Cold exposure aggravates cardiac dysfunction in aged mice via METTL14/TLR4 signaling

Objective Epidemiological studies have established a strong association between low ambient temperature and increased cardiovascular mortality, particularly among older populations. However, the molecular mechanisms underlying cold-induced cardiovascular vulnerability during aging remain poorly understood. This study aimed to investigate the cardiac responses of naturally aged mice to prolonged cold stress and to elucidate the molecular pathways involved in cold-associated cardiac dysfunction. Methods Naturally aged mice (21 months old) were subjected to prolonged cold exposure, and cardiac function and structural remodeling were evaluated by echocardiography. Transcriptomic profiling was performed to identify differentially expressed genes (DEGs) and enriched biological pathways in cardiac tissues following cold exposure. The expression of key inflammatory mediators and methyltransferase-like 14 (METTL14) was further evaluated to explore potential molecular mechanisms involved in cold-induced cardiac injury. Results Prolonged cold exposure resulted in significant cardiac systolic dysfunction and structural remodeling in aged mice, characterized by reduced ejection fraction (EF) and fractional shortening (FS), accompanied by increased left ventricular internal diameter at end-systole (LVIDs). Transcriptomic analysis revealed extensive remodeling of the cardiac gene expression landscape, with DEGs predominantly enriched in inflammation-related signaling pathways. Consistently, multiple inflammatory mediators were markedly dysregulated in cold-exposed aged hearts. Notably, METTL14 expression was significantly upregulated following cold stress. Mechanistically, increased METTL14 was associated with enhanced cardiac inflammatory activation, accompanied by stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway. Conclusions Chronic cold exposure promotes cardiac inflammation, systolic dysfunction, and structural remodeling in aged mice. These findings identify METTL14 as a potential molecular mediator linking cold exposure to inflammatory cardiac remodeling through activation of the TLR4/MyD88/NF-κB pathway, providing new mechanistic insights into the increased cardiovascular risk associated with cold exposure in aging populations. Targeting METTL14-associated inflammatory signaling may provide a therapeutic approach for mitigating cold-induced cardiac vulnerability in susceptible individuals.