Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress

Obesity and type 2 diabetes mellitus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, anecdotal evidence contradicts this common belief. Accordingly, obese patients with cardiovascular disease have better prognoses relative to leaner patients with the same diagnoses, whereas treatment of T2DM patients with thiazolidinedione, one of the popular insulin-sensitizer drugs, significantly increases the risk of heart failure. Using mice with skeletal musclespecific ablation of the insulin receptor gene (MIRKO), we addressed this paradox by demonstrating that insulin signaling in skeletal muscles specifically mediated cross talk with the heart, but not other metabolic tissues, to prevent cardiac dysfunction in response to metabolic stress. Despite severe hyperinsulinemia and aggregating obesity, MIRKO mice were protected from myocardial insulin resistance, mitochondrial dysfunction, and metabolic reprogramming in response to diet-induced obesity. Consequently, the MIRKO mice were also protected from myocardial inflammation, cardiomyopathy, and left ventricle dysfunction. Together, our findings suggest that insulin resistance in skeletal muscle functions as a double-edged sword in metabolic diseases.