Role of PERM1 in the Development of Insulin Resistance and Diabetic Cardiomyopathy During High-Fat Diet Feeding

Heart failure is a leading cause of death in the United States, impacting approximately 6.7 million people. Several comorbidities are associated with heart failure, contributing to adverse clinical outcomes. Among these comorbidities, diabetes is highlighted as a prominent risk factor for heart failure, with approximately 20-40% of heart failure patients having type 2 diabetes. As the prevalence of heart failure continues to rise, there is a need for novel therapeutic methods to address this concern. PPARGC1 and ESRR Induced Regulator in Muscle 1 (PERM1) is a striated muscle-specific regulator of mitochondrial bioenergetics, predominantly expressed in skeletal and cardiac muscle. Our group has previously demonstrated that PERM1 is downregulated in both human and mouse failing hearts, and that Perm1-knockout mice exhibit reduced cardiac contractility and energy reserve. However, the role of PERM1 in cardiac dysfunction in diabetes remains unknown. We hypothesized that loss of PERM1 increases vulnerability to metabolic insults and exacerbates diet-induced insulin resistance and cardiac dysfunction. To test this, C57BL/6N male wild-type (WT) and Perm1-knockout (Perm1-KO) mice were fed either a normal diet or a high-fat diet (HFD; 60% calories from fat) for up to 43 weeks. We found that PERM1 expression was upregulated in the hearts of WT mice after 8 weeks of HFD feeding, coinciding with an increased level of carnitine palmitoyltransferase 2 (CPT2), a key enzyme involved in mitochondrial fatty acid uptake. Importantly, both WT and Perm1-KO mice exhibited similar increases in total body weight, fat mass, and fasting blood glucose levels throughout 43 weeks of HFD feeding, suggesting that loss of PERM1 did not accelerate the development of either obesity or diabetes. Echocardiographic assessments showed that WT mice maintained systolic and diastolic function, despite moderate cardiac remodeling, manifested as a subtle but significant increase of left ventricle posterior (LVPW) wall thickness. Unexpectedly, 8 weeks HFD feeding partially restored systolic function in Perm1-KO mice with no change in LVPW thickening. These findings show that while HFD feeding induced obesity and insulin resistance, its effect on cardiac function was relatively moderate and neither was exacerbated by the loss of PERM1. Unexpectedly, this study suggests that HFD feeding in Perm1-KO mice could partially compensate for cardiac dysfunction.