Rapamycin ameliorates dystrophic phenotype in mdx mouse skeletal muscle

Mol Med. Sep-Oct 2011;17(9-10):917-24. doi: 10.2119/molmed.2010.00256. Epub 2011 May 20.

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked, lethal, degenerative disease that results from mutations in the dystrophin gene, causing necrosis and inflammation in skeletal muscle tissue. Treatments that reduce muscle fiber destruction and immune cell infiltration can ameliorate DMD pathology. We treated the mdx mouse, a model for DMD, with the immunosuppressant drug rapamycin (RAPA) both locally and systemically to examine its effects on dystrophic mdx muscles. We observed a significant reduction of muscle fiber necrosis in treated mdx mouse tibialis anterior (TA) and diaphragm (Dia) muscles 6 wks post-treatment. This effect was associated with a significant reduction in infiltration of effector CD4(+) and CD8(+) T cells in skeletal muscle tissue, while Foxp3(+) regulatory T cells were preserved. Because RAPA exerts its effects through the mammalian target of RAPA (mTOR), we studied the activation of mTOR in mdx TA and Dia with and without RAPA treatment. Surprisingly, mTOR activation levels in mdx TA were not different from control C57BL/10 (B10). However, mTOR activation was different in Dia between mdx and B10; mTOR activation levels did not rise between 6 and 12 wks of age in mdx Dia muscle, whereas a rise in mTOR activation level was observed in B10 Dia muscle. Furthermore, mdx Dia, but not TA, muscle mTOR activation was responsive to RAPA treatment.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism
  • Diaphragm / drug effects
  • Diaphragm / metabolism
  • Diaphragm / pathology
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscle Fibers, Skeletal / drug effects*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Animal / metabolism
  • Muscular Dystrophy, Animal / pathology
  • Muscular Dystrophy, Animal / prevention & control*
  • Muscular Dystrophy, Duchenne / metabolism
  • Muscular Dystrophy, Duchenne / pathology
  • Muscular Dystrophy, Duchenne / prevention & control
  • Phosphorylation / drug effects
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors

Substances

  • Immunosuppressive Agents
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus