Figure 1.

Overview of the major oxidant and antioxidant systems in skeletal muscle. Mitochondrial respiration shifts from state 4 to active state 3 when muscle contractions start, which is characterized by a lower superoxide (O₂^•−) production than at rest. NADPH oxidase (NOX) enzymes become activated in response to sarcolemma depolarization, ATP release, and fiber stretching associated with exercise. NOX2 resides in the plasma membrane and transverse tubules, and it is the main source for cytosolic O₂^•− generation in contracting muscle. NOX4 was reported to localize in the sarcoplasmic reticulum and mitochondrial intermembrane space. Xanthine oxidase (XO) is abundant in endothelial cells and activates via increases in shear stresses applied to skeletal muscle and ATP hydrolysis. The release of polyunsaturated fatty acids (PUFAs) from plasma membrane is stimulated by phospholipase A₂ (PLA₂), and the released free PUFAs are subsequently oxidized by lipoxygenase (LOX). The formed O₂^•− is detoxified with the assistance of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxiredoxin (PRDX) or thioredoxin (TRX). The PRDX-mediated reduction in H₂O₂ uses TRX as the electron donor. In the course of the reaction, one sulfhydryl group of the cysteine residues in PRDX is oxidized and a disulfide bridge is formed. Then, the disulfide bridge is reduced by TRX at the expense of NADPH oxidation. Abbreviations: DHPR, dihydropyridine receptor; ETC, mitochondrial electron transport chain; GR, glutathione reductase; RyR1, ryanodine receptor 1; TR3, thioredoxin reductase 3; VDAC, voltage-dependent anion channel.