title: Skeletal muscle is a primary target of SOD1G93A-mediated toxicity.
abstract: The antioxidant enzyme superoxide dismutase 1 (SOD1) is a critical player of the antioxidative defense whose activity is altered in several chronic diseases, including amyotrophic lateral sclerosis. However, how oxidative insult affects muscle homeostasis remains unclear. This study addresses the role of oxidative stress on muscle homeostasis and function by the generation of a transgenic mouse model expressing a mutant SOD1 gene (SOD1(G93A)) selectively in skeletal muscle. Transgenic mice developed progressive muscle atrophy, associated with a significant reduction in muscle strength, alterations in the contractile apparatus, and mitochondrial dysfunction. The analysis of molecular pathways associated with muscle atrophy revealed that accumulation of oxidative stress served as signaling molecules to initiate autophagy, one of the major intracellular degradation mechanisms. These data demonstrate that skeletal muscle is a primary target of SOD1(G93A) -mediated toxicity and disclose the molecular mechanism whereby oxidative stress triggers muscle atrophy.
authors.affiliation: Institute Pasteur Cenci-Bolognetti, Department of Histology and Medical Embryology, CE-BEMM and IIM, Sapienza University of Rome,Via A. Scarpa, 14 Rome 00161, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Dobrowolny
authors.forename: Michela
authors.initials: M
authors.lastname: Aucello
authors.forename: Emanuele
authors.initials: E
authors.lastname: Rizzuto
authors.forename: Sara
authors.initials: S
authors.lastname: Beccafico
authors.forename: Cristina
authors.initials: C
authors.lastname: Mammucari
authors.forename: Simona
authors.initials: S
authors.lastname: Boncompagni
authors.forename: Simona
authors.initials: S
authors.lastname: Bonconpagni
authors.forename: Silvia
authors.initials: S
authors.lastname: Belia
authors.forename: Francesca
authors.initials: F
authors.lastname: Wannenes
authors.forename: Carmine
authors.initials: C
authors.lastname: Nicoletti
authors.forename: Zaccaria
authors.initials: Z
authors.lastname: Del Prete
authors.forename: Nadia
authors.initials: N
authors.lastname: Rosenthal
authors.forename: Mario
authors.initials: M
authors.lastname: Molinaro
authors.forename: Feliciano
authors.initials: F
authors.lastname: Protasi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fanò
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012508:Sarcolemma / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D000072105:Superoxide Dismutase-1
chemical_list: D017382:Reactive Oxygen Species; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1