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 (pO(2))] that can interfere with NO signaling (95% O-2). 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 pO(2) and an inhibitory influence at higher physiological pO(2), which depend on endogenous nNOS. At 95% O-2 (which produces oxidative stress; muscle core pO(2) approximate to400 mmHg), force production is enhanced but control of contractility by NO/nitrosylation is greatly attenuated. In addition, responsivity to pO(2) is altered significantly in nNOS mutant muscle. These results reveal a fundamental role for the concerted action of NO and O-2 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.