Role of nitric oxide in skeletal muscle: synthesis, distribution and functional importance

Over the last two decades, nitric oxide (NO) has been established as a novel mediator of biological processes, ranging from vascular control to long-term memory, from tissue inflammation to penile erection. This paper reviews recent research which shows that NO and its derivatives also are synthesized within skeletal muscle and that NO derivatives influence various aspects of muscle function. Individual muscle fibres express one or both of the constitutive NO synthase (NOS) isoforms. Type I (neuronal) NOS is localized to the sarcolemma of fast fibres; type III (endothelial) NOS is associated with mitochondria. Isolated skeletal muscle produces NO at low rates under resting conditions and at higher rates during repetitive contraction. NO appears to mediate cell-cell interactions in muscle, including vasodilation and inhibition of leucocyte adhesion. NO also acts directly on muscle fibres to alter cell function. Muscle metabolism appears to be NO-sensitive at several sites, including glucose uptake, glycolysis, mitochondrial oxygen consumption and creatine kinase activity. NO also modulates muscle contraction, inhibiting force output by altering excitation-contraction coupling. The mechanisms of NO action are likely to include direct effects on redox-sensitive regulatory proteins, interaction with endogenous reactive oxygen species, and activation of second messengers such as cyclic guanosine monophosphate (cGMP). In conclusion, research published over the past few years makes it clear that skeletal muscle produces NO and that endogenous NO modulates muscle function. Much remains to be learned, however, about the physiological importance of NO actions and about their underlying mechanisms.