Skeletal muscle atrophy in sedentary Zucker obese rats is not caused by calpain-mediated muscle damage or lipid peroxidation induced by oxidative stress

Abstract

Background: Skeletal muscle undergoes significant atrophy in Type 2 diabetic patients and animal models. W aimed to determine if atrophy of Zucker rat skeletal muscle was due to the activation of intracellular damag pathways induced by excess reactive oxygen species production (specifically those associated with the peroxidatio of lipid membranes) and calpain activity. 14 week old obese Zucker rats and littermate lean controls were injecte with 1% Evan's Blue Dye. Animals were anaesthetised and extensor digitorum longus and soleus muscles wer dissected, snap frozen and analysed for ROS-mediated F2-isoprostane production and calpain activation/autolysis Contralateral muscles were histologically analysed for markers of muscle membrane permeability and atrophy Results: Muscle mass was lower in extensor digitorum longus and soleus of obese compared with lean animals concomitant with reduced fibre area. Muscles from obese rats had a higher proportional area of Evan's Blue Dy fluorescence, albeit this was localised to the interstitium/external sarcolemma. There were no differences i F2-isoprostane production when expressed relative to arachidonic acid content, which was lower in the obese ED and soleus muscles. There were no differences in the activation of either ?-calpain or calpain-3 Conclusions: This study highlights that atrophy of Zucker rat skeletal muscle is not related to sarcolemmal damage sustained hyperactivation of the calpain proteases or excessive lipid peroxidation. As such, establishing the correc pathways involved in atrophy is highly important so as to develop more specific treatment options that target th underlying cause. This study has eliminated two of the potential pathways theorised to be responsible.