Exercise Capacity is Improved by Levosimendan in Heart Failure and Sarcopenia Mice via the Alleviation of Atrophy and Apoptosis of Skeletal Muscle

Abstract Background Sarcopenia, a common complication of heart failure (HF), dramatically reduces the benefits of exercise training. Levosimendan is an effective drug for the treatment of heart failure, but its relationship with sarcopenia is still unclear. We aimed to investigate the effect of levosimendan on heart failure with sarcopenia and to explore whether levosimendan can enhance skeletal muscle contractibility, improve skeletal muscle atrophy, and thus improve exercise tolerance of individuals with heart failure.Methods C57BL6/J mice were used to establish the heart failure with sarcopenia model by ligating of the left anterior descending branch combined with hindlimb unloading and were injected of levosimendan (3mg/Kg, once a week, four times in total). Mice (n=40) were divided into control group, sham operation group, HF group, HF + solvent group, HF + levosimendan group, HF + sarcopenia group, HF + sarcopenia + solvent group, HF+ sarcopenia + levosimendan group. After the treatment, exercise capacity and cardiac function were evaluated. Serum BNP, LDH, and CK content were measured. Muscle morphology, fiber type, inflammation level, and apoptosis levels were detected by histopathological and molecular biological methods. Mitochondrial function and oxidative stress level were assessed by mitochondrial membrane potential and SOD activity.Result Levosimendan could improve EF and FS in mice with HF and sarcopenia (P<0.001) and increase their forelimb grip strength, hanging impulse, maximum running distance and time (P<0.05). After correcting for EF, the improvement of exercise capacity by levosimendan remained (P<0.05). HE staining showed that levosimendan directly increased the CSA of gastrocnemius in mice with HF and sarcopenia (P<0.001). After levosimendan injection, the proportion of slow muscle fibers increased, but this improvement of muscle fiber typing might be attributed to improved cardiac function (P>0.05). Levosimendan also maintained mitochondrial membrane potential, decreased cleaved caspase-3, cleaved caspase-9, Bax expression, and increased Bcl2 expression (P<0.05). This effect is independent of improved cardiac function. IL-6, TNF-α expression decreased and SOD activity, GSH/GSSG ratio significantly increased (P<0.05) in skeletal muscle after injection of levosimendan, improved oxidative stress level. The improvement in oxidative stress level was attributed to improved cardiac function (P>0.05).Conclusion Levosimendan reduce the loss of skeletal muscle mitochondrial membrane potential, decrease the apoptosis, alleviate the inflammation and oxidative stress, and ultimately improve the exercise capacity of mice with heart failure and sarcopenia. Therefore, levosimendan may be a potential drug for the treatment of heart failure with sarcopenia.