title: PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model.
abstract: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease causing death of motor neurons. This study investigated the roles of energy metabolism in the pathogenesis of ALS in the SOD1(G93A) transgenic mouse model. Control and SOD1(G93A) mice were administered with shcontrol or shPGC-1α in combination with PBS or thiazolidinedione (TZD) for 8 weeks. Gene expression was analyzed by quantitative real-time PCR and Western blot. ROS and fibrosis were assessed with a colorimetric kit and Sirius staining, respectively. Inflammatory cytokines were measured using ELISA kits. The levels of tissue ROS and serum inflammatory cytokines were significantly higher in SOD1(G93A) mice compared to control mice, and knocking down peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) drastically increased cytokine levels in both control and SOD1(G93A) mice. Muscle fibrosis was much severer in SOD1(G93A) mice, and worsened by silencing PGC-1α and attenuated by TZD. The expression levels of PGC-1α, SOD1, UCP2, and cytochrome C were substantially reduced by shPGC-1α and increased by TZD in muscle of both control and SOD1(G93A) mice, whereas the level of NF-κB was significantly elevated in SOD1(G93A) mice, which was further increased by PGC-1α silencing. These data indicated that disruption of energy homeostasis would exacerbate the pathological changes caused by SOD1 mutations to promote the pathogenesis of ALS.
authors.affiliation: Department of Neurology, The First Clinical College of Harbin Medical University , Harbin , China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Neurology, The First Clinical College of Harbin Medical University , Harbin , China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Neurology, The First Clinical College of Harbin Medical University , Harbin , China.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Clinical College of Harbin Medical University , Harbin , China.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Neurology, The First Clinical College of Harbin Medical University , Harbin , China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, Uniformed Services University of the Health Sciences , Bethesda, MD , USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Ren
authors.affiliation: College of Biological and Pharmaceutical Sciences, China Three Gorges University , Yichang , China.
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Su
authors.affiliation: College of Biological and Pharmaceutical Sciences, China Three Gorges University , Yichang , China.
authors.forename: Shi
authors.initials: S
authors.lastname: Lei
authors.affiliation: Department of Neurology, The First Clinical College of Harbin Medical University , Harbin , China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Feng
keywords: ALS; PGC-1α; SOD1(G93A); energy metabolism; fibrosis; inflammation