Impaired PGC-1α function in muscle in Huntington's disease

Rajnish K. Chaturvedi, Peter Adhihetty, Shubha Shukla, Thomas Hennessy, Noel Calingasan, Lichuan Yang, Anatoly Starkov, Mahmoud Kiaei, Milena Cannella, Jenny Sassone, Andrea Ciammola, Fernando Squitieri, M. Flint Beal

Research output: Contribution to journalArticle


We investigated the role of PPAR γ coactivator 1α (PGC-1α) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1α and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor β-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1α. Treatment with GPA resulted in increased expression of AMPK, PGC-1α 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-1α, PGC-1β and oxidative fibers. Oxygen consumption, PGC-1α, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1α expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1α resulted increased expression of PGC-1α and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1α plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1α function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.

Original languageEnglish
Pages (from-to)3048-3065
Number of pages18
JournalHuman Molecular Genetics
Issue number16
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Chaturvedi, R. K., Adhihetty, P., Shukla, S., Hennessy, T., Calingasan, N., Yang, L., Starkov, A., Kiaei, M., Cannella, M., Sassone, J., Ciammola, A., Squitieri, F., & Beal, M. F. (2009). Impaired PGC-1α function in muscle in Huntington's disease. Human Molecular Genetics, 18(16), 3048-3065.