Cardioprotective Effect of Metformin Treatment in Mouse Model of Experimental Autoimmune Myocarditis

BACKGROUND: Metformin is a well-established treatment for Type 2 diabetes. Beyond its role in glycemic control, metformin has gained attention for its pleiotropic effects, including cardioprotective properties. However, its role in autoimmune myocarditis and subsequent postinflammatory dilated cardiomyopathy remains poorly understood. METHODS: To investigate the role of metformin in autoimmune-mediated cardiac disease, we employed the experimental autoimmune myocarditis mouse model. Six to eight weeks old Balb/c mice were immunized twice with an α-myosin heavy chain peptide emulsified in complete Freund's adjuvant to induce myocarditis and progression toward dilated cardiomyopathy. Metformin was administered in two approaches: a preventive (from Days 0 to 21 or 40) and a therapeutic (from Days 21 to 40). Cardiac function and disease progression were evaluated at two time points: Day 21 (inflammatory phase) and Day 40 (fibrotic phase), using echocardiography, histopathological assessment, and molecular analyses. RESULTS: Treatment with metformin resulted in activation of the AMP-activated protein kinase-dependent signaling pathway during the inflammatory phase of myocarditis. This treatment was associated with activation of apoptosis-related pathways and a moderate reduction in inflammatory cell infiltration. Mice receiving metformin in the preventive approach exhibited preserved cardiac function. This was accompanied by decreased cardiomyocyte cross-sectional area and altered expression of hypertrophy-associated genes (Acta1 and Myh6). In contrast, neither preventive nor therapeutic administration of metformin significantly reduced the extent of myocardial fibrosis. CONCLUSION: Our findings suggest that metformin provides cardioprotective effects during the early inflammatory stages of autoimmune myocarditis and, to a lesser extent, during the later fibrotic remodeling phase. SIGNIFICANCE STATEMENT: Untreated acute myocarditis can lead to functional decline and postinflammatory dilated cardiomyopathy. Using an autoimmune myocarditis mouse model, we demonstrate that preventive metformin treatment reduces cardiac inflammation and preserves cardiac function. These findings suggest that metformin, in addition to its applications in diabetes, could be used to prevent inflammatory heart disease.