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

Jerry P. Eu, Joshua 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 journalArticle

73 Citations (Scopus)

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
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

Fingerprint

Nitric Oxide
Skeletal Muscle
Oxygen
Muscles
Sarcomeres
Partial Pressure
Nitric Oxide Synthase
Muscle Cells
Oxidative Stress
Calcium

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide. / Eu, Jerry P.; Hare, Joshua; Hess, Douglas T.; Skaf, Michel; Sun, Junhui; Cardenas-Navina, Isabella; Sun, Qi An; Dewhirst, Mark; Meissner, Gerhard; Stamler, Jonathan S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 25, 09.12.2003, p. 15229-15234.

Research output: Contribution to journalArticle

Eu, Jerry P. ; Hare, Joshua ; Hess, Douglas T. ; Skaf, Michel ; Sun, Junhui ; Cardenas-Navina, Isabella ; Sun, Qi An ; Dewhirst, Mark ; Meissner, Gerhard ; Stamler, Jonathan S. / Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 25. pp. 15229-15234.
@article{e40b08d59861458e8a12c23bda0d9969,
title = "Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide",
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.",
author = "Eu, {Jerry P.} and Joshua Hare and Hess, {Douglas T.} and Michel Skaf and Junhui Sun and Isabella Cardenas-Navina and Sun, {Qi An} and Mark Dewhirst and Gerhard Meissner and Stamler, {Jonathan S.}",
year = "2003",
month = "12",
day = "9",
doi = "10.1073/pnas.2433468100",
language = "English",
volume = "100",
pages = "15229--15234",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "25",

}

TY - JOUR

T1 - Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide

AU - Eu, Jerry P.

AU - Hare, Joshua

AU - Hess, Douglas T.

AU - Skaf, Michel

AU - Sun, Junhui

AU - Cardenas-Navina, Isabella

AU - Sun, Qi An

AU - Dewhirst, Mark

AU - Meissner, Gerhard

AU - Stamler, Jonathan S.

PY - 2003/12/9

Y1 - 2003/12/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=10744219879&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744219879&partnerID=8YFLogxK

U2 - 10.1073/pnas.2433468100

DO - 10.1073/pnas.2433468100

M3 - Article

C2 - 14645704

AN - SCOPUS:10744219879

VL - 100

SP - 15229

EP - 15234

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 25

ER -