Inside the body with MOTS-c

MOTS-c is translated from a 51-nucleotide short open reading frame within the mitochondrial 12S rRNA gene (MT-RNR1), giving a 16-residue peptide. It is reported to be expressed in several tissues, including skeletal muscle, and to be present in blood. It was described as a mitochondrial-DNA-encoded peptide that regulates insulin sensitivity and metabolic homeostasis.[src][src][src]

In 10 sedentary healthy young men (mean age 24.5) performing stationary cycling, endogenous MOTS-c in skeletal muscle (western blot) rose 11.9-fold after exercise and stayed raised after 4 hours of rest, with a trend back toward baseline; plasma MOTS-c (ELISA) rose 1.6-fold during and 1.5-fold after exercise and returned to baseline after 4 hours of rest. Measurement of endogenous plasma MOTS-c is unsettled: an LC-MS method could not confirm the ELISA-derived concentration range in 20 healthy subjects, and FDA notes the peptide is rapidly cleaved in human whole blood in vitro, so how long an injected dose stays active is unknown.[src][src][src]

In cells, MOTS-c inhibits the folate cycle and tethered de novo purine biosynthesis, causing AICAR accumulation and AMPK activation. In mice, MOTS-c treatment activated AMPK in skeletal muscle and raised expression of the glucose transporter GLUT4, and the authors concluded that skeletal muscle appears to be the primary target organ. All of this is preclinical (mouse and cell) evidence; the upstream molecular target is unknown.[src][src][src]

Following metabolic stress (glucose restriction) MOTS-c translocates to the nucleus in an AMPK-dependent manner, where it regulates a broad set of genes including those with antioxidant response elements and interacts with stress-responsive transcription factors such as NFE2L2 (NRF2). This was shown in cultured cells; the in-vivo and human significance is not established.[src]

In male CD-1 mice on a high-fat diet, MOTS-c treatment prevented diet-induced obesity and hyperinsulinemia, and in C57BL/6 mice it prevented high-fat-diet-induced and age-dependent insulin resistance; FDA reviewers cite about 20% lower body weight than vehicle after 8 weeks of treatment on a high-fat diet. FDA also notes that dose-response relationships are missing and that the clinical relevance of these rodent findings is unknown. Mouse-only evidence.[src][src]

MOTS-c levels fall with ageing and senescence in pancreatic islet cells. In aged C57BL/6 mouse islets MOTS-c reduced senescence by modulating nuclear gene expression and metabolites, and it improved glucose intolerance in S961-treated and non-obese diabetic mice. In humans, circulating MOTS-c was lower in people with type 2 diabetes than in healthy controls (cross-sectional association only). A separate short report proposed that the m.1382A>C variant in the MOTS-c coding region, specific to Northeast Asian populations, may help explain the high longevity of Japanese people; this is a hypothesis, not a demonstrated effect.[src][src]

As summarised by FDA reviewers, preclinical studies report that MOTS-c promoted osteogenic differentiation of rat bone marrow mesenchymal stem cells in vitro, inhibited osteolysis in vivo and in vitro, and reduced vascular calcification with associated myocardial remodeling in a rat model. These are rodent and cell findings only, and FDA did not identify clinical studies for osteoporosis or vascular uses.[src]