Mechanical Stretch-Induced Activation of ROS/RNS Signaling in Striated Muscle

Abstract

Significance: Mechanical activation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) occurs in striated muscle and affects Ca 2+ signaling and contractile function. ROS/RNS signaling is tightly controlled, spatially compartmentalized, and source specific. Recent Advances: Here, we review the evidence that within the contracting myocyte, the trans-membrane protein NADPH oxidase 2 (Nox2) is the primary source of ROS generated during contraction. We also review a newly characterized signaling cascade in cardiac and skeletal muscle in which the microtubule network acts as a mechanotransduction element that activates Nox2-dependent ROS generation during mechanical stretch, a pathway termed X-ROS signaling. Critical Issues: In the heart, X-ROS acts locally and affects the sarcoplasmic reticulum (SR) Ca 2+ release channels (ryanodine receptors) and tunes Ca 2+ signaling during physiological behavior, but excessive X-ROS can promote Ca 2+ -dependent arrhythmias in pathology. In skeletal muscle, X-ROS sensitizes Ca 2+ -permeable sarcolemmal ''transient receptor potential'' channels, a pathway that is critical for sustaining SR load during repetitive contractions, but when in excess, it is maladaptive in diseases such as Duchenne Musclar dystrophy. Future Directions: New advances in ROS/RNS detection as well as molecular manipulation of signaling pathways will provide critical new mechanistic insights into the details of X-ROS signaling. These efforts will undoubtedly reveal new avenues for therapeutic intervention in the numerous diseases of striated muscle in which altered mechanoactivation of ROS/RNS production has been identified. Antioxid. Redox Signal. 20,[929][930][931][932][933][934][935][936]

Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation

“…The origin of ROS production remains unclear during VIDD although recent studies rather consider that mitochondria represent the main source of ROS (10). Recent studies have identified a new transduction pathway in which the microtubule network acts as a mechano-transduction element that activates NADPHoxidase 2 (Nox2)-dependent ROS generation during mechanical stretch (36). Such pathway could therefore contribute to this primary ROS production.…”

Differential Expression of NADPH Oxidases Depends on Skeletal Muscle Fiber Type in Rats

“…NOX4 was also found in the mitochondria, more specifically in the inner mitochondrial membranes [8]. NOX4 is constitutively active and does not require association with regulatory subunits, being mainly regulated by its expression levels [5, 8, 9]. NOX2 can be activated by specific agonists, such as angiotensin II, growth factors, and cytokines, as well as mechanical stress/contraction, which induce the association of regulatory subunits (p47phox, p67phox, p40phox, and Rac1) and the activation of this enzyme [9].…”

Regulation of NADPH oxidases in skeletal muscle

“…3, [133–135]). Another possibility is that Nox-derived ROS cause sarcoplasmic reticulum Ca 2+ leak [89, 140] or extracellular Ca 2+ entry into the sarcoplasm through ‘transient receptor potential’ channels [131, 141, 142]. These processes heighten cytosolic Ca 2+ concentration.…”

“…This phenomenon has been termed X-ROS and was reviewed in detail by Ward et al [141]. The working hypothesis is that Rac1 is associated with microtubules and activates pre-assembled Nox2 complexes upon mechanical perturbation [141]. Stretching causes pronounced increases in ROS production by muscle [25, 176, 180].…”