Role of antioxidant signaling in mitochondrial adaptation to muscle contraction

Generation of reactive oxygen species (ROS) is a ubiquitous biological phenomenon in eukaryotic cell life. It has become clear that ROS at the physiological concentration are not merely damaging agents inflicting random destruction to the cell structure and function but useful signaling molecules to regulate a wide range of physiological functions such as metabolism, antioxidant defense, organ remodeling, and aging (Hawley and Zierath 2004; D'Autréaux and Toledano 2007; Pourova et al. 2010; Collins et al. 2012). Understanding how the cell controls the level of ROS production and regulates the signal transduction process is essential for us to develop strategies in order to prevent diseases and improve cell functionality. In healthy people, muscle contraction-induced generation of ROS represents a major portion of all the ROS produced in the body and can stimulate a host of events that modulate energy metabolism, oxidative-antioxidant homeostasis, cellular structural changes (such as mitochondrial biogenesis, fiver hypertrophy), and even muscle force production. The majority of these adaptations require de novo protein synthesis through transcription, translation, and protein transport. These cellular events have been termed signal transduction or simply signaling. It is noteworthy that signaling pathways do not operate separately but often interact with each other to process and transfer signals, termed cross talk, that involves multiple organelles and cellular compartments. Mitochondria as the main organelle that generate the balk of ROS and tightly regulate ROS removal and release maintain a stable ROS output mainly in form of H₂O₂, but also in other forms such as NO. Mitochondria also participate in the regulation of its proliferation and remodeling mainly through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1) family transcriptional cofactors (Handschin and Spiegelman 2008). This chapter will briefly describe the mechanism, gene targets and functions of several most important cell signaling pathways, and the role of mitochondria in such regulation. In this chapter, skeletal muscle is the main focus of discussion because of its high plasticity and a wide range of adaptations demonstrated in response to increased metabolic demand and stress. The role of muscle contraction will be highlighted throughout the discussions. For basic antioxidant signaling mechanisms, the readers are referred to an abundant volume of review articles published during the past decade; some of them will be selectively quoted whenever applicable.