TY - JOUR
T1 - Oxidative stress mediates impairment of muscle function in transgenic mice with elevated level of wild-type Cu/Zn superoxide dismutase
AU - Peled-Kamar, M.
AU - Lotem, J.
AU - Wirguin, I.
AU - Weiner, L.
AU - Hermalin, A.
AU - Groner, Y.
PY - 1997/4/15
Y1 - 1997/4/15
N2 - Cases of familial amyotrophic lateral sclerosis (fALS; a neurodegenerative disorder) have been reported in which the gene for Cu/Zn superoxide dismutase (CuZnSOD) was mutated. Several studies with the fALS mutant 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 (O2/·) but also produces hydroxyl radicals (·OH) with H2O2 as substrate. Two laboratories have recently demonstrated that the ·OH production ability was preferentially enhanced by the fALS mutant CuZnSOD, suggesting that this might be the function gained in fALS. In this study, we used transgenic CuZnSOD (Tg-CuZnSOD) mice with elevated levels of CuZnSOD to determine whether overexpression of wild-type CuZnSOD was also associated with increased ·OH production and impaired muscle function. Enhanced formation of ·OH was detected, by spin trapping, in brain and muscle extracts of the Tg- CuZnSOD mice. Three 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 used herbicide and O2/·-generating compound, muscle disability significantly deteriorated in Tg-CuZnSOD mice but not in control mice. The results indicate that elevated levels of CuZnSOD cause indigenous long-term oxidative stress leading to impairment of muscle function. These findings may provide valuable clues about the concurred role 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.
AB - Cases of familial amyotrophic lateral sclerosis (fALS; a neurodegenerative disorder) have been reported in which the gene for Cu/Zn superoxide dismutase (CuZnSOD) was mutated. Several studies with the fALS mutant 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 (O2/·) but also produces hydroxyl radicals (·OH) with H2O2 as substrate. Two laboratories have recently demonstrated that the ·OH production ability was preferentially enhanced by the fALS mutant CuZnSOD, suggesting that this might be the function gained in fALS. In this study, we used transgenic CuZnSOD (Tg-CuZnSOD) mice with elevated levels of CuZnSOD to determine whether overexpression of wild-type CuZnSOD was also associated with increased ·OH production and impaired muscle function. Enhanced formation of ·OH was detected, by spin trapping, in brain and muscle extracts of the Tg- CuZnSOD mice. Three 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 used herbicide and O2/·-generating compound, muscle disability significantly deteriorated in Tg-CuZnSOD mice but not in control mice. The results indicate that elevated levels of CuZnSOD cause indigenous long-term oxidative stress leading to impairment of muscle function. These findings may provide valuable clues about the concurred role 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.
UR - http://www.scopus.com/inward/record.url?scp=0030970281&partnerID=8YFLogxK
U2 - 10.1073/pnas.94.8.3883
DO - 10.1073/pnas.94.8.3883
M3 - Article
C2 - 9108073
AN - SCOPUS:0030970281
SN - 0027-8424
VL - 94
SP - 3883
EP - 3887
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
ER -