MOTS-c Research

Lee C, Zeng J, Drew BG, et al.

The foundational study that first identified MOTS-c and established its role in metabolic regulation. Researchers found that MOTS-c is encoded by mitochondrial DNA, is released into circulation in response to metabolic stress, and acts on skeletal muscle to improve glucose uptake via AMPK activation. In mice fed a high-fat diet, MOTS-c treatment significantly reduced obesity and insulin resistance without altering food intake — suggesting a direct effect on metabolic rate. This paper established MOTS-c as a novel mitochondrial-derived hormone with broad metabolic relevance.

Reynolds JC, Lai RW, Woodhead JST, et al.

This study established MOTS-c as an exercise-induced peptide — showing that MOTS-c levels increase 11.9-fold in skeletal muscle after exercise in humans. More strikingly, MOTS-c treatment significantly enhanced physical performance in young, middle-aged, and old mice. When treatment was started very late in life (equivalent to human old age), it still improved physical capacity and healthspan — suggesting therapeutic potential even when initiated after decline has begun. This positions MOTS-c as a potential exercise mimetic for aging populations with limited mobility.

Zhu Y, Gu L, Lin X, et al.

A comprehensive review synthesizing a decade of MOTS-c research across multiple disease models. The review covers MOTS-c’s mechanisms including AMPK activation, nuclear translocation during stress, anti-inflammatory effects, and insulin sensitization. It documents lower MOTS-c levels in type 2 diabetes, gestational diabetes, and obese children — establishing clinical associations between MOTS-c deficiency and metabolic disease. The paper also discusses MOTS-c’s cardiovascular protective effects and its potential applications in aging, noting that no effective clinical application method has yet been established.

Lim YX, et al.

One of the most recent MOTS-c studies, examining its effects in a type 2 diabetic heart model. MOTS-c treatment restored mitochondrial respiratory function, reduced cardiac oxidative stress, and delayed weight gain in diabetic rats — without affecting food intake. The study confirms that MOTS-c directly increases whole-body metabolic rate rather than simply reducing appetite, and extends its relevance beyond skeletal muscle to cardiac metabolic function — a significant finding given that heart failure is the leading cause of death in type 2 diabetes.