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

Feb 10, 2025Cardiovascular research

The diabetes drug tirzepatide helps break down certain amino acids to prevent heart attacks in non-diabetic mice

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Abstract

Tirzepatide reduced mortality following myocardial infarction in mice by decreasing the infarct area and cardiomyocyte necrosis.

Tirzepatide was associated with increased cardiac tissue repair and decreased inflammation after myocardial infarction.
Untargeted metabolomics analysis indicated a positive correlation between tirzepatide and the pathway responsible for breaking down branched-chain amino acids (BCAAs).
Tirzepatide was shown to bind with a specific enzyme (BCKDHA) involved in BCAA metabolism.
Administration of tirzepatide reduced phosphorylation of BCKDHA, which enhanced BCAA breakdown and activated the mTOR signaling pathway.
Mice on a low-BCAA diet after myocardial infarction showed improved cardiac outcomes, which were further enhanced when combined with tirzepatide.

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AIMS: A novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, tirzepatide (LY3298176, TZP), has been developed to treat Type 2 diabetes mellitus (T2DM). In ischaemic heart diseases, TZP is involved in cardiac metabolic processes. However, its efficacy and safety in treating heart failure (HF) following myocardial infarction (MI) remain uncertain.

METHODS AND RESULTS: Herein, 12 week C57BL/6J mice were subjected to MI surgery, followed by administration of TZP. The effects of TZP on cardiac function and metabolism were thoroughly assessed by physiological, histological, and cellular analyses. Downstream effectors of TZP were screened through untargeted metabolomics analysis and molecular docking. Construct a lower branched chain amino acid (BCAA) diet model to determine whether TZP's cardioprotective effect is associated with reducing BCAA levels. Our results demonstrated that TZP reduced mortality following MI, decreased the infarct area, and attenuated cardiomyocyte necrosis. Pathological evaluation of cardiac tissues demonstrated increased fibrosis repair and decreased inflammatory infiltration. Mechanistically, untargeted metabolomics analysis uncovered a positive correlation between TZP and the BCAA catabolism pathway. The molecular docking verified that TZP could bind with branched-chain keto acid dehydrogenase E1 subunit α (BCKDHA). TZP reduced BCKDHA phosphorylation at S293, enhanced BCAA catabolism, and inhibited the activation of metabolism by activating rapamycin (mTOR) signalling pathway. Furthermore, mice fed a low-BCAA diet post-MI demonstrated reduced cardiomyocyte necrosis, increased fibrosis repair, and decreased inflammatory infiltration. These cardioprotective effects were further enhanced when used synergistically with TZP.

CONCLUSION: Taken together, our findings provide new perspectives on the unrecognized role of TZP in cardiac protection. TZP enhanced BCAA catabolism and attenuated BCAA/mTOR signalling pathway in MI mice. Consequently, this study may present novel therapeutic options for patients with HF.

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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

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