Impaired cardiac branched-chain amino acid metabolism in a novel model of diabetic cardiomyopathy

BACKGROUND: Systemic insulin resistance plays an important role in the pathogenesis of type 2 diabetes and its complications. Although impaired branched-chain amino acid (BCAA) metabolism has been reported to be involved in the development of diabetes, the relationship between cardiac BCAA metabolism and the pathogenesis of diabetic cardiomyopathy (DbCM) remains unclear. OBJECTIVES: The aim of this study was to investigate BCAA metabolism in insulin-resistant hearts by using a novel mouse model of DbCM. METHODS: The cardiac phenotypes of adipocyte-specific 3'-phosphoinositide-dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice were assessed by histological analysis and echocardiography. The metabolic characteristics and cardiac gene expression were determined by mass spectrometry or RNA sequencing, respectively. Cardiac protein expression was evaluated by Western blot analysis. RESULTS: A-PDK1KO mouse hearts exhibited hypertrophy with prominent insulin resistance, consistent with cardiac phenotypes and metabolic disturbances previously reported as DbCM characteristics. RNA sequencing revealed the activation of BCAA uptake in diabetic hearts. In addition, the key enzymes involved in cardiac BCAA catabolism were downregulated at the protein level in A-PDK1KO mice, leading to the accumulation of BCAAs in the heart. Mechanistically, the accumulation of the BCAA leucine caused cardiac hypertrophy via the activation of mammalian target of rapamycin complex 1 (mTORC1). CONCLUSIONS: A-PDK1KO mice closely mimic the cardiac phenotypes and metabolic alterations observed in human DbCM and exhibit impaired BCAA metabolism in the heart. This model may contribute to a better understanding of DbCM pathophysiology and to the development of novel therapies for this disease.