title: Deficiency of inducible nitric oxide synthase attenuates immobilization-induced skeletal muscle atrophy in mice.
abstract: The present study examined the effects of inducible nitric oxide synthase (iNOS) deficiency on skeletal muscle atrophy in single leg-immobilized iNOS knockout (KO) and wild-type (WT) mice. The left leg was immobilized for 1 wk, and the right leg was used as the control. Muscle weight and contraction-stimulated glucose uptake were reduced by immobilization in WT mice, which was accompanied with increased iNOS expression in skeletal muscle. Deficiency of iNOS attenuated muscle weight loss and the reduction in contraction-stimulated glucose uptake by immobilization. Phosphorylation of Akt, mTOR, and p70S6K was reduced to a similar extent by immobilization in both WT and iNOS KO mice. Immobilization decreased FoxO1 phosphorylation and increased mRNA and protein levels of MuRF1 and atrogin-1 in WT mice, which were attenuated in iNOS KO mice. Aconitase and superoxide dismutase activities were reduced by immobilization in WT mice, and deficiency of iNOS normalized these enzyme activities. Increased nitrotyrosine and carbonylated protein levels by immobilization in WT mice were reversed in iNOS KO mice. Phosphorylation of ERK and p38 was increased by immobilization in WT mice, which was reduced in iNOS KO mice. Immobilization-induced muscle atrophy was also attenuated by an iNOS-specific inhibitor N(6)-(1-iminoethyl)-l-lysine, and this finding was accompanied by increased FoxO1 phosphorylation and reduced MuRF1 and atrogin-1 levels. These results suggest that deficiency of iNOS attenuates immobilization-induced skeletal muscle atrophy through reduced oxidative stress, and iNOS-induced oxidative stress may be required for immobilization-induced skeletal muscle atrophy.
authors.affiliation: Department of Orthopedic Surgery, College of Medicine, Yeungnam University, Daegu, Korea.
authors.forename: Sang-Keun
authors.initials: SK
authors.lastname: Bae
authors.forename: Hey-Na
authors.initials: HN
authors.lastname: Cha
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Ju
authors.forename: Yong-Woon
authors.initials: YW
authors.lastname: Kim
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Yong-Dae
authors.initials: YD
authors.lastname: Kim
authors.forename: Jin-Myoung
authors.initials: JM
authors.lastname: Dan
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Se-Dong
authors.initials: SD
authors.lastname: Kim
authors.forename: So-Young
authors.initials: SY
authors.lastname: Park
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D019417:Hindlimb Suspension; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000201:enzymology*; D009133:Muscular Atrophy / Q000201:enzymology*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation; D050050:Protein Carbonylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009124:Muscle Proteins; C090663:N(6)-(1-iminoethyl)lysine; D000070584:Tripartite Motif Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D000154:Aconitate Hydratase; D005947:Glucose; D008239:Lysine