Multimodal Therapeutic Strategies Targeting BCAA Metabolism in Diabetic Cardiomyopathy: A Path to Cardioprotection.

A serious consequence of diabetes mellitus, diabetic cardiomyopathy (DCM) is marked by structural and functional abnormalities leading to diastolic dysfunction, eventually leading to systolic dysfunction and heart failure. Branched-chain amino acids (BCAAs), leucine, isoleucine, and valine have a dual role in cardiac metabolism. Although they are essential for mitochondrial function and protein synthesis, elevated levels of BCAA contribute to insulin resistance, stimulate mTOR signaling, and proinflammatory pathways, resulting in cardiac hypertrophy and heart failure in DCM. This review explores therapeutic approaches to target BCAA metabolism. By suppressing mTOR signaling and cardiac reprogramming, strategies such as restriction of dietary BCAA and substitution with plant-based protein can improve insulin sensitivity and cardiac reprogramming. For enhancement of BCAA catabolism, alleviation of oxidative stress, and reduction in myocardial fibrosis, pharmacological agents such as mTOR inhibitors, branched-chain α-keto acid dehydrogenase (BCKDH) activators, and fibroblast growth factor 21 (FGF21) analogs can be utilized. PPARα agonists, insulin sensitizers, can indirectly benefit cardiac health by improving glucose metabolism and systemic inflammation. While lifestyle modification, such as physical activity, enhances mitochondrial function and autophagy, novel and innovative approaches, such as leucine deprivation or L-type amino acid transporter (LAT1) inhibitors, can manage the cardiac damage arising due to BCAA. Future studies should focus on personalized and multidisciplinary treatments incorporating pharmacological and lifestyle modifications to better understand the complex function of BCAA metabolism in DCM. Advanced molecular studies and clinical trials are essential for optimizing these strategies to investigate innovative ways of cardioprotection in diabetic patients.