title: Spinal Cord Injury Leads to Hyperoxidation and Nitrosylation of Skeletal Muscle Ryanodine Receptor-1 Associated with Upregulation of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4.
abstract: Spinal cord injury (SCI) results in marked atrophy and dysfunction of skeletal muscle. There are currently no effective treatments for SCI-induced muscle atrophy or the dysfunction of the remaining muscle tissue. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4 (Nox4) produces reactive oxygen species (ROS) in sarcoplasmic reticulum (SR) and has been identified as an important O2sensor in skeletal muscle. Ryanodine receptors (RyRs) are calcium (Ca2+) channels that are responsible for Ca2+release from SR. In skeletal muscle, type1 RyR (RyR1) is predominantly functional. RyR1 is regulated by multiple proteins, including calstabin1, which assures that they close appropriately once contraction has ceased. RyR1 function is also regulated by oxidation and redox-dependent cysteine nitrosylation. Excessive oxidation/nitrosylation of RyR1 is associated with dissociation of calstabin1 and reduced muscle force generation. However, whether Nox4 levels in skeletal muscle are elevated or whether RyR1 is oxidized or nitrosylated after SCI has not been determined. In this study, we examined Nox4 expression, oxidation/nitrolysation status, and association of calstabin1 with RyR1 in skeletal muscle derived from rats that were subjected to T4 complete transection (SCI), and observed elevated expression of Nox4 messenger RNA and protein in muscle after SCI associated with enhanced binding of Nox4 to RyR1, increased oxidation and nitrosylation of RyR1, and dissociation of calstabin1 from RyR1 in SCI rat muscle. Our data suggest that RyR1 dysfunction resulting from excessive oxidation/nitrosylation may contribute to reduced specific force after SCI and suggest that Nox4 may be the source of ROS responsible for increased oxidation and nitrosylation of RyR1.
authors.affiliation: 1 National Center for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center , Bronx, New York.|2 Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, New York.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Liu
authors.affiliation: 1 National Center for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center , Bronx, New York.
authors.forename: Lauren
authors.initials: L
authors.lastname: Harlow
authors.affiliation: 1 National Center for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center , Bronx, New York.|2 Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, New York.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Graham
authors.affiliation: 1 National Center for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center , Bronx, New York.|2 Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, New York.|3 Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai , New York, New York.
authors.forename: William A
authors.initials: WA
authors.lastname: Bauman
authors.affiliation: 1 National Center for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center , Bronx, New York.|2 Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, New York.|3 Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai , New York, New York.|4 Department of Pharmacologic Science, Icahn School of Medicine at Mount Sinai , New York, New York.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cardozo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D000074663:NADPH Oxidase 4 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D000074663:NADPH Oxidase 4
keywords: Nox4; ryanodine receptor-1; skeletal muscle; spinal cord injury