MOTS-c suppresses systemic and cardiac NLRP3 inflammasome activation in diabetic rats

Chronic systemic and cardiac inflammation is a hallmark of Type 2 diabetes mellitus (T2DM), significantly contributing to the development of diabetic cardiomyopathy (DCM), a common and severe complication with limited effective treatments. The NLRP3 inflammasome pathway is a key driver of this inflammation, exacerbating metabolic dysfunction and tissue damage. Mitochondrial-derived peptide MOTS-c has emerged as a promising regulator of both metabolic and inflammatory pathways, offering a potential novel therapeutic avenue to address the inflammatory burden and cardiovascular risk in diabetic patients.

Researchers established a Type 2 diabetes mellitus (T2DM) rat model using a high-fat diet combined with streptozotocin induction to mimic human disease pathology. Animals were then subjected to MOTS-c treatment (specific dose not detailed in abstract). The study assessed systemic metabolic and inflammatory parameters, including fasting blood glucose and circulating C-reactive protein (CRP) levels. Plasma inflammatory cytokines, specifically interleukin (IL)-10 and IL-1β, were quantified. To evaluate cardiac inflammation, immunohistochemical analysis was performed on left ventricular tissue, targeting NLRP3, ASC, and cleaved caspase-1 protein expression. Correlation analyses were also conducted to explore relationships between inflammatory markers and metabolic parameters.

MOTS-c treatment significantly reduced fasting blood glucose levels, a key marker of glycemic control in diabetes. Concurrently, circulating C-reactive protein (CRP) levels, a systemic inflammatory biomarker, were also significantly decreased. The peptide selectively modulated plasma inflammatory cytokines, specifically increasing anti-inflammatory interleukin (IL)-10 and reducing pro-inflammatory IL-1β. Immunohistochemical analysis of left ventricular tissue revealed a marked reduction in key components of the NLRP3 inflammasome pathway: NLRP3 itself, apoptosis-associated speck-like protein containing a caspase activation and recruitment card (ASC), and cleaved caspase-1. These reductions indicate a direct suppression of cardiac inflammation at the molecular level. Correlation analyses further linked elevated levels of pro-inflammatory cytokines like IL-18 and IL-1β with other adverse markers such as low-density lipoprotein (LDL) and uric acid, underscoring the interconnectedness of metabolic dysregulation and inflammasome activation in T2DM.

MOTS-c treatment effectively suppressed both systemic and cardiac NLRP3 inflammasome activation, leading to improved glycemic control and reduced inflammatory burden in diabetic rats.