Possible role for nitric oxide dysregulation in critical illness myopathy.
Muscle fiber inexcitability and myosin loss underlie weakness in critical illness myopathy (CIM). Nitric oxide (NO) takes part in the maintenance of muscle fiber resting potential and, in pathological conditions accompanied by oxidative stress, may damage proteins through peroxynitrite generation. Sepsis and other conditions associated with CIM may differentially affect expression of NO synthases (NOSs), so that both downregulation and upregulation with excessive peroxynitrite production can be hypothesized. In six patients with CIM we studied NOS1, NOS2, and NOS3 protein expression by immunohistochemistry and Western blot. To investigate peroxynitrite production, we performed immunohistochemistry for nitrotyrosine and measured nitrotyrosine levels by enzyme-linked immunosorbent assay. In three patients, sarcolemmal staining for NOS1 was selectively absent. In the others, it was absent in atrophic fibers and absent or reduced in non-atrophic fibers. Total NOS1 protein content was reduced by 41% in patients compared to controls, whereas no significant changes were found in levels and localization of NOS2, NOS3, and nitrotyrosine. Further studies are warranted to determine whether NOS1 loss plays a role in the pathophysiology of CIM, possibly reducing the release of NO at the sarcolemma and affecting muscle fiber excitability.
Capasso
Margherita
M
Neuromuscular Diseases Unit, Center for Excellence on Aging, G. d'Annunzio University Foundation, Clinica Neurologica, Ospedale SS Annunziata, Via dei Vestini, 66013 Chieti, Italy.
Di Muzio
Antonio
A
Pandolfi
Assunta
A
Pace
Marta
M
Di Tomo
Pamela
P
Ragno
Michele
M
Uncini
Antonino
A
D000328:Adult; D000368:Aged; D016638:Critical Illness; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism
D030421:Peroxynitrous Acid; C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III