Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide

Jerry P. Eu, Joshua M. Hare, Douglas T. Hess, Michel Skaf, Junhui Sun, Isabella Cardenas-Navina, Qi An Sun, Mark Dewhirst, Gerhard Meissner, Jonathan S. Stamler

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

It is generally accepted that inhibition of nitric oxide synthase (NOS) facilitates, and thus nitric oxide (NO) inhibits, contractility of skeletal muscle. However, standard assessments of contractility are carried out at a nonphysiological oxygen tension [partial pressure of oxygen (pO2)] that can interfere with NO signaling (95% O2). We therefore examined, in normal and neuronal NOS (nNOS)-deficient mice, the influence of pO 2 on whole-muscle contractility and on myocyte calcium flux and sarcomere shortening. Here, we demonstrate a significant enhancement of these measures of muscle performance at low physiological pO2 and an inhibitory influence at higher physiological pO2, which depend on endogenous nNOS. At 95% O2 (which produces oxidative stress; muscle core pO2 ≈400 mmHg), force production is enhanced but control of contractility by NO/nitrosylation is greatly attenuated. In addition, responsivity to pO2 is altered significantly in nNOS mutant muscle. These results reveal a fundamental role for the concerted action of NO and O2 in physiological regulation of skeletal muscle contractility, and suggest novel molecular aspects of myopathic disease. They suggest further that the role of NO in some cellular systems may require reexamination.

Original languageEnglish (US)
Pages (from-to)15229-15234
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number25
DOIs
StatePublished - Dec 9 2003
Externally publishedYes

ASJC Scopus subject areas

  • General

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