The role of Nrf2 in skeletal muscle contractile and mitochondrial function.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that confers cellular protection by upregulating antioxidant enzymes in response to oxidative stress. However, Nrf2 function within skeletal muscle remains to be further elucidated. We examined the role of Nrf2 in determining muscle phenotype using young (3 mo) and older (12 mo) Nrf2 wild-type (WT) and knockout (KO) mice. Basally, the absence of Nrf2 did not impact mitochondrial content. In intermyofibrillar mitochondria, lack of Nrf2 resulted in a 40% reduction in state 4 respiration, which coincided with a 68% increase in reactive oxygen species (ROS) emission. Nrf2 abrogation impaired in situ muscle performance, characterized by a 48% greater rate of fatigue and a 35% decrease in force within the first 5 min of stimulation. Acute treadmill exercise resulted in a 1.5-fold increase in Nrf2 activation via enhanced DNA binding in WT animals. In response to training, cytochrome-c oxidase activity increased by 20% in the WT animals; however, this response was attenuated in KO mice. Nrf2 protein was reduced 30% by training. Despite this, exercise training normalized respiration, ROS production, and muscle performance in KO mice. Our results suggest that Nrf2 transcriptional activity is increased by exercise and that Nrf2 is required for the maintenance of basal mitochondrial function as well as for the normal increase in specific mitochondrial proteins in response to training. Nonetheless, the decrements in mitochondrial function in Nrf2 KO muscle can be rescued by exercise training, suggesting that this restorative function operates via a pathway independent of Nrf2.