title: X-ROS signaling in the heart and skeletal muscle: stretch-dependent local ROS regulates [Ca²⁺]i.
abstract: X-ROS signaling is a novel redox signaling pathway that links mechanical stress to changes in [Ca(2+)]i. This pathway is activated rapidly and locally within a muscle cell under physiological conditions, but can also contribute to Ca(2+)-dependent arrhythmia in the heart and to the dystrophic phenotype in the heart and skeletal muscle. Upon physiologic cellular stretch, microtubules serve as mechanotransducers to activate NADPH oxidase 2 in the transverse tubules and sarcolemmal membranes to produce reactive oxygen species (ROS). In the heart, the ROS acts locally to activate ryanodine receptor Ca(2+) release channels in the junctional sarcoplasmic reticulum, increasing the Ca(2+) spark rate and "tuning" excitation-contraction coupling. In the skeletal muscle, where Ca(2+) sparks are not normally observed, the X-ROS signaling process is muted. However in muscular dystrophies, such as Duchenne Muscular Dystrophy and dysferlinopathy, X-ROS signaling operates at a high level and contributes to myopathy. Importantly, Ca(2+) permeable stretch-activated channels are activated by X-ROS and contribute to skeletal muscle pathology. Here we review X-ROS signaling and mechanotransduction in striated muscle, and highlight important questions to drive future work on stretch-dependent signaling. We conclude that X-ROS provides an exciting mechanism for the mechanical control of redox and Ca(2+) signaling, but much work is needed to establish its contribution to physiologic and pathophysiologic processes in diverse cell systems.
authors.affiliation: Department of Physiology, Center for Biomedical Engineering and Technology (BioMET), University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Prosser
authors.forename: Ramzi J
authors.initials: RJ
authors.lastname: Khairallah
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Ziman
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ward
authors.forename: W J
authors.initials: WJ
authors.lastname: Lederer
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium