Mitochondria‐targeted antioxidant treatment prevents elevation in diaphragm mitochondrial reactive oxygen species and weakness in chronic heart failure

Abstract

BACKGROUND The primary symptoms of chronic heart failure (CHF) are exercise intolerance and dyspnea. These symptoms are determined, in part, by diaphragm muscle weakness. The diaphragm abnormalities in CHF include heightened cytosolic and mitochondrial reactive oxygen species (ROS) and loss of force. Importantly, ROS cause diaphragm weakness in vitro. Therefore, we designed the present study to examine the specific role of elevated mitochondrial ROS on diaphragm weakness in CHF. METHODS: We induced CHF via ligation of the coronary artery, or performed sham surgery. The treatments consisted of the mitochondria-targeted superoxide dismutase mimetic MitoTEMPO (1 mg/kg/day) or sterile saline (vehicle). Hence, our study included four groups: Sham-Vehicle; CHF-Vehicle; Sham-MitoTEMPO; CHF-MitoTEMPO. We started the experimental treatment eight weeks post-surgery and continued treatment for 8-10 weeks – animals were studied 16-18 weeks post-surgery. We measured diaphragm mitochondrial ROS in saponin-permeabilized fibers and isometric force in diaphragm bundles in vitro. RESULTS: Diaphragm mitochondrial ROS was elevated 3-fold in CHF-Vehicle vs. Sham-Vehicle (P < 0.05), and treatment with MitoTEMPO prevented the increase in mitochondrial ROS in CHF. CHF decreased maximal tetanic force by ~20% in vehicle-treated animals (P < 0.05), while MitoTEMPO prevented the loss of diaphragm force in CHF. Echocardiography data suggest similar decreases in left ventricular function in CHF-Vehicle and CHF-MitoTEMPO. CONCLUSION Our data suggest that elevated diaphragm mitochondrial ROS causes diaphragm weakness in CHF.