Nitric oxide in skeletal muscle

Abstract

Reactive oxygen intermediates modulate skeletal muscle contraction, but little is known about the role of nitric oxide (NO). Here we show that rat skeletal muscle expresses neuronal-type NO synthase and that activity varies among several respiratory and limb muscles. Immunohistochemistry showed prominent staining of type II (fast) fibre cell membranes with antibodies against neuronal-type NO synthase. NO synthase activity in muscles correlated with type II fibre density. Resting diaphragm muscle produced detectable NO chi, but no reactive oxygen intermediates. In contrast, actively contracting muscle generated increased levels of reactive oxygen intermediates. Contractile function was augmented by blockers of NO synthase, extracellular NO chelation, and guanylyl cyclase inhibition; it was depressed by NO donors and by increased levels of cyclic GMP. Force-frequency plots of different muscles showed an inverse correlation between NO synthase activity and force development. Our results support two physiological functions of NO in skeletal muscle. The first is to promote relaxation through the cGMP pathway. The second is to modulate increases in contraction that are dependent on reactive oxygen intermediates and which are thought to occur through reactions with regulatory thiols on the sarcoplasmic reticulum.

Inhibition of creatine kinase by S‐nitrosoglutathione

“…One is related to activation of guanylyl cyclase which decreases the force generation by skeletal muscle fibers [3]. The other involves a possible Snitrosylation of thiol groups in the sarcoplasmic reticulum such as those from the Ca 2+ pump [3]. In the present report, we investigate whether NO donors affect the Ca 2+ transport of sarcoplasmic reticulum.…”

Expression of the skeletal muscle dystrophin–dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto–Kakizaki rat

“…In skeletal muscle, nitric oxide mediates diverse functions related to fibre development, metabolism, contraction and blood flow (Lee et al, 1994;Kobzik et al, 1994;Roberts et al, 1997). Loss of nNOS may also result in aberrant regulation of adrenergic vasoconstriction (Thomas et al, 1998).…”

Accumulation of nitrotyrosine on the SERCA2a isoform of SR Ca‐ATPase of rat skeletal muscle during aging: a peroxynitrite‐mediated process?

“…The observation that skeletal muscle of aged individuals shows increased relaxation times has been correlated with a potential age-related dysfunction of the sarcoplasmic reticulum (SR) Ca-ATPase [14]. Pending a detailed analytical characterization of possible age-related covalent modifications of this protein, it appears reasonable that reactive oxygen species could be responsible for such modifications since they are actively involved in the modulation of skeletal muscle function [15,16]. For example, superoxide dismutase-sensitive reactive oxygen species have been found to account for 85% of a 6-fold increase of cytochrome c reducing equivalents in actively contracting muscle as compared to resting muscle [16], suggesting a specific role for superoxide.…”

“…Pending a detailed analytical characterization of possible age-related covalent modifications of this protein, it appears reasonable that reactive oxygen species could be responsible for such modifications since they are actively involved in the modulation of skeletal muscle function [15,16]. For example, superoxide dismutase-sensitive reactive oxygen species have been found to account for 85% of a 6-fold increase of cytochrome c reducing equivalents in actively contracting muscle as compared to resting muscle [16], suggesting a specific role for superoxide. Moreover, it has been demonstrated that constitutive nitric oxide synthase is highly expressed in skeletal muscle [17] and that nitric oxide (NO) may modulate skeletal muscle contraction [16].…”

“…For example, superoxide dismutase-sensitive reactive oxygen species have been found to account for 85% of a 6-fold increase of cytochrome c reducing equivalents in actively contracting muscle as compared to resting muscle [16], suggesting a specific role for superoxide. Moreover, it has been demonstrated that constitutive nitric oxide synthase is highly expressed in skeletal muscle [17] and that nitric oxide (NO) may modulate skeletal muscle contraction [16].…”