Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Am J Pathol. 2009 Mar;174(3):999-1008. doi: 10.2353/ajpath.2009.080537. Epub 2009 Jan 29.

Valproic acid activates the PI3K/Akt/mTOR pathway in muscle and ameliorates pathology in a mouse model of Duchenne muscular dystrophy.

Author information

  • 1Department of Cell and Developmental Biology, University of Illinois, B107 CLSL, 601 S. Goodwin Ave., Urbana, IL 61801, USA.

Abstract

Duchenne muscular dystrophy is a lethal neuromuscular disease that currently has no effective therapy. Transgenic overexpression of the alpha7 integrin in mdx/utrn(-/-) mice, a model of Duchenne muscular dystrophy ameliorates the disease. We have isolated and used alpha7(+/-) muscle cells expressing beta-galactosidase, driven by the endogenous alpha7 promoter, to identify compounds that increase alpha7 integrin levels. Valproic acid (VPA) was found to enhance alpha7 integrin levels, induce muscle hypertrophy, and inhibit apoptosis in myotubes by activating the Akt/mTOR/p70S6K pathway. This activation of the Akt pathway occurs within 1 hour of treatment and is mediated by phosphatidylinositol 3-OH kinase. To evaluate the potential use of VPA to treat muscular dystrophy, mdx/utrn(-/-) mice were injected with the drug. Treatment with VPA lowered collagen content and fibrosis, and decreased hind limb contractures. VPA-treated mice also had increased sarcolemmal integrity and decreased damage, decreased CD8-positive inflammatory cells, and higher levels of activated Akt in their muscles. Thus, VPA has important biological effects that may be applicable for the treatment of muscular dystrophy.

PMID:
19179609
[PubMed - indexed for MEDLINE]
PMCID:
PMC2665759
Free PMC Article

Images from this publication.See all images (8)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk