title: Impaired PGC-1alpha function in muscle in Huntington's disease.
abstract: We investigated the role of PPAR gamma coactivator 1alpha (PGC-1alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1alpha and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor beta-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1alpha target genes, genes for oxidative phosphorylation, electron transport chain and mitochondrial biogenesis, increased oxidative muscle fibers, numbers of mitochondria and motor performance in wild-type, but not in HD mice. In muscle biopsies from HD patients, there was decreased PGC-1alpha, PGC-1beta and oxidative fibers. Oxygen consumption, PGC-1alpha, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1alpha expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1alpha resulted increased expression of PGC-1alpha and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1alpha plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1alpha function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA. rajnish@iitr.res.in
authors.forename: Rajnish K
authors.initials: RK
authors.lastname: Chaturvedi
authors.forename: Peter
authors.initials: P
authors.lastname: Adhihetty
authors.forename: Shubha
authors.initials: S
authors.lastname: Shukla
authors.forename: Thomas
authors.initials: T
authors.lastname: Hennessy
authors.forename: Noel
authors.initials: N
authors.lastname: Calingasan
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: Anatoly
authors.initials: A
authors.lastname: Starkov
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: Milena
authors.initials: M
authors.lastname: Cannella
authors.forename: Jenny
authors.initials: J
authors.lastname: Sassone
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciammola
authors.forename: Fernando
authors.initials: F
authors.lastname: Squitieri
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases