title: Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS.
abstract: The transcriptional coactivator PGC-1α induces multiple effects on muscle, including increased mitochondrial mass and activity. Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, adult-onset neurodegenerative disorder characterized by selective loss of motor neurons and skeletal muscle degeneration. An early event is thought to be denervation-induced muscle atrophy accompanied by alterations in mitochondrial activity and morphology within muscle. We now report that elevation of PGC-1α levels in muscles of mice that develop fatal paralysis from an ALS-causing SOD1 mutant elevates PGC-1α-dependent pathways throughout disease course. Mitochondrial biogenesis and activity are maintained through end-stage disease, accompanied by retention of muscle function, delayed muscle atrophy, and significantly improved muscle endurance even at late disease stages. However, survival was not extended. Therefore, muscle is not a primary target of mutant SOD1-mediated toxicity, but drugs increasing PGC-1α activity in muscle represent an attractive therapy for maintaining muscle function during progression of ALS.
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Da Cruz
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Parone
authors.forename: Vanda S
authors.initials: VS
authors.lastname: Lopes
authors.forename: Concepción
authors.initials: C
authors.lastname: Lillo
authors.forename: Melissa
authors.initials: M
authors.lastname: McAlonis-Downes
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Lee
authors.forename: Anne P
authors.initials: AP
authors.lastname: Vetto
authors.forename: Susanna
authors.initials: S
authors.lastname: Petrosyan
authors.forename: Martin
authors.initials: M
authors.lastname: Marsala
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010243:Paralysis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C000606290:SOD1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1