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.

Summary

In a mouse MI model, tirzepatide reduced mortality, infarct size, and cardiomyocyte necrosis, while promoting reparative fibrosis and dampening inflammation. Mechanistically, tirzepatide enhanced BCAA catabolism by binding BCKDHA, lowering its S293 phosphorylation, and attenuating BCAA/mTOR signaling; a low-BCAA diet synergized with tirzepatide.

Key Findings

• Tirzepatide reduced mortality and infarct size after MI and attenuated cardiomyocyte necrosis.
• Untargeted metabolomics linked tirzepatide to activation of BCAA catabolism; molecular docking showed binding to BCKDHA.
• Tirzepatide decreased BCKDHA S293 phosphorylation and suppressed BCAA/mTOR signaling.
• Low-BCAA diet post-MI reduced necrosis/inflammation and synergized with tirzepatide to enhance cardioprotection.

Clinical Implications

While preclinical, the data support clinical trials testing tirzepatide (and dietary BCAA restriction) in post-MI and HF populations, even without diabetes, and motivate biomarker-driven strategies targeting BCAA/mTOR signaling.

Limitations

• Preclinical mouse study with unspecified dosing/exposure-duration details and no human data
• Potential off-target effects of tirzepatide and species differences; safety in HF populations not assessed

Future Directions

Conduct randomized clinical trials of tirzepatide in post-MI/HF (with biomarker stratification by BCAA/mTOR signatures); investigate dose-response, timing post-MI, and interaction with dietary BCAA restriction.