PGC‐1α plays a protective role against oxidative stress in skeletal muscle

Abstract

PGC‐1α is a transcription coactivator that regulates various biological processes such as mitochondria biogenesis, fatty acid oxidation, and oxidative fiber determination. It has also been shown to regulate genes of the reactive oxygen species (ROS) detoxifying systems. We hypothesize that PGC‐1α plays a protective role against oxidative stress in the highly oxidative tissue, skeletal muscle. To test this hypothesis, we will use a PGC‐1α transgenic mouse (PGC‐1α Tg+/0) that has ubiquitously elevated PGC‐1α in all tissues. We will study primary myoblasts and skeletal muscle tissue to examine the effect of increased PGC‐1α level on the ability to protect against oxidative stress in vitro and in vivo. PGC‐1α protein is overexpressed by 40% in skeletal muscle from the PGC‐1α Tg+/0mice and levels of downstream targets mtTFA, COX II, COX IVa are elevated as measured by real‐time PCR. Muscle mitochondrial ATP generation is unchanged, yet mitochondrial hydrogen peroxide (H2O2) production is significantly reduced by 50%. In a sciatic nerve cut denervation model known to increase muscle mitochondrial ROS generation, PGC‐1α transgenic mice appear to have attenuated release of H2O2. In addition, primary myoblasts exhibited increased resistance to hydrogen peroxide toxicity. In conclusion our data support a significant role for PGC‐1α in protection against oxidative stress in skeletal muscle.