Rapamycin Ameliorates Dystrophic Phenotype in mdx Mouse Skeletal Muscle
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.
We thank Daniel P Reay for providing valuable technical support and for breeding mice used in these studies. This work was supported by F31-NS056780-01A2 (S Eghtesad) from the National Institutes of Health (NIH), KL2 RR024154 (SR Little) from the National Center for Research Resources (NCRR), a component of the NIH and grant W81XWH-05-1-0334 (PR Clemens) from the United States Army Medical Research and Materiel Command. The myosin (embryonic) monoclonal antibody developed by HM Blau was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA, USA.