MOTS-c

Description

   

MOTS-c Vial Peptide

Research suggests MOTS-c vial is a mitochondrial peptide designed to regulate metabolism and insulin action . It is an MDP (mitochondrial-derived peptide) encoded as an sORF (short open reading frames) in the mitochondrial 12S rRNA. MOTS-c has a range of biological functions such as stress response and metabolic regulation. MOT-c can translocate to the nucleolus to respond to metabolic stress.

ABOUT MOTS-C PEPTIDE

MOTS‐c is a peptide of 16 amino acids expressed by a mitochondrial gene. Research  provides evidence that mitochondria play a key role in signaling and in energy production.

MOTS-c regulates metabolic functions throughout the body, including turning glucose into usable energy. Preliminary studies show evidence for improved control over blood sugar levels for those with type 2 diabetes and obesity.

Research also shows that skeletal muscle is the major target tissue of MOTS‐c. The skeletal muscle enhances insulin sensitivity and increases glucose uptake in myocytes (muscle cells) by activating the AMPK pathway and at the same time without increasing insulin. It is fair to call MOTS‐c an exercise‐mimetic, meaning it imitates exercise on the body. Exercise also increases muscle glucose uptake without stimulating insulin.

AMPK (AMP‐activated protein kinase), was identified in 1999 as the master switch for metabolism and the central regulator of both glucose and lipid (fat) metabolism. Since then it has been a target for therapeutic intervention against metabolic conditions such as type‐2 diabetes.

Cellular Metabolism Regulation

HEK293 cells treated with MOT-c were subjected to microarray analysis, the results showed that MOT-c vial is a biologically active peptide. A clear global gene expression profile shifted 72 hours after MOT-c treatment, this was showed by PCA (principal component analysis). Parametric analysis of gene  set enrichment showed that gene expression was altered significantly four hours after MOTS-c treatment and became more distinct after 72 hours.

Genes associated with cellular metabolism and inflammation showed a distinct expression after MOTS-c treatment. An examination of the effects of MOTS-c on cellular metabolism showed that 194 metabolites out of the 356 known metabolites altered significantly by MOTS-c ST cells, 49 of the metabolites were altered 24 hours after the MOTS-c ST treatment and 177 metabolites were altered after 72 hours. The pattern of the metabolites progressed with time with most biochemicals remaining consistently altered at both 24 and 72 hours.

There was an overlap between the metabolites altered in MOTS-c ST(stably expressing MOTS-c) and MOTS-c (exogenous synthetic MOTS-c) most of the metabolites altered in MOTS-c ST cells overlapped with those treated with MOTS-c for 72 hours. Metabolites involved in purine metabolism and dipeptide metabolism were constantly reduced while the metabolites involved acylcarnitine metabolism and methionine cycle were constantly increased.

Benefits of Mots-C Vial

  • Enhances the liver’s ability to process fatty acids.
  • Enhances metabolic adaptability and balance.
  • Mitochondrial energy is regulated.
  • Has a protective effect against insulin resistance and obesity caused by ageing and poor nutrition.
  • Helps with weight loss.
  • Strengthens the body’s ability to withstand the effects of metabolic stress.
  • Exercise capability is increased.
  • Osteoporosis can be prevented.
  • Glucose levels are better controlled.
  • Cellular differentiation into osteoblasts is enhanced.

 

Properties: 

❖ MOTS-c is a 16-amino-acid peptide encoded in the mitochondrial genome.

