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Oxidative stress in skeletal muscle stimulates early expression of Rad in a mouse model of amyotrophic lateral sclerosis.

Abstract
Motor neuron degeneration and progressive muscle atrophy characterize amyotrophic lateral sclerosis (ALS) in humans and related mutant superoxide dismutase-1 (SOD1) transgenic mice. Our previous microarray studies on ALS muscle revealed strong up-regulation of Ras-related associated with diabetes (Rad), an inhibitor of voltage-gated calcium channels. The mechanisms controlling Rad expression in disease are unknown. We analyzed Rad expression in skeletal muscle from ALS patients and animal models and investigated whether it is regulated by oxidative stress. In mutant SOD1 mice, Rad up-regulation preceded motor symptoms and markedly increased as disease progressed. Increased Rad expression was also obtained in surgically denervated muscle. No clinical signs of denervation were seen in asymptomatic mice, however. We therefore suspected that muscular mutant SOD1 toxicity causes precocious Rad up-regulation. We confirmed the accumulation of reactive oxygen species (ROS) at asymptomatic stages, coincident with the rise in Rad expression. By subjecting muscle to ischemia-reperfusion, we observed ROS accumulation and Rad overexpression. The cell-permeative antioxidant Tempol inhibited the stimulatory effect of ischemia-reperfusion. Tempol also reduced Rad up-regulation after experimental denervation. Our study provides strong evidence for the implication of oxidative stress in modulating Rad expression, in association with the initiation and progression of ALS muscle atrophy.
AuthorsBenoît Halter, José-Luis Gonzalez de Aguilar, Frédérique Rene, Susanne Petri, Bastien Fricker, Andoni Echaniz-Laguna, Luc Dupuis, Yves Larmet, Jean-Philippe Loeffler
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 48 Issue 7 Pg. 915-23 (Apr 01 2010) ISSN: 1873-4596 [Electronic] United States
PMID20079427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright2010 Elsevier Inc. All rights reserved.
Chemical References
  • Antioxidants
  • Cyclic N-Oxides
  • Mutant Proteins
  • RRAD protein, human
  • Reactive Oxygen Species
  • SOD1 protein, human
  • Spin Labels
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • ras Proteins
  • tempol
Topics
  • Amyotrophic Lateral Sclerosis (genetics, metabolism, pathology)
  • Animals
  • Antioxidants (pharmacology)
  • Cyclic N-Oxides (pharmacology)
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle Denervation
  • Muscle, Skeletal (drug effects, pathology)
  • Mutant Proteins (genetics, metabolism)
  • Oxidative Stress (drug effects)
  • Reactive Oxygen Species (metabolism)
  • Reperfusion Injury
  • Spin Labels
  • Superoxide Dismutase (genetics, metabolism)
  • Superoxide Dismutase-1
  • ras Proteins (biosynthesis, genetics)

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