Oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel by NADPH oxidase 4

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-09, Vol.108 (38), p.16098-16103
• Main Authors: Sun, Qi-An, Hess, Douglas T, Nogueira, Leonardo, Yong, Sandro, Bowles, Dawn E, Eu, Jerry, Laurita, Kenneth R, Meissner, Gerhard, Stamler, Jonathan S
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Blotting, Western; Calcium; Calcium - metabolism; Cell Line; cysteine; Gene Expression; HEK293 Cells; HeLa Cells; Humans; hydrogen peroxide; Hydrogen Peroxide - metabolism; mammals; Mice; Muscle Contraction - physiology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Muscles; Myoblasts - cytology; Myoblasts - metabolism; NADP (coenzyme); NADP - pharmacology; NADPH Oxidase 4; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Oxidases; Oxidation; Oxidation-Reduction; Oxygen; Oxygen - metabolism; Physiological regulation; Rabbits; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; sarcoplasmic reticulum; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - metabolism; Skeletal muscle; striated muscle; Sulfhydryl Compounds - metabolism; Thiols
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1109546108

Physiological sensing of O2 tension (partial O2 pressure, pO2) plays an important role in some mammalian cellular systems, but striated muscle generally is not considered to be among them. Here we describe a molecular mechanism in skeletal muscle that acutely couples changes in pO2 to altered calcium release through the ryanodine receptor–Ca2+-release channel (RyR1). Reactive oxygen species are generated in proportion to pO2 by NADPH oxidase 4 (Nox4) in the sarcoplasmic reticulum, and the consequent oxidation of a small set of RyR1 cysteine thiols results in increased RyR1 activity and Ca2+ release in isolated sarcoplasmic reticulum and in cultured myofibers and enhanced contractility of intact muscle. Thus, Nox4 is an O2 sensor in skeletal muscle, and O2-coupled hydrogen peroxide production by Nox4 governs the redox state of regulatory RyR1 thiols and thereby governs muscle performance. These findings reveal a molecular mechanism for O2-based signaling by an NADPH oxidase and demonstrate a physiological role for oxidative modification of RyR1.