Cargando…

PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model

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-...

Descripción completa

Detalles Bibliográficos
Autores principales: Qi, Yan, Yin, Xiang, Wang, Shuyu, Jiang, Hongquan, Wang, Xudong, Ren, Ming, Su, Xiang-ping, Lei, Shi, Feng, Honglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611176/
https://www.ncbi.nlm.nih.gov/pubmed/26539112
http://dx.doi.org/10.3389/fnagi.2015.00204
_version_ 1782396069090426880
author Qi, Yan
Yin, Xiang
Wang, Shuyu
Jiang, Hongquan
Wang, Xudong
Ren, Ming
Su, Xiang-ping
Lei, Shi
Feng, Honglin
author_facet Qi, Yan
Yin, Xiang
Wang, Shuyu
Jiang, Hongquan
Wang, Xudong
Ren, Ming
Su, Xiang-ping
Lei, Shi
Feng, Honglin
author_sort Qi, Yan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4611176
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-46111762015-11-04 PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model Qi, Yan Yin, Xiang Wang, Shuyu Jiang, Hongquan Wang, Xudong Ren, Ming Su, Xiang-ping Lei, Shi Feng, Honglin Front Aging Neurosci Neuroscience 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. Frontiers Media S.A. 2015-10-20 /pmc/articles/PMC4611176/ /pubmed/26539112 http://dx.doi.org/10.3389/fnagi.2015.00204 Text en Copyright © 2015 Qi, Yin, Wang, Jiang, Wang, Ren, Su, Lei and Feng. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Qi, Yan
Yin, Xiang
Wang, Shuyu
Jiang, Hongquan
Wang, Xudong
Ren, Ming
Su, Xiang-ping
Lei, Shi
Feng, Honglin
PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model
title PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model
title_full PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model
title_fullStr PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model
title_full_unstemmed PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model
title_short PGC-1α Silencing Compounds the Perturbation of Mitochondrial Function Caused by Mutant SOD1 in Skeletal Muscle of ALS Mouse Model
title_sort pgc-1α silencing compounds the perturbation of mitochondrial function caused by mutant sod1 in skeletal muscle of als mouse model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611176/
https://www.ncbi.nlm.nih.gov/pubmed/26539112
http://dx.doi.org/10.3389/fnagi.2015.00204
work_keys_str_mv AT qiyan pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel
AT yinxiang pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel
AT wangshuyu pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel
AT jianghongquan pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel
AT wangxudong pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel
AT renming pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel
AT suxiangping pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel
AT leishi pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel
AT fenghonglin pgc1asilencingcompoundstheperturbationofmitochondrialfunctioncausedbymutantsod1inskeletalmuscleofalsmousemodel