Figure 5.

Upper part. Localization of the different ROS production sites and resulting ROS are linked by red arrows. Main enzymatic and non-enzymatic antioxidant defenses are represented in green. The main source of ROS is the mitochondria respiratory chain. Xanthine oxidase (XO) and neuronal NO synthase (nNOS) play also a large part in ROS production. Phospholipase A2 (PLA₂) is activated by ROS and will be responsible for the hydrolysis of various products from the plasma membrane such as peroxidized fatty acids. The first antioxidant defenses are provided by superoxide dismutase (SOD) but the most important antioxidant is glutathione (GSH), a substrate of glutathione peroxidase (GPX) that neutralizes hydrogen peroxide by conversion into water. CSQ1 = Calsequestrin, the major calcium binding protein in the sarcoplasmic reticulum (SR). RyR = Ryanodine receptor, located in the SR membrane and responsible for the release of Ca²⁺ from the SR during excitation-contraction coupling. DHPR = dihydropyridine receptor, voltage-dependent Ca²⁺ channel located in T-tubule and also involved in excitation-contraction coupling. SERCA = sarcoplasmic reticulum Ca²⁺-ATPase allowing Ca²⁺ active transport from the cytoplasm to the lumen of the SR during muscle relaxation. Lower part. ROS sensitive molecular targets in skeletal muscle. ROS mainly modify muscle function by altering calcium concentration regulation and by oxidizing and consequently altering contractile muscle protein structure and function. Pro-oxidant environment can lead to the activation of CAMKII (Ca²⁺/calmodulin-dependent protein kinase II) which is known to cause RyR1 phosphorylation resulting in a leakiness of Ca²⁺ release from the SR.