Mitochondrial peptide MOTS‐c suppresses systemic and cardiac inflammasome activation in a diabetic rat model

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Type 2 diabetes mellitus (T2DM) is associated with chronic systemic and cardiac inflammation, contributing to the development of diabetic cardiomyopathy. The mitochondrial-derived peptide mitochondrial open reading frame of the 12S rRNA type-C (MOTS-c) has emerged as a promising regulator of metabolic and inflammatory pathways. In this study, we investigated the effects of MOTS-c treatment on leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome activity in a high-fat diet and streptozotocin-induced T2DM rat model. MOTS-c treatment significantly reduced fasting blood glucose and circulating C-reactive protein levels, while selectively modulating plasma inflammatory cytokines, including interleukin (IL)-10 and IL-1β. Immunohistochemical analysis revealed reduced levels of NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and cleaved caspase-1 in left ventricular tissue following MOTS-c administration. Correlation analyses linked IL-18 and IL-1β with elevated markers, including low-density lipoprotein and uric acid, suggesting interplay between overall health and inflammasome activity. These results indicate that MOTS-c modulates both systemic and cardiac inflammation in T2DM, providing a novel therapeutic approach for reducing cardiovascular risk in diabetic patients.