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A more recent version of this article appeared on March 1, 2009

Published online before print January 29, 2009
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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080537

Accepted for publication December 4, 2008.

Article

Valproic Acid Activates the PI3K/Akt/mTOR Pathway in Muscle and Ameliorates Pathology in a Mouse Model of Duchenne Muscular Dystrophy

Praveen B. Gurpur*{dagger}, Jianming Liu*, Dean J. Burkin{dagger}, and Stephen J. Kaufman*@

From the Department of Cell and Developmental Biology,* University of Illinois at Urbana–Champaign, Urbana, Illinois; and the Department of Pharmacology,{dagger} University of Nevada, Reno, Nevada

@ To whom correspondence should be addressed. E-mail: stephenk{at}illinois.edu.


  Abstract

Duchenne muscular dystrophy is a lethal neuromuscular disease that currently has no effective therapy. Transgenic overexpression of the {alpha}7 integrin in mdx/utrn-/- mice, a model of Duchenne muscular dystrophy ameliorates the disease. We have isolated and used {alpha}7+/- muscle cells expressing {beta}-galactosidase, driven by the endogenous {alpha}7 promoter, to identify compounds that increase {alpha}7 integrin levels. Valproic acid (VPA) was found to enhance {alpha}7 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.




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