OXIDATIVE STRESS MEDIATES IMPAIRMENT OF MUSCLE FUNCTION IN TRANSGENICMICE WITH ELEVATED LEVEL OF WILD-TYPE CU ZN SUPEROXIDE-DISMUTASE/

Cases of familial amyotrophic lateral sclerosis (fALS; a neurodegenera tive disorder) have been reported in which the gene for Cu/Zn superoxi de dismutase (CuZnSOD) was mutated. Several studies with the fALS muta nt CuZnSOD in transgenic mice and cells showed that the fALS mutations act through an as yet undefined dominant gain-of-function mechanism. Wild-type CuZnSOD catalyzes the dismutation of superoxide (O-2(radical anion)) but also produces hydroxyl radicals ((OH)-O-.) with H2O2 as s ubstrate. Two laboratories have recently demonstrated that the (OH)-O- . production ability was preferentially enhanced by the fALS mutant Cu ZnSOD, suggesting that this might be the function gained in fALS. In t his study, we used transgenic CuZnSOD (Tg-CuZnSOD) mice with elevated levels of CuZnSOD to determine whether overexpression of wild-type CuZ nSOD was also associated with increased (OH)-O-. production and impair ed muscle function. Enhanced formation of (OH)-O-. was detected, by sp in trapping, in brain and muscle extracts of the Tg-CuZnSOD mice. Thre e independently derived Tg-CuZnSOD lines showed muscle abnormalities, reflected by altered electromyography (EMG) and diminished performance in the rope grip test. After treatment with paraquat (PQ), a widely u sed herbicide and O-2(radical anion)-generating compound, muscle disab ility significantly deteriorated in Tg-CuZnSOD mice but not in control mice. The results indicate that elevated levels of CuZnSOD cause indi genous long-term oxidative stress leading to impairment of muscle func tion. These findings may provide valuable clues about the concurred ro le of indigenous oxidative stress and exogenous agents in the etiology of sporadic ALS and several other neurodegenerative diseases in which a specific subset of neurons is affected.