The role of Glutaredoxin-2 in the modulation of fat metabolism and ROS production in skeletal muscle mitochondria

Mitochondria are major suppliers of ATP and reactive oxygen species (ROS) in skeletal muscle. While ATP is integral for muscle contraction and relaxation, ROS has a bi-functional relationship with muscle. Bursts in ROS release by muscle mitochondria is vital for normal muscle physiology, whereas, chronic overproduction correlates with obesity and its related diseases. Protein S-glutathionylation (PGLU) reactions in mitochondria, catalyzed by glutaredoxin-2 (GRX2), have been shown to regulate carbon catabolism, oxidative phosphorylation and ROS production in muscle mitochondria in response to changes in redox buffering capacity. In addition, deletion of the Grx2 gene increases phosphorylating respiration and proton leaks in muscle tissue which correlates with decreased fat mass and body weight. However, the role of GRX2 in regulating fat combustion in muscle has never been investigated.

Our objective was to examine the potential anti-obesity effect associated with the absence of the Grx2 gene in C57Bl/6N mice. Mice heterozygous for the Grx2 gene (GRX2+/-) and wild-type littermates were challenged with a high-fat diet or a matched control diet. Here we demonstrate that GRX2+/- mice were protected from diet-induced weight gain and insulin resistance. This correlated with a small but significant increase in mitochondrial ROS, a critical factor involved in the adaptation of muscle to exercise, as well as increases in respiration and proton leak. Collectively, our results demonstrate that PGLU reactions are integral for regulating muscle metabolism and fat combustion and reveal that manipulation of GRX2 signaling may serve as an exercise mimetic that can be employed to treat/prevent diet-induced obesity.