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

Am J Pathol. 2009 Mar;174(3):999-1008. doi: 10.2353/ajpath.2009.080537. Epub 2009 Jan 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Culture Techniques
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Genetic Engineering
  • Hypertrophy
  • Mice
  • Mice, Inbred mdx
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Duchenne / enzymology*
  • Muscular Dystrophy, Duchenne / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / metabolism*
  • TOR Serine-Threonine Kinases
  • Valproic Acid / pharmacology*
  • beta-Galactosidase / genetics


  • Carrier Proteins
  • Valproic Acid
  • Phosphotransferases (Alcohol Group Acceptor)
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • beta-Galactosidase