Skeletal muscle is a primary target of SOD1G93A-mediated toxicity.
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.
Dobrowolny
Gabriella
G
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.
Aucello
Michela
M
Rizzuto
Emanuele
E
Beccafico
Sara
S
Mammucari
Cristina
C
Boncompagni
Simona
S
Bonconpagni
Simona
S
Belia
Silvia
S
Wannenes
Francesca
F
Nicoletti
Carmine
C
Del Prete
Zaccaria
Z
Rosenthal
Nadia
N
Molinaro
Mario
M
Protasi
Feliciano
F
Fanò
Giorgio
G
Sandri
Marco
M
Musarò
Antonio
A
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
D017382:Reactive Oxygen Species; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1