Myocardial ischemia/reperfusion-induced glycolysis enhances damage through TRPM7 histone lactylation

Myocardial ischemia-reperfusion (I/R) is pivotal in myocardial infarction. Transient receptor potential melastatin 7 (TRPM7) plays an instrumental role in sustaining intracellular ion concentration and osmotic pressure. This study aimed to explore the function and mechanism of TRPM7 in the myocardial I/R model.

AC16 cardiomyocytes were exposed to hypoxia for 4 h and reoxygenated for 2, 4, 6, 8, and 12 h (H/R1 to H/R5). Cellular functions were evaluated using the MTT assay and flow cytometry. Protein expression was assessed by western blotting. Metabolic variations were detected with pyruvate and lactate kits. Chromatin Immunoprecipitation assays elucidated transcriptional regulation. A myocardial I/R model was constructed, and a TRPM7 inhibitor was administered in the corresponding group; immunohistochemistry, HE staining, and TUNEL assays were conducted for tissue-level detection.

The findings revealed a significant decline in cell survival rates, and an increase in apoptosis and TRPM7 expression of AC16 cardiomyocytes under hypoxia/reoxygenation (H/R) conditions, with peak effects in the H/R3 condition. Silencing TRPM7 significantly reversed H/R-induced Ca²⁺ influx, cell survival rates, and apoptosis. Metabolic analyses indicated an upregulation of glycolysis in AC16 cardiomyocytes under the early stage of H/R, evidenced by elevated glycolysis-related proteins, pyruvate, and lactate levels, and the glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) inhibited the expression of TRPM7. Subsequent assays showed that H/R-induced glycolysis promoted TRPM7 transcription through histone lactylation, a finding corroborated by the in vivo I/R model.

This study highlighted that histone lactylation could be a potential therapeutic target for modulating TRPM7 expression and mitigating I/R injury.