FIG. 7.

ROS and RNS production and their role in exercise-mediated skeletal muscle plasticity. (A) Several ROS and RNS are produced in skeletal muscle both at rest and during contraction. NO^• is produced by NOS (eNOS in the endothelial cells and nNOS in the muscle fibers). The O₂^•− is generated into mitochondria in at least five sites (three of which being well characterized) within the mitochondrial respiratory chain through incomplete reduction of oxygen in the electron transport system. O₂^•− can also be generated as a specific product of some enzymes into mitochondria. Moreover, NADH oxidase, xanthine oxidase, and PLA₂ are other O₂^•− generators. O₂^•− can undergo spontaneous dismutation or dismutation catalyzed by MnSOD (in the matrix) and Cu/ZnSOD (in the intermembrane space and in the cytosol) and form H₂O₂. H₂O₂ is cytotoxic; however, it is poorly reactive and is considered a relatively weak oxidizing agent. H₂O₂ is unable to oxidize DNA or lipids directly, but it can inactivate some enzymes. H₂O₂ might be de-tossificated in H₂O by catalase or GPX or be transformed, through the Fenton reaction, into OH^• which is, by contrast, highly reactive and able to damage most macromolecules, including DNA, proteins, and lipids. O₂^•− can react with NO^• and produce ONOO⁻. ONOO⁻ is able to rapidly cross membranes and is a strong oxidant agent that can lead to DNA damage and nitration of proteins. Sub-intracellular measurements and detection of ROS are usually prone to artifacts, while O₂^•− intracellular catabolism is extremely complex and controversial. Therefore, the earlier description is an oversimplification. Skeletal muscle has a well-developed system that prevents potentially deleterious effects of ROS (such as catalases, SODs, glutathione, GPX, peroxiredoxins, and thioredoxins). The abundance of scavengers abrogates free-radical chain reaction propagation under physiological conditions. If redox homeostasis is disrupted, the cell becomes damaged, thus leading to a pathological condition. (B) ROS and NO^• mediate a contraction-induced adaptive response to exercise. NO^• and ROS mediate the up-regulation of PGC-1α, GLUT4, mitochondrial genes, and slow genes. Moreover, ROS increase Glu uptake by triggering p38 MAPK (and also ERK) phosphorylation and activation, which possibly phosphorylates and activates PGC-1α. ROS and RNS trigger PGC-1α phosphorylation and Glu uptake also through AMPK. Moreover, ROS induce NF-κB-mediated transcription of PGC-α. Contraction also induces NO^• production by NOS. NO^•, in turn, activates calcineurin/NFAT induction of fast-to-slow phenotype. NOS is a Ca²⁺/calmodulin-dependent enzyme that should be dephosphorylated in order to produce NO^•, and this might depend on calcineurin. NOS is also regulated by AMPK. NO^•, nitric oxide; O₂^•−, superoxide anion; H₂O₂, hydrogen peroxide; GPX, glutatione peroxidase; NF-κB, nuclear factor-kappa B; NOS, nitric oxide synthases; OH^•, hydroxyl radical; ONOO⁻, peroxynitrite; PLA₂, phospholipase A₂; RNS, reactive nitrogen species; SOD, superoxide dismutase.