[Psoralen attenuates skeletal muscle atrophy in mice with heart failure after myocardial infarction by regulating NLRP3/Caspase-1/GSDMD pathway].

This study aimed to explore the therapeutic effects of psoralen(PSO) on skeletal muscle atrophy in chronic heart failure(CHF) and its underlying mechanisms. Male mice were randomly assigned to control, CHF, high-dose PSO, low-dose PSO, and empagliflozin(empa) groups. A CHF model was established by ligating the left anterior descending coronary artery, which was followed by 8 weeks of treatment starting 2 weeks post-surgery. In vitro, C2C12 myoblasts were cultured and exposed to angiotensin Ⅱ(Ang Ⅱ) to induce skeletal muscle injury, and divided into control, Ang Ⅱ, low-/medium-/high-dose PSO, and pyroptosis induction(nigericin) groups. General conditions, body weight, and skeletal muscle mass were recorded. The left ventricular ejection fraction(LVEF) was assessed by echocardiography. Skeletal muscle function was evaluated using grip strength and rotarod tests. Histopathological changes were examined by hematoxylin-eosin(HE) staining. Levels of interleukin IL-1β and tumor necrosis factor-α(TNF-α) in skeletal muscle tissue were measured. Transcriptomic profiling was performed to observe gene changes of mice and thereby predict relevant biological processes. Immunohistochemistry was used to evaluate NOD-like receptor family pyrin domain containing 3(NLRP3), cleaved-Caspase-1(c-Caspase-1), and N-terminal fragment of gasdermin D(GSDMD-N) expression. Western blot quantified NLRP3, GSDMD, GSDMD-N, Caspase-1, c-Caspase-1, and IL-1β protein levels. Immunofluorescence was employed to assess myotube diameter and NLRP3 expression, while quantitative polymerase chain reaction(qPCR) detected Nlrp3, Caspase-1, and Gsdmd mRNA levels. RESULTS:: showed that compared with the control group, the CHF group exhibited significantly reduced LVEF, gastrocnemius-to-body weight ratio, forelimb grip strength, rotarod time, and running distance, along with decreased myofiber cross-sectional area. IL-1β and TNF-α levels, as well as NLRP3, GSDMD, GSDMD-N, Caspase-1, c-Caspase-1, and IL-1β protein expression, were significantly increased in gastrocnemius. Compared with the CHF group, PSO at all doses improved LVEF, muscle mass, forelimb grip strength, and exercise endurance, increased myofiber cross-sectional area, and reduced inflammatory cytokine levels(IL-1β and TNF-α), with the high-dose group showing the most pronounced effects. Transcriptomic analysis revealed that PSO significantly downregulated pyroptosis-related genes. The Western blot results showed that PSO significantly decreased the protein expression of NLRP3, GSDMD, GSDMD-N, Caspase-1, c-Caspase-1, and IL-1β. The qPCR results indicated the significant decreases in mRNA expression of NLRP3, Caspase-1, and GSDMD. In vitro, PSO at 20 and 40 μmol·L~(-1) significantly increased myotube diameter of Ang Ⅱ-induced C2C12 cells and reduced expression of NLRP3, GSDMD, GSDMD-N, Caspase-1, c-Caspase-1, and IL-1β. Compared with the 40 μmol·L~(-1) PSO group, nigericin treatment reversed these effects. In conclusion, PSO effectively attenuates skeletal muscle atrophy in CHF mice, potentially through suppression of skeletal muscle cell pyroptosis via downregulation of the NLRP3/Caspase-1/GSDMD pathway.