Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide.
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 pO2 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 approximately 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.
Eu
Jerry P
JP
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Hare
Joshua M
JM
Hess
Douglas T
DT
Skaf
Michel
M
Sun
Junhui
J
Cardenas-Navina
Isabella
I
Sun
Qi-An
QA
Dewhirst
Mark
M
Meissner
Gerhard
G
Stamler
Jonathan S
JS
D000818:Animals; D001681:Biological Assay; D002118:Calcium / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010100:Oxygen; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester