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

Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16098-103. doi: 10.1073/pnas.1109546108. Epub 2011 Sep 6.


Physiological sensing of O(2) tension (partial O(2) pressure, pO(2)) 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 pO(2) to altered calcium release through the ryanodine receptor-Ca(2+)-release channel (RyR1). Reactive oxygen species are generated in proportion to pO(2) 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 Ca(2+) release in isolated sarcoplasmic reticulum and in cultured myofibers and enhanced contractility of intact muscle. Thus, Nox4 is an O(2) sensor in skeletal muscle, and O(2)-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 O(2)-based signaling by an NADPH oxidase and demonstrate a physiological role for oxidative modification of RyR1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium / metabolism
  • Cell Line
  • Gene Expression
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide / metabolism
  • Mice
  • Muscle Contraction / physiology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiology
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • NADP / pharmacology
  • NADPH Oxidase 4
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Oxidation-Reduction
  • Oxygen / metabolism*
  • RNA Interference
  • Rabbits
  • Rats
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism
  • Sulfhydryl Compounds / metabolism


  • Reactive Oxygen Species
  • Ryanodine Receptor Calcium Release Channel
  • Sulfhydryl Compounds
  • NADP
  • Hydrogen Peroxide
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse
  • Oxygen
  • Calcium