Glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist tirzepatide promotes branched chain amino acid catabolism to prevent myocardial infarction in non-diabetic mice.

This article investigates the cardioprotective effects of tirzepatide (TZP), a novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, in non-diabetic mice following myocardial infarction (MI). The study demonstrates that TZP reduces mortality, infarct size, cardiomyocyte necrosis, and inflammation while promoting early fibrotic repair and improving cardiac function post-MI. Mechanistically, TZP enhances branched-chain amino acid (BCAA) catabolism by binding to and activating the key enzyme branched-chain keto acid dehydrogenase E1 subunit α (BCKDHA), reducing its phosphorylation at S293, which decreases BCAA accumulation and inhibits the mTOR signalling pathway implicated in cardiac remodelling. Additionally, a low-BCAA diet independently improves cardiac outcomes after MI and synergizes with TZP to further enhance BCAA catabolism and cardiac protection. These findings suggest TZP as a potential therapeutic agent for heart failure post-MI through modulation of BCAA metabolism.