title: Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis.
abstract: Skeletal muscle mitochondrial dysfunction is believed to play a role in the progression and severity of amyotrophic lateral sclerosis (ALS). The regulation of transcriptional co-activators involved in mitochondrial biogenesis and function in ALS is not well known. When compared with healthy control subjects, patients with ALS, but not neurogenic disease (ND), had lower levels of skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA and protein and estrogen-related receptor-α (ERRα) and mitofusin-2 (Mfn2) mRNA. PGC-1β, nuclear respiratory factor-1 (NRF-1) and Mfn1 mRNA as well as cytochrome C oxidase subunit IV (COXIV) mRNA and protein were lower in patients with ALS and ND. Both patient groups had reductions in citrate synthase and cytochrome c oxidase activity. Similar observations were made in skeletal muscle from transgenic ALS G93A transgenic mice. In vitro, PGC-1α and PGC-1β regulated Mfn1 and Mfn2 in an ERRα-dependent manner. Compared to healthy controls, miRNA 23a, 29b, 206 and 455 were increased in skeletal muscle of ALS patients. miR-23a repressed PGC-1α translation in a 3' UTR dependent manner. Transgenic mice over expressing miR-23a had a reduction in PGC-1α, cytochome-b and COXIV protein levels. These results show that skeletal muscle mitochondrial dysfunction in ALS patients is associated with a reduction in PGC-1α signalling networks involved in mitochondrial biogenesis and function, as well as increases in several miRNAs potentially implicated in skeletal muscle and neuromuscular junction regeneration. As miR-23a negatively regulates PGC-1α signalling, therapeutic inhibition of miR-23a may be a strategy to rescue PGC-1α activity and ameliorate skeletal muscle mitochondrial function in ALS.
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, 3125 Burwood, Australia. Electronic address: aaron.russell@deakin.edu.au.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.affiliation: Division of Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo, 113-0033 Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Wada
authors.affiliation: Neurosciences Department, University of Padua, 35129 Padua, Italy.
authors.forename: Lodovica
authors.initials: L
authors.lastname: Vergani
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute,92037 La Jolla, USA.
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Hock
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, 3125 Burwood, Australia.
authors.forename: Séverine
authors.initials: S
authors.lastname: Lamon
authors.affiliation: Clinique romande de réadaptation, 1951 Sion, Switzerland.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Léger
authors.affiliation: Division of Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo, 113-0033 Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ushida
authors.affiliation: Clinique romande de réadaptation, 1951 Sion, Switzerland.
authors.forename: Romain
authors.initials: R
authors.lastname: Cartoni
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, 3125 Burwood, Australia.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Wadley
authors.affiliation: Research Centre for Exercise and Health, Faculty of Kinesiology and Rehabilitation Sciences, K.U. Leuven, B-3001 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Hespel
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute,92037 La Jolla, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kralli
authors.affiliation: Neurosciences Department, University of Padua, 35129 Padua, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Soraru
authors.affiliation: Neurosciences Department, University of Padua, 35129 Padua, Italy; I.R.C.S.S. S. Camillo, 30126 Venice, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.affiliation: Division of Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo, 113-0033 Tokyo, Japan. Electronic address: akimoto@m.u-tokyo.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Akimoto
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D055815:Young Adult
chemical_list: C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1