Enhanced generation of reactive oxygen species in the limb skeletal muscles from a murine infarct model of heart failure

Background-The generation of reactive oxygen species (ROS) is enhanced in t he failing myocardium. We hypothesized that ROS were also increased in the limb skeletal muscles in heart failure. Methods and Results-Myocardial infarction (MI) was created in mice by ligat ing the left coronary artery. After 4 weeks, the left ventricle was dilated and contractility was diminished by echocardiography. Left ventricular end -diastolic pressure was elevated after MI in association with an increase i n lung weight/body weight and the presence of pleural effusion. The generat ion of ROS in the limb muscles, including the soleus and gastrocnemius musc les, which were excised after MI, was measured by electron spin resonance s pectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-T EMPO). Overall, generation was increased, but it was attenuated in the pres ence of dimethylthiourea or 4,5-dihydroxy-1,2-benzenedisulfonic disodium sa lt in the reaction mixture, indicating increased generation of hydroxyl rad icals originating from superoxide anion. Thiobarbituric acid-reactive subst ance formation was also increased in muscles after MI. Mitochondrial comple x I and III activities were both decreased after MI, which may have caused the functional uncoupling of the respiratory chain and ROS production. Anti oxidant enzyme activities, including superoxide dismutase, catalase, and gl utathione peroxidase, were comparable between groups. Conclusions-Skeletal muscle in post-MI heart failure expressed an increased amount of ROS in association with ROS-mediated lipid peroxidation. This su pports the hypothesis that oxidative stress may cause (at least in part) sk eletal muscle dysfunction in heart failure.