Effects and mechanisms of methylmalonic acid on myocardial ischemia/reperfusion injury
LIU Zhiyuan
WANG Xinyi
SUN Fangfang
TAO Ling
CHEN Xiyao
ZHANG Fuyang
Abstract：Objective To elucidate the impact of methylmalonic acid(MMA)on myocardial ischemia/reperfusion(MI/R)injury and to explore its downstream molecular mechanisms.Methods C57BL/6J mice were subcutaneously implanted with micro-osmotic pumps to continuously infuse either Vehicle or MMA.The mice were then randomly subjected to MI/R via left anterior descending coronary artery ligation or a Sham operation.Left ventricular tissues were collected 3 h post-surgery,and the changes of gene expression in left ventricle were analyzed by RNA-sequencing(RNA-Seq).Left ventricular systolic function was assessed using M-mode echocardiography 24 h post-surgery.The percentage of apoptosis in cardiomyocytes was evaluated using TUNEL staining.The degree of left ventricular interstitial fibrosis was assessed using Masson's trichrome staining 14 d post-surgery.Primary cardiomyocytes isolated from neonatal C57BL/6J mice were incubated with cell membrane-permeable diethyl methylmalonic acid(D-MMA)or Vehicle for 12 h.Cardiomyocyte viability was determined using a cell viability assay kit.Mitochondrial ultrastructural changes were observed via transmission electron microscopy,and mitochondrial function changes of cardiomyocytes were detected using the Seahorse analyzer.Results Compared with MI/R+Vehicle group,MMA significantly exacerbated MI/R-induced left ventricular systolic dysfunction(P＜0.01),increased the percentage of apoptosis in cardiomyocytes(P＜0.01),and worsened myocardial interstitial fibrosis 14 d post-surgery(P＜0.01).RNA-Seq analysis indicated that MMA significantly inhibited gene expression of a series of mitochondrial-related pathways in cardiomyocytes.Consistent with the results of in vivo experiments,D-MMA incubation directly reduced neonatal mouse cardiomyocyte viability(P＜0.05,P＜0.01),and damaged the ultrastructure of mitochondria.Seahorse analysis showed that D-MMA incubation significantly inhibited mitochondrial respiration of primary neonatal rat cardiomyocytes(P＜0.01).Conclusion MMA induces mitochondrial dysfunction in cardiomyocytes and exacerbates MI/R injury.
Keywords：methylmalonic acidmyocardial ischemia/reperfusionmitochondriamice
Publication Date：2025-02-27
Online Publishing Date：2026-08-26(First online date of this platform, not the publication date of the document)
Pages：7( 160-166 )