Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy

Isabella Palazzolo, Conor Stack, Lingling Kong, Antonio Musaro, Hiroaki Adachi, Masahisa Katsuno, Gen Sobue, J. Paul Taylor, Charlotte Sumner, Kenneth H. Fischbeck, Maria Pennuto

Research output: Contribution to journalArticle

Abstract

Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA.

Original languageEnglish (US)
Pages (from-to)316-328
Number of pages13
JournalNeuron
Volume63
Issue number3
DOIs
StatePublished - Aug 13 2009

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Atrophic Muscular Disorders
Androgen Receptors
Somatomedins
Muscles
Receptor Aggregation
Phosphorylation
Skeletal Muscle
Proteasome Endopeptidase Complex
Ubiquitin
Transgenic Mice
Spinal Cord
Protein Isoforms
Pathology
Ligands

Keywords

  • HUMDISEASE
  • MOLNEURO
  • PROTEINS

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy. / Palazzolo, Isabella; Stack, Conor; Kong, Lingling; Musaro, Antonio; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Taylor, J. Paul; Sumner, Charlotte; Fischbeck, Kenneth H.; Pennuto, Maria.

In: Neuron, Vol. 63, No. 3, 13.08.2009, p. 316-328.

Research output: Contribution to journalArticle

Palazzolo, I, Stack, C, Kong, L, Musaro, A, Adachi, H, Katsuno, M, Sobue, G, Taylor, JP, Sumner, C, Fischbeck, KH & Pennuto, M 2009, 'Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy', Neuron, vol. 63, no. 3, pp. 316-328. https://doi.org/10.1016/j.neuron.2009.07.019
Palazzolo, Isabella ; Stack, Conor ; Kong, Lingling ; Musaro, Antonio ; Adachi, Hiroaki ; Katsuno, Masahisa ; Sobue, Gen ; Taylor, J. Paul ; Sumner, Charlotte ; Fischbeck, Kenneth H. ; Pennuto, Maria. / Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy. In: Neuron. 2009 ; Vol. 63, No. 3. pp. 316-328.
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