AIM To investigate the preventive and therapeutic effects of Qishen Keli (QSKL) on heart failure (HF) combined with atrophy in rats and its underlying molecular mechanisms. METHODS To establish the model, twenty-four male Sprague-Dawley (SD) rats aged 6-8 weeks underwent the ligation of the left anterior descending coronary artery. Rats were randomly divided into the model group, QSKL-treated group, and the sham-operated group serving as the control. Drug administration was continued for 12 weeks after the surgery. Cardiac function parameters were assessed using small animal echocardiography. Serum concentration of N-terminal pro-brain natriuretic peptide (NT-pro BNP) was measured by Enzyme-Linked Immunosorbent Assay (ELISA). Grip strength and gastrocnemius muscle weight were recorded. Pathological morphology of the gastrocnemius muscle was observed using Hematoxylin and Eosin (HE) staining. The number of autolysosomes in the gastrocnemius muscle was examined by transmission electron microscopy. Western blotting (WB) was performed to detect the expression levels of Muscle RING Finger Protein 1 (MuRF-1), F-box protein 32 (FBXO32/Atrogin-1), PTEN-induced kinase 1 (PINK1), E3 ubiquitin ligase (Parkin), microtubule-associated protein 1 light chain 3 (LC3), and forkhead box protein O3a (FOXO3a). RESULTS Compared to the sham-operated group, rats in the model group exhibited significantly decreased cardiac function parameters (P < 0.01). The concentration of NT-pro BNP in the serum was elevated (P < 0.01). The grip strength and gastrocnemius muscle weight of rats were decreased (P< 0.01); HE staining revealed irregularly arranged gastrocnemius muscle fibers and significantly reduced cross-sectional area. Transmission electron microscopy indicated the structural integrity of the gastrocnemius muscle was impaired and an increased number of autolysosomes. WB demonstrated the expressions of MuRF-1, FBXO32, PINK1, Parkin, LC3, and FOXO3a were increased (P < 0.01). Compared to the model group, rats in QSKL-treated group showed significantly improved cardiac function parameters (P < 0.01). The concentration of NT-pro BNP in the serum was decreased (P < 0.01). The grip strength and gastrocnemius muscle weight of rats were significantly increased (P < 0.01). The gastrocnemius muscle fibers were more regularly arranged with increased cross-sectional area and narrowed intercellular spaces. The structural integrity of the gastrocnemius was improved, as well as fewer autolysosomes. WB revealed the expressions of MuRF-1, FBXO32, PINK1, Parkin, LC3, and FOXO3a were significantly decreased (P < 0.01). CONCLUSION QSKL can significantly ameliorate heart failure combined with muscle atrophy in rats, which may be associated with the suppression of autophagy through the regulation of FOXO3a.
Keywords: heart failure; muscle atrophy; Qishen Keli; autophagy; fork head box O3a |