully understand MOTS-c’s effects on insulin regulation.

Osteoporosis

MOTS-c contributes to bone health by promoting type I collagen synthesis through the TGF-beta/SMAD signaling pathway, which supports osteoblast survival. Studies show MOTS-c also enhances osteogenic differentiation of bone marrow stem cells via the same pathway, leading to increased bone formation. Thus, MOTS-c not only protects existing bone cells but also encourages new bone development.

Longevity

Research has identified a variant of the MOTS-c gene linked to exceptional longevity in populations such as the Japanese. This variant substitutes glutamate for lysine at position 14 of the peptide, likely altering its structure and function. While the exact impact is unclear, this genetic difference may contribute to the increased lifespan observed in Northeast Asian populations.

Dr. Changhan David Lee of USC Leonard Davis School of Gerontology emphasizes the crucial role of mitochondrial biology in extending human lifespan and healthspan. Until recently, dietary restriction was the only proven way to influence mitochondrial function and longevity. Peptides like MOTS-c offer new potential to directly enhance mitochondrial performance.

Heart Health

Studies measuring MOTS-c levels in patients undergoing coronary angiography found that lower MOTS-c correlates with greater endothelial dysfunction. Endothelial cells line blood vessels and regulate blood pressure, clotting, and plaque formation. Research in rats shows that while MOTS-c may not directly alter vessel responsiveness, it enhances endothelial sensitivity to signaling molecules like acetylcholine, improving vascular function.

MOTS-c is one of several mitochondria-derived peptides (MDPs) that protect cardiac cells from stress and inflammation. Dysregulation of MDPs is believed to contribute to cardiovascular disease development, reperfusion injury, and endothelial dysfunction.

About the Researchers

Dr. Changhan David Lee and Dr. Pinchas Cohen are leading scientists researching mitochondrial peptides like MOTS-c and their therapeutic potential in diabetes, Alzheimer’s, and aging-related diseases. Dr. Cohen, dean of the USC Leonard Davis School of Gerontology, discovered several mitochondrial peptides including humanin and MOTS-c, which have shown promise as insulin sensitizers and metabolic regulators.

Note: These scientists do not endorse or promote any product sales related to MOTS-c. Their work is cited here to credit their extensive research contributions.

Research Applications

Studies have investigated the potential therapeutic effects of MOTS-c in various conditions associated with mitochondrial dysfunction, including:

• Neurological Disorders: Research suggests that MOTS-c may play a role in protecting against age-related cognitive decline and neurodegenerative diseases.
• Metabolic Diseases: MOTS-c has been shown to improve insulin sensitivity and reduce obesity in animal models.
• Cardiovascular Conditions: Preliminary studies indicate that MOTS-c may help improve endothelial function and reduce vascular calcification.
• Musculoskeletal Health: MOTS-c treatment has been associated with increased exercise capacity and muscle strength in aging models.

While these findings are promising, further research is needed to fully understand the therapeutic potential and safety profile of MOTS-c in humans.

Safety and Usage

MOTS-c is currently available for research purposes only and is not approved for human consumption. It is typically provided in a lyophilized (powder) form to ensure maximum stability. Researchers interested in studying MOTS-c should adhere to appropriate safety protocols and ethical guidelines.

Referenced Citations

• Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016 Nov;100:182-187. [PMC] 
• Lu H, et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med (Berl). 2019 Apr;97(4):473-485. [PubMed] 
• Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018 Sep;28(3):516-524.e7. [PMC] 
• Kim S-J, et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol Rep. 2019 Jul;7(13):e14171. [PubMed] 
• Crescenzo R, Bianco F, Mazzoli A, Giacco A, Liverini G, Iossa S. A possible link between hepatic mitochondrial dysfunction and diet-induced insulin resistance. Eur J Nutr. 2016 Feb;55(1):1-6. [BMJ] 
• Cataldo LR, Fernandez-Verdasio R, Santos JL, Galgani JE. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not obese individuals. J Investig Med. 2018 Aug;66(6):1019-1022. [PubMed] 
• Che N, et al. MOTS-c improves osteoporosis by promoting the synthesis of type I collagen in osteoblasts via TGF-β/SMAD signaling pathway. Eur Rev Med Pharmacol Sci. 2019 Apr;23(8):3183-3189. [PubMed] 
• Hu BT, Chen WZ. MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway. Eur Rev Med Pharmacol Sci. 2018 Nov;22(21):7156-7163. [PubMed] 
• Fuku N, et al. The mitochondrial-derived peptide MOTS-c: A player in exceptional longevity? Aging Cell. 2015 Aug;14(4):e12308. [ResearchGate] 
• Qin Y, et al. Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction. Int J Cardiol. 2018 Jan;254:23-27. [PubMed] 
• Yang Y, et al. The role of mitochondria-derived peptides in cardiovascular disease: Recent updates. Biomed Pharmacother. 2019 Jun;117:109075. [PubMed]