Branched-chain amino acids deficiency promotes diabetic cardiomyopathy by activating autophagy of cardiac fibroblasts

Rationale: More than half of the patients with type II diabetes mellitus (T2D) develop diabetic cardiomyopathy (DCM). Glycemic control alone cannot effectively prevent or alleviate DCM. Methods: Herein, we concentrated on the variations in levels of metabolites between DCM and T2D patients without cardiomyopathy phenotype. In high-fat diet/low-dose streptozotocin-induced T2D and leptin receptor-deficient diabetic mouse models, we investigated the effect of altering branched-chain amino acids (BCAAs) levels on DCM. Results: We discovered that the levels of plasma BCAAs are notably lower in 15 DCM patients compared to 19 T2D patients who do not exhibit cardiomyopathy phenotype, using nuclear magnetic resonance analysis. This finding was further validated in two additional batches of samples, 123 DCM patients and 129 T2D patients based on the BCAA assay kit, and 30 DCM patients and 30 T2D patients based on the LC-MS/MS method, respectively. Moreover, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated cardiomyopathy phenotypes in diabetic mice. Furthermore, BCAA deficiency promoted cardiac fibroblast activation by stimulating autophagy in DCM mice. Mechanistically, BCAA deficiency activated autophagy via the AMPK-ULK1 signaling pathway in cardiac fibroblasts. Using pharmacological approaches, we validated our findings that autophagy inhibition relieved, whereas autophagy activation aggravated, DCM phenotypes. Conclusions: Taken together, we describe a novel perspective wherein BCAA supplementation may serve as a potential therapeutic agent to mitigate DCM and fibrosis. Our findings provide insights for the development of preventive measures for DCM.