❖ Sequence: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Leu-Phe-Tyr-Pro-Arg-Lys-Leu-Arg
❖ MW: 2288.6 g/mol
❖ Molecular formula: C10H152N28O22S2
Description: (Description by International Peptide Society)
Mitochondrial-derived peptides (MDPs), encoded by mitochondrial DNA, play a cytoprotective role by helping preserve mitochondrial function and cell viability under stressful conditions. MDPs signal within the cell or are released to act as autocrine/paracrine/endocrine cytoprotective factors and play a key role in the cellular stress response.
The MDP family includes human and SHLPs encoded from the 16S rRNA region and have broad protective effects and MOTS-c which is encoded from the 12S rRNA region and has metabolic signaling activity with potent anti-obesity effects. MDPs have been used clinically in various disease models and reported to play a role in many pathologies, including senolytic activity and delaying the progression of atherosclerosis, Alzheimer’s and chemotherapy-induced side-effects, supporting glucose/insulin regulation, weight management, and cardiovascular health, among other functions.
One of these MDPs, MOTS-c, holds great potential as a target to treat metabolic signaling issues by regulating muscle and fat physiology, and perhaps even extend a healthy lifespan.
MOTS-c is a 16-amino acid peptide encoded within the 12S rRNA region of mtDNA. It is measured in plasma and multiple tissues including muscle, brain, and liver. MOTS-c levels are correlated with insulin resistance in lean, not obese, individuals, and circulating MOTS-c levels are reduced in obese male children and adolescents, but not in obese females. MOTS-c is also involved in lung, bone, and cardiovascular disease.
Metabolic Signaling/ Insulin Sensitivity
MOTS-c bottom line is it helps turn available glucose into energy in the mitochondria. MOTS-c dramatically increases endogenous 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) levels and activates 5′ AMP-activated protein kinase (AMPK). MOTS-c increases glucose utilization, and fatty acid oxidation, and alters mitochondrial function and nucleotide metabolism. MOTS-c has been reported to target the skeletal muscle and enhance glucose metabolism.
MOTS-c levels are correlated with markers of insulin resistance and obesity including BMI, waist circumference, waist-to-hip ratio, fasting insulin level, HOMA-IR, and HbA1c. In addition, MOTS-c levels are correlated with endothelial function in humans. The effects of MOTS-c include:
❖ Increased glucose utilization and fatty acid oxidation
❖ Decreased oxidative phosphorylation
❖ Increased endogenous AICAR levels
❖ AMPK activation
❖ Increased glucose uptake into muscle cells
In laboratory studies, MOTS-c administration in high-fat diet-fed mice decreases weight gain by increasing energy expenditure and significantly decreases fat accumulation in the liver. The levels of insulin also were lower in MOTS-c–injected mice, suggesting that MOTS-c improves insulin sensitivity in high-fat diet-induced mice.
MOTS-c is reported to increase adipose thermogenic activation to promote cold adaptation. MOTS-c is reported to dramatically upregulate brown adipose tissue (BAT) thermogenic gene expression and increase white fat “browning”, probably mediated by activated phosphorylation of the ERK signaling pathway by MOTS-c.
MOTS-c is reported as a potential biomarker for metabolic function. As discussed earlier, MOTS-c levels are inversely correlated with markers of insulin resistance and obesity.
Aging and Longevity:
MOTS-c levels decline with age. Mitochondria are strongly implicated in aging and age-related diseases, and with the promising research and potential beneficial effects of MOTS-c in regulating metabolic homeostasis, the therapeutic implications in obesity and diabetes are evident.
There are metabolic links between known age modifiers and MOTS-c. NAD+ is a key metabolic coenzyme involved in redox reactions that decline with age, and restoring its levels can improve age-related disease conditions. Further, NAD+ is a potent activator of sirtuins, which are conserved multifunctional regulators of aging and age-related diseases in various model organisms from yeast to mammals. MOTS-c is reported to increase intracellular NAD+ levels and MOTS-c-dependent glycolytic effects are mediated by sirtuin 1 (SIRT1).
