Glycolysis inhibition by sodium oxamate attenuates cardiac fibrosis and improves adverse outcomes after myocardial infarction

Myocardial infarction (MI) leads to robust extracellular matrix remodeling in the left ventricle (LV), resulting in the formation of a reparative collagenous scar that replaces the non-functional necrotic tissue. This process is mediated by cardiac fibroblasts, which undergo transition to active myofibroblasts that secrete high amounts of collagen during injury. While fibrosis is necessary for normal scar maturation, it can ultimately promote LV stiffness and dysfunction and progression to heart failure. Recent studies have indicated that metabolic reprogramming plays a key role in myofibroblast transition. Thus, we hypothesized that inhibiting glycolysis after MI would attenuate cardiac fibrosis. To investigate the role of glycolytic metabolism in post-MI remodeling, we used adult male or female C57BL/6J mice (15-20 weeks old) subjected to permanent left coronary artery ligation. Cardiac fibroblasts were extracted by immunomagnetic sorting from D0 (no MI), D3, or D7 LVs and subjected to phenotypic profiling by metabolic flux analysis (SeahorseTM) and gene expression analysis. Beginning 3 days after MI, mice received daily intraperitoneal injections of sodium oxamate, a well-recognized competitive inhibitor of lactate dehydrogenase A (LDHa), at a dose of 750mg/kg for 7 days (male and female) or 14 days (female only). Cardiac remodeling was assessed by picrosirius red to stain collagen, quantitative gene expression profiling, and echocardiography. Metabolic profiling of cardiac fibroblasts demonstrated a marked increase in glycolytic activity at D3 and D7 post-MI, accompanied by elevated expression of myofibroblast markers (Col1a1, Postn) and key glycolytic pathway genes, including the glycolytic enzymes Pkm2 and Ldha, the glycolysis regulators Hif1a and Pfkfb3, and the glycolysis-supporting transporters GLUT1 and Mct1. Oxamate treatment improved survival in male mice (69% oxamate vs. 41% control) and significantly reduced Col1a1 expression and collagen deposition within the infarct region in females at D7. At D14, oxamate trended to decrease the wet and dry lung weights in females (p=0.09), indicating that glycolysis may play a role in post-MI lung injury and fibrosis. In conclusion, inhibition of LDH and cardiac fibroblast glycolysis may be an important therapeutic avenue for treating excessive cardiac fibrosis after MI. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.