Neuronal nitric oxide synthase and dystrophin-deficient muscular dystrophy.

Abstract

Neuronal nitric oxide synthase (nNOS) in fast-twitch skeletal muscle fibers is primarily particulate in contrast to its greater solubility in brain. Immunohistochemistry shows nNOS localized to the sarcolemma, with enrichment at force transmitting sites, the myotendinous junctions, and costameres. Because this distribution is similar to dystrophin, we determined if nNOS expression was affected by the loss of dystrophin. Significant nNOS immunoreactivity and enzyme activity was absent in skeletal muscle tissues from patients with Duchenne muscular dystrophy. Similarly, in dystrophin-deficient skeletal muscles from mdx mice both soluble and particulate nNOS was greatly reduced compared with C57 control mice. nNOS mRNA was also reduced in mdx muscle in contrast to mRNA levels for a dystrophin binding protein, cal-syntrophin. nNOS levels increased dramatically from 2 to 52 weeks of age in C57 skeletal muscle, which may indicate a physiological role for NO in aging-related processes. Biochemical purification readily dissociates nNOS from the dystrophin-glycoprotein complex. Thus, nNOS is not an integral component of the dystrophin-glycoprotein complex and is not simply another dystrophin-associated protein since the expression of both nNOS mRNA and protein is affected by dystrophin expression.

Nitric oxide synthase inhibition reduces muscle inflammation and necrosis in modified muscle use

“…The apparently opposing effects of NO in vitro make it difficult to predict the biological effects of NO because its role may vary with differences in the tissue in which the inflammation occurs [38][39][40][41], differences in the presence of other pro-inflammatory or anti-inflammatory molecules, and its concentration or rate of delivery in the tissue [42]. The possibility that NO production by muscle can influence the occurrence of muscle injury and inflammation has been suggested by the observation that mdx mouse muscles, which express very low levels of NOS [43,44], experience extensive muscle inflammation and necrosis [45,46]. Although it is not expected that NOS deficiency is a major cause of muscle inflammation and necrosis in dystrophic mdx muscle, it is feasible that the low levels of NO production by mdx muscle may exacerbate muscle inflammation if NO release by muscle serves an anti-inflammatory role.…”

nNOS regulation of skeletal muscle fatigue and exercise performance

“…DMD, BMD, α-, β-, and γ-sarcoglycanopathies as well as other neuromuscular diseases are characterized by reduced nNOSμ expression, particularly sarcolemmal nNOSμ, due to disruption of the dystrophin glycoprotein complex. (Brenman et al 1995;Chang et al 1996;Crosbie et al 2002;Kobayashi et al 2008;Finanger-Hedderick et al 2011).…”

“…The sarcolemmal nNOSμ association requires α-syntrophin, dystrophin, and α-dystrobrevin (Brenman et al 1995(Brenman et al , 1996Grady et al 2000;Adams et al 2000Adams et al , 2008. In mice, nNOSμ is not only localized at the sarcolemma, but is also normally expressed at relatively high levels in the cytoplasm (Chang et al 1996;Kameya et al 1999;Thomas et al 2003). However, in human muscle approximately 75% of nNOSμ is associated with the sarcolemmal DGC, suggesting species-specific differences in nNOSμ distribution (Chang et al 1996).…”

“…In mice, nNOSμ is not only localized at the sarcolemma, but is also normally expressed at relatively high levels in the cytoplasm (Chang et al 1996;Kameya et al 1999;Thomas et al 2003). However, in human muscle approximately 75% of nNOSμ is associated with the sarcolemmal DGC, suggesting species-specific differences in nNOSμ distribution (Chang et al 1996). A pool of nNOSμ is associated with the ryanodine receptor 1 Ca 2+ release channel (RyR1) at the sarcoplasmic reticulum (SR) Ca 2+ store where it can S-nitrosylate and regulate RyR1 channel activity (Xu et al 1999;Stamler and Meissner 2001;Salanova et al 2008;Li et al 2011a, Figure 1).…”

Microtubule binding distinguishes dystrophin from utrophin

“…A precedent for this hypothesis has already been shown in regard to nNOS. In normal muscle, dystrophin localizes nNOS to the sarcolemma, where it functions to regulate vasodilation during active muscle contraction (36)(37)(38)(39)(40). However,…”