MOTS-c, a mitochondrial-derived peptide, has garnered attention for its multifaceted roles in metabolic regulation, cardiovascular protection, and cellular resilience. Recent rat studies have elucidated its potential therapeutic applications across various physiological systems.

In diabetic sand rats, an eight-week regimen of moderate-intensity interval training elevated MOTS-c levels, correlating with improved insulin sensitivity and increased expression of metabolic markers such as PGC-1α, GLUT4, and AMPK. These findings suggest that it may enhance mitochondrial biogenesis and glucose metabolism, offering a promising avenue for managing type 2 diabetes.

Beyond metabolic regulation, MOTS-c has demonstrated cardioprotective effects. In models of myocardial ischemia-reperfusion injury, MOTS-c administration suppressed ferroptosis—a form of regulated cell death—by activating the PPARγ signaling pathway. This intervention mitigated acute lung injury, highlighting it’s potential in preserving cardiac and pulmonary function post-surgery.

Neurologically, MOTS-c exhibits protective properties against oxidative stress. In rats exposed to rotenone, a neurotoxin, MOTS-c pretreatment activated the Nrf2/HO-1/NQO1 pathway, reducing oxidative damage and preserving dopaminergic neurons. This mechanism underscores its potential in neurodegenerative disease models.

Furthermore, MOTS-c has shown efficacy in skeletal health. In osteoporotic rat models, it promoted osteogenic differentiation of bone marrow mesenchymal stem cells via the TGF-β/Smad pathway, enhancing bone formation and offering a novel approach to osteoporosis treatment.

Collectively, these studies position MOTS-c as a versatile peptide with broad therapeutic potential. Its roles in metabolic enhancement, cardiovascular protection, neuroprotection, and bone health warrant further investigation to translate these findings into clinical applications.