In addition, MOTS-c restricts the folate/methionine cycle, causing a reduction in methionine metabolism. This leads to a depletion of intracellular 5MTHF, increased levels of AICAR, and activation of AMPK in the presence of ATP accumulation and decreased mitochondrial respiration. It also may lead to increased homocysteine levels and folate depletion. In rodents, methionine restriction can increase lifespan by about 45%, decrease age-related diseases (such as cancer and type 2 diabetes), delay lens deterioration, reduce visceral fat, and increase the major antioxidant glutathione (GSH). Note this regulation of the folate-AICAR-AMPK pathway is similar to the drug methotrexate.
MOTS-c: Mitochondrial-encoded regulator of metabolic homeostasis
Exercise:
Mitochondria are key bioenergetics sources that fuel skeletal muscle during exercise, but they are also actively engaged in transmitting exercise-induced signals to other organs. Although the effect of exercise on regulating MOTS-c production and secretion is unknown, its beneficial effects on a high-fat diet (HFD) are mirrored by MOTS-c. As discussed earlier, MOTS-c increases cellular levels of AICAR (an AMPK agonist) and activates AMPK, a well-described regulator of exercise. In laboratory studies, MOTS-c injections were reported to activate mouse skeletal muscle AMPK and increase the level of the downstream glucose transporter GLUT4. MOTS-c may also act as a potential mitochondrial signal that mediates an exercise-induced mitohormesis response, thereby stimulating physiological adaptation and increased tolerance to exercise.
MOTS-c Promotes Metabolic Homeostasis
Cardiovascular Health
Aging, hyperlipidemia, insulin resistance, and atherosclerosis are all risk factors for cardiovascular diseases. MOTS-c is reported to protect against coronary endothelial dysfunction by the reduction of the release of pro-inflammatory cytokines and adhesion molecules, which results from the inhibition of NF-κB. MOTS-c is also involved in lipid metabolism. MOTS-c improves lipid utilization by stimulating carnitine shuttles to increase the level of β-oxidation. Moreover, MOTS-c can also reduce HFD-induced visceral fat accumulation and hepatic steatosis, but it is unclear whether this is due to decreased lipogenesis or increased lipolysis. In vitro, MOTS-c reduces triglyceride content, promotes AKT activity, and reduces lipid droplet deposition through the AMPK pathway in adipocytes. Although the genes associated with lipid oxidation did not change, the genes related to lipogenesis were significantly inhibited by MOTS-c treatment.
Studies also report MDPs to play a protective role in myocardial ischemia-reperfusion injury. A laboratory study reported MOTS-c attenuated vascular calcification and secondary myocardial remodeling by activating the adenosine monophosphate-activated protein kinase signaling pathway (AMPK) and suppressing the expression of the angiotensin II type 1 (AT-1) and endothelin B (ET-B) receptors.
Osteoporosis Prevention/Treatment
MOTS-c is reported to play a role in the synthesis of type 1 collagen by osteoblasts in bone tissue. MOTS-c is reported to suppress ovariectomy-induced osteoporosis via AMPK activation and improve osteoporosis via the TGF-βeta/SMAD pathway. MOTS-c also inhibits osteolysis by affecting osteocyte-osteoclast crosstalk and inhibiting inflammation in laboratory studies.
MOTS-c Osteolysis Inhibition
Benefits:
❖ Assists in mitochondrial biogenesis
❖ Activates AMPK
❖ Restores homeostasis by initiating a catabolic process for ATP production
❖ Decreases insulin resistance
❖ Increases GLUT4 uptake in muscle
❖ Improves athletic performance
❖ Improves weight loss
Clinical Pearls:
❖ This is an amazing peptide; an overall favorite
❖ The serum can be thick and sometimes there is some pruritus locally at the injection site for 5-15 minutes. We have our patients split the dose into two separate syringes; do ½ into one glute and ½ into the other to reduce the intensity of any local irritation.
❖ We follow a customary protocol of injecting once weekly for 4-6 weeks
❖ Always allow 2-3 months off in between uses
Dosing:
❖ Advitam Dosing: 10mg (split into two separate syringes) injected SubQ once weekly x 4-5 weeks
❖ Alternative dosing: 5mg injected SubQ 3x/wk x 4 wks
Safety/side effects:
❖ MOTS-c is reported safe in recommended dosages.
❖ Injection site pruritus.
❖ As with all injections, redness, and pain at the site of injection may be present.
❖ As MOTS-c targets the folate cycle and de novo purine biosynthesis pathways, it is possible a depletion of intracellular 5-methyl tetrahydrofolate (5-MTHF) may occur when using MOTS-c protocols. It may be advised to supplement the diet with folate as folinic acid or 5-MTHF, up to 1,200 mcg daily, between injections in the protocol, especially in those prone to folate deficiencies or methylation issues.
❖ It is recommended to check homocysteine and folate levels in patients taking MOTS-c.