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BiP deficiency and ER stress in skeletal muscle of a mouse model of amyotrophic lateral sclerosis
Author(s) -
Chen Dapeng,
Mazala Davi A.G.,
English Samuel A,
Chin Eva R
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb783
Subject(s) - unfolded protein response , endoplasmic reticulum , sod1 , skeletal muscle , chemistry , protein disulfide isomerase , amyotrophic lateral sclerosis , caspase 12 , protein kinase a , atf6 , muscle atrophy , genetically modified mouse , endocrinology , kinase , apoptosis , medicine , microbiology and biotechnology , biology , programmed cell death , transgene , superoxide dismutase , caspase , oxidative stress , biochemistry , disease , gene
Mutations in Cu/Zn superoxide dismutase (SOD1) is a cause of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 protein induces cell death in motor neurons and skeletal muscle, although the molecular mechanism of mutant SOD1‐induced cell death remains controversial. The purpose of this study was to determine whether the endoplasmic reticulum (ER) stress pathway and apoptosis are activated in skeletal muscle with ALS. Gastrocnemius muscle (GAS) was removed from 120–140d old wild‐type control (CON) and SOD1 G93A transgenic (ALS) mice and analyzed for ER stress signaling proteins: protein kinase RNA‐activated like ER kinase (PERK), inositol‐requiring kinase 1‐alpha (IRE1α), protein disulfide isomerase (PDI), immunoglobulin binding protein (BiP) and ER stress‐specific induced apoptotic mediator C/EBP homologous protein (CHOP). PERK and IRE1α were up‐regulated 5.2 ± 0.9 and 4.9 ± 0.1‐fold ( p <0.05) in ALS vs. CON GAS, respectively, while PDI was up‐regulated 2.3± 0.1‐fold ( p <0.05) in ALS mice. Unexpectedly, BiP was found to be deficient in all GAS muscles examined for ALS mice. CHOP was dramatically up‐regulated 13.3 ± 1.7‐fold ( p <0.05) in ALS vs. CON mice, in conjunction with caspase‐12 activation. This study shows that ER stress is induced in skeletal muscle of transgenic SOD1 G93A mice. Further, findings of a deficiency in ER chaperone BiP, up‐regulation of CHOP and activation of caspase‐12 cleavage suggest that defects in the ER stress response induce apoptosis and may contribute to the muscle atrophy process in ALS.