Exogenous Lactate administration impairs survival and promotes maladaptive remodeling after myocardial infarction in male mice

Lactate, once considered a metabolic byproduct, has emerged as a signaling metabolite with proposed anti-inflammatory and cardioprotective roles. Endogenous lactate accumulation is a common finding following myocardial infarction (MI), but the therapeutic potential and consequences of exogenous lactate supplementation in this context remain controversial. We hypothesized that exogenous administration of sodium lactate following MI would be detrimental, impairing survival and promoting adverse cardiac remodeling, particularly in young adult male mice. Adult male and female C57BL/6 mice (15-20 weeks old) underwent permanent left coronary artery ligation to induce MI. Cardiac lactate levels and expression of lactate dehydrogenase isoforms were measured in the remote myocardium at D0 (Day0), D1, D3, and D7 post-MI by colorimetric assay and Western blot, respectively. In a separate cohort of mice, Sodium lactate (2 g/kg, intraperitoneal) or vehicle (PBS) was administered post-MI for 2 cohorts. either starting at D1 and euthanized at D3, or starting at D3 and euthanized at D7. Survival and cardiac remodeling (left ventricular anterior wall thickness in diastole (LVAWd), Left ventricular posterior wall thickness in diastole (LVPWd), Left ventricular weight normalized to tibia length (LV/Tibia) ratio) were assessed by D7. LV functions were assessed by transthoracic echocardiography. Long- and short-axis B-mode and short-axis M-mode images were analyzed to obtain ejection fraction, LV volumes, wall thickness and chamber diameters. Infarct tissue was analyzed at D7 for inflammatory mediators and extracellular matrix components. Collagen density was measured histologically. Macrophage phenotypes (CD68+, CD206+) were analyzed at D3 post-MI. The acute systemic and myocardial inflammatory response was assessed as a 30 minutes post-lactate injection in D3 MI mice, including circulating blood cell counts and myocardial cytokine expression. Endogenous lactate accumulated in the remote myocardium at D7 post-MI (p< 0.01 for male). This was associated with a significant increase in LDHA expression (D3 and D7 in males) and a decrease in LDHB expression (D1 and D3 in males), resulting in an elevated LDHA/LDHB ratio. Exogenous sodium lactate administration significantly reduced survival in male mice. Echocardiography at D3 showed significantly decreased LVAWd and LVPWd in lactate-treated males, indicating accelerated wall thinning. In the D7 infarct zone of lactate-treated males: Inflammation was exacerbated, with significant increases in inflammatory gene expression. Remodeling was impaired, evidenced by a significant decrease in infarct collagen density and reduced expression of Eln (elastin, p=0.056). Macrophage dynamics were altered, with a significant reduction in total CD68+ and CD68+CD206+ macrophage populations at D3 post-MI. Acute lactate exposure (30 min) significantly increased circulating neutrophil counts (neutrophilia) while decreasing circulating monocyte counts (monocytopenia). This acute effect also triggered significant increases in myocardial inflammatory gene expression, including Il1b and Tnf in the remote area. In conclusion, while lactate naturally accumulates in the remote myocardium post-MI, exogenous sodium lactate administration is detrimental in young adult male mice. It significantly reduces survival, drives maladaptive remodeling characterized by wall thinning and poor extracellular matrix deposition (collagen/elastin), and enhances systemic and local inflammation. These findings underscore the context- and sex-dependent effects of lactate and serve as a strong caution against its therapeutic use in the setting of acute 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.