Introduction
The exploration of novel therapeutic avenues for weight management and metabolic health has led to the investigation of mitochondrial-derived peptides (MDPs), particularly Mitochondrial Open Reading Frame of the 12S rRNA Type-C (MOTS-c). This article delves into the multifaceted role of MOTS-c, its mechanisms of action, and its potential implications for weight loss and related metabolic disorders.
What is MOTS-c?
MOTS-c is a 16-amino acid peptide encoded within the mitochondrial DNA, specifically from the 12S rRNA region. Functioning as a regulator of metabolic homeostasis, MOTS-c is expressed in multiple tissues, especially skeletal muscles, and can be detected as a circulating hormone in the blood. It acts as an exercise-induced regulator of metabolic homeostasis and a modulator of obesity-, diet-, and aging-dependent metabolic function by acting as a systemic, endocrine-acting mitokine.
Mechanisms of Action
MOTS-c dynamically translocates to the nucleus in response to metabolic stress to directly regulate the expression of a broad spectrum of genes, including antioxidant response element-containing target genes. The mechanisms of action (MoA) of MOTS-c involve:
- Insulin sensitization.
- Enhanced glucose utilization.
- Suppression of mitochondrial respiration.
- Targeting of the folate-AICAR-AMPK pathway. By targeting folate-dependent de novo purine biosynthesis, MOTS-c boosts the levels of the endogenous AMP analog 5-aminomidazole-4-carboxamide ribonucleotide (AICAR), which in turn activates the master energy sensor AMP-activated protein kinase (AMPK).
These mechanisms overlap significantly with those of metformin, a widely used anti-diabetic drug.
MOTS-c and Exercise: An Exercise Mimetic?
Exercise interventions show promise as effective adjunct strategies to prevent and/or attenuate chemotherapy-associated toxicity in patients with early-stage breast cancer (BC). Pharmacological therapeutics that partially mimic the systemic impact of exercise have also been proposed for those cancer patients for whom exercise training may not be an option.
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Given that MOTS-c is a mitochondrially-encoded “exercise-mimetic peptide,” one might expect its levels to increase with exercise. Indeed, exercise interventions might also modulate host- and tumor-related pathways in patients on standard chemotherapy. Metformin shares many mechanistic features with MOTS-c, including insulin sensitization, enhancing glucose utilization, suppressing mitochondrial respiration, and targeting the folate-AICAR-AMPK pathway.
MOTS-c and Metformin: A Complex Relationship
While MOTS-c's mechanisms of action largely overlap with those of metformin, studies have explored whether metformin can influence the expression of MOTS-c in cancer patients. A study involving HER2-positive breast cancer patients randomized to receive metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin, found no significant alteration of circulating MOTS-c in response to 24 weeks of treatment with or without daily metformin.
Changes in circulating MOTS-c levels also failed to reach statistical significance when comparing patients achieving pathological complete response (pCR), irrespective of metformin treatment. The study suggests that the inability of metformin to target skeletal muscle, the major tissue for MOTS-c production and secretion, might limit its regulatory effects on circulating MOTS-c.
Potential Limitations and Considerations
Several limitations and considerations must be taken into account when interpreting studies on MOTS-c:
- Endogenous levels of circulating MOTS-c vary significantly depending on the assay method used.
- The exercise-induced augmentation of circulating MOTS-c in young subjects returns to baseline after only 4 hours of resting.
- Plasma and muscle MOTS-c show opposing responses to aging in older men, thereby suggesting that the primary source of circulating MOTS-c is not skeletal muscle or the pharmacokinetics of MOTS-c changes with age.
- The ability of muscle cells to release MOTS-c can be impaired due to changes in the export process and/or to the exhausted capacity of muscle (or hepatic) cells to tolerate or adapt to systemic metabolic stress occurring in cancer patients.
MOTS-c and Bone Metabolism
Recent studies have demonstrated a direct hormonal link between bone remodeling, food intake, and glucose metabolism, and the involvement of MOTS-c in bone metabolism. These studies demonstrated that MOTS-c promotes osteoblast proliferation, differentiation, and mineralization. Furthermore, it inhibits the osteoclastic differentiation involved in the regulation of bone metabolism and remodeling and possesses anti-osteoporotic effects.
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Potential Mechanisms of MOTS-c Involvement in Bone Metabolism in Osteoblasts
- Role of MOTS-c in TGF-β-mediated osteoblasts: MOTS-c has been shown to promote osteoblast differentiation and rescue bone loss by local injection into the area of ultra-high molecular weight polyethylene particle (UHMWPE) implantation, protecting the bone mass.
- Role of MOTS-c in osteoblasts mediated via the TGF-β/Smad pathway: TGF-β and Smad act synergistically to participate in the regulation of osteoblasts, directly or indirectly promoting osteoblast differentiation, inhibiting bone resorption, and promoting bone formation.
- Role of MOTS-c in the synthesis of type I collagen by osteoblasts: MOTS-c not only promoted the protein synthesis of TGF-β and Smad7 in osteoblasts, but also promoted the expression of type I collagen-related genes COL1A1 and COL1A2.
MOTS-c and Menopause
Postmenopausal women exhibit physiological alterations including weight gain, changes in adipose tissue distribution, and deterioration of insulin secretion, and sensitivity. These changes predispose them to develop type 2 diabetes. Furthermore, decreased levels of estrogen are associated with non-alcoholic steatohepatitis, osteoporosis, and cardiovascular diseases.
MOTS-c has been shown to prevent negative metabolic effects associated with menopause in an ovariectomized mouse model. It reduces both the weight gain as well as the insulin resistance associated with experimental menopause. Furthermore, MOTS-c also suppresses the increase in inflammatory markers such as IL-1ß and IL-6 in adipose tissue.
MOTS-c and Insulin Resistance
MOTS-c increases insulin sensitivity in skeletal muscle from aged, and high-fat fed, mice. Furthermore, MOTS-c dramatically decreases weight gain during high-fat-diet-induced obesity in mice, and prevents fat accumulation in liver, making it a potential target in NASH.
Plasma MOTS-c levels are lower in obese male children and adolescents, and are negatively correlated with markers of insulin resistance. MOTS-c levels are also positively correlated with coronary endothelial function in humans, and MOTS-c improves endothelial function in rats.
MOTS-c and Aging
Gradually disordered metabolic level is one of the signs of aging, which inhibit the normal physiological function of the body and even lose the ability to take care of themselves. The aging process could lead to a decrease in MOTS-c levels. In fact, MOTS-c levels in skeletal muscle and blood circulation in both humans and mice decrease with age. Studies have shown that blood MOTS-c levels in young people are 11% and 21% higher than those in middle- and old-aged people, respectively.
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MOTS-c and Cardiovascular Disease
Clinical evidence showed that nearly 1/3 of severely obese people suffered from heart failure. Recent studies have shown a protective effect of MOTS-c against cardiac dysfunction and pathological remodeling. MOTS-c prevented the development of heart failure via the activation of the AMPK pathway. MOTS-c improved angiogenesis, inflammation and apoptosis in terms of cell function, suggesting that MOTS-c may have the same effect as aerobic exercise and improve heart failure in patients with diabetes through NRG1-ErbB4 pathway.
MOTS-c and Inflammation
MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. MOTS-c has analgesic and anti-inflammatory effects through activation of AMPK pathway and inhibition of MAP kinase/c-Fos pathway.