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

Metabolic alterations occur in the heart of patients with type 2 diabetes mellitus (T2DM). However, the relationships between branched-chain amino acid (BCAA) metabolism and the pathophysiology of diabetic cardiomyopathy (DbCM) remain unclear. Here, we sought to establish a novel model of DbCM and reveal its metabolic alterations, especially focusing on BCAA metabolism. Using adipocyte-specific 3′-phosphoinositide–dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice as a new model of DbCM, we demonstrated that cardiac BCAA catabolic enzymes were down-regulated in these mice, leading to the accumulation of BCAAs in the heart. Mechanistically, the accumulation of the BCAA leucine could cause cardiac hypertrophy via the activation of mammalian target of rapamycin complex 1 (mTORC1). A-PDK1KO mice mimic the cardiac phenotypes and metabolic alterations seen in human DbCM and exhibit impaired BCAA metabolism in the heart. This model may contribute to a better understanding of DbCM pathophysiology and the development of novel therapies for it. Heart tissues of adipocyte-specific 3′-phosphoinositide–dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice and PDK1 flox/flox mice (control). The tissues were collected and snap frozen in liquid nitrogen, subsequently stored at -80℃ until further analysis.