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Skeletal Muscle Is a Primary Target of SOD1G93A-Mediated Toxicity

2008; Cell Press; Volume: 8; Issue: 5 Linguagem: Inglês

10.1016/j.cmet.2008.09.002

1932-7420

Gabriella Dobrowolny, Michela Aucello, Emanuele Rizzuto, Sara Beccafico, Cristina Mammucari, Simona Bonconpagni, Silvia Belia, Francesca Wannenes, Carmine Nicoletti, Zaccaria Del Prete, Nadia Rosenthal, Mario Molinaro, Feliciano Protasi, Giorgio Fanò, Marco Sandri, Antonio Musarò,

Biochemical Acid Research Studies

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 (SOD1G93A) 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 SOD1G93A -mediated toxicity and disclose the molecular mechanism whereby oxidative stress triggers muscle atrophy.