Potential mechanisms underlying pathological fatigue‐induced cardiac dysfunction

Pathological fatigue has emerged as a significant contributor to cardiac dysfunction. Unfortunately, suitable animal models to study cardiac dysfunction caused by fatigue are lacking, and the underlying mechanisms remain unclear. This study aimed to establish a pathological fatigue model induced by 5-week combined stress and explore the mechanisms of cardiac dysfunction triggered by fatigue. Five-week combined stress induced fatigue-like phenotypes, which included reluctance to move, reduced exercise endurance, and muscle strength. Moreover, the 5-week combined stress resulted in a significant reduction in both EF and FS, along with a marked upregulation of several myocardial injury biomarkers, thereby confirming the presence of abnormal cardiac function. Targeted metabolomics analysis indicated that 80% of the differential metabolites were downregulated, suggesting a hypometabolic profile in the heart. Interestingly, among the downregulated fatty acid metabolites, we identified two bacterial metabolites, namely acetate and butyrate. More importantly, we observed an inverse correlation between the levels of acetate and butyrate and the concentrations of certain cardiac injury markers. We then observed disturbances in gut bacteria, and group differences at the genus level revealed that all six differential bacteria, which ranked in the top 10 in terms of relative abundance, may directly or indirectly influence the production of acetic acid and butyric acid. Among them, the abundance of Akkermansia bacteria was positively correlated with reduced acetic acid levels. In summary, the present study provides a novel animal model of pathological fatigue-induced cardiac dysfunction and suggests that hypometabolic features and gut microbiota dysbiosis may be an important mechanism.