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.
Highlights
Duchenne muscular dystrophy (DMD)is a fatal, X-linked disorder affecting 1:3,600 to 1:6,000 male births worldwide that causes degeneration of striated muscle [1,2,3]
Given that infiltration of effector T cells in dystrophic muscles of mdx mice plays an important role in the pathology associated with the disease, we hypothesized that RAPA would improve the pathology of mdx muscle by reducing the level of infiltrating T cells
In the study presented here, we explored the effect of RAPA on inflammation, necrosis, regeneration and mammalian target of RAPA (mTOR) activation in dystrophic mdx mouse muscle
Summary
Is a fatal, X-linked disorder affecting 1:3,600 to 1:6,000 male births worldwide that causes degeneration of striated muscle [1,2,3]. This progressive disease is due to mutations in the dystrophin gene that result in absence of expression of a functional dystrophin protein. The mdx mouse is a disease model of DMD [7] in which a mutation in the dystrophin gene causes absence of dystrophin protein in muscles and leads to necrosis and inflammation in muscle tissue. The ongoing necrosis of dystrophic skeletal muscle leads to infiltration in the diseased muscle of immune cells that may be, in part, autoreactive. The only proven treatment for human DMD, prednisone, is a known immunosuppressant [10], suggesting that downregulation of the immune system in a dystrophic setting may have therapeutic effects
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