title: Rapamycin ameliorates dystrophic phenotype in mdx mouse skeletal muscle.
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.
authors: Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Saman
authors: S
authors: Eghtesad
authors: Siddharth
authors: S
authors: Jhunjhunwala
authors: Steven R
authors: SR
authors: Little
authors: Paula R
authors: PR
authors: Clemens
references: J Control Release. 2009 Feb 10;133(3):191-7
references: 19000726
references: Clin Immunol. 2001 Feb;98(2):235-43
references: 11161980
references: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7797-802
references: 18509048
references: Nat Rev Immunol. 2009 May;9(5):324-37
references: 19390566
references: Cell. 1987 Dec 24;51(6):919-28
references: 3319190
references: Saudi J Kidney Dis Transpl. 2007 Nov;18(4):617-20
references: 17951954
references: J Pathol. 2007 Oct;213(2):229-38
references: 17668421
references: Transpl Int. 2003 Oct;16(10):765-7
references: 12827229
references: Proc Natl Acad Sci U S A. 1984 Feb;81(4):1189-92
references: 6583703
references: Neuromuscul Disord. 1991;1(1):19-29
references: 1822774
references: Cardiovasc Res. 2005 Nov 1;68(2):186-96
references: 16061215
references: Nature. 2009 Jul 16;460(7253):392-5
references: 19587680
references: Kidney Int. 2007 Jul;72(1):114-20
references: 17410097
references: Bull Cancer. 2006 May;93(5):E39-43
references: 16777616
references: Neuromuscul Disord. 2001 Sep;11(6-7):556-64
references: 11525885
references: Arch Dis Child. 2003 Jan;88(1):91-2
references: 12495984
references: J Clin Neuromuscul Dis. 2010 Sep;12(1):1-21
references: 20808159
references: Transplantation. 1995 Feb 15;59(3):422-6
references: 7871574
references: J Immunol. 2007 Jan 1;178(1):320-9
references: 17182569
references: Transpl Int. 2008 May;21(5):483-94
references: 18266776
references: Nat Cell Biol. 2001 Nov;3(11):1009-13
references: 11715022
references: Blood. 2005 Jun 15;105(12):4743-8
references: 15746082
references: Am J Transplant. 2005 May;5(5):1085-9
references: 15816890
references: Curr Protein Pept Sci. 2010 Sep;11(6):409-24
references: 20491627
references: J Anim Sci. 2008 Apr;86(14 Suppl):E36-50
references: 17998426
references: Am J Physiol Cell Physiol. 2009 Dec;297(6):C1434-44
references: 19794149
references: Nat Cell Biol. 2001 Nov;3(11):1014-9
references: 11715023
references: Methods Enzymol. 2009;452:165-80
references: 19200882
references: Transplant Proc. 1981 Mar;13(1 Pt 1):339-43
references: 7022849
references: J Musculoskelet Neuronal Interact. 2008 Oct-Dec;8(4):338-9
references: 19147966
references: Mol Aspects Med. 1991;12(3):175-94
references: 1770836
references: Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1070-5
references: 15304378
references: J Cell Biol. 2009 Dec 14;187(6):859-74
references: 20008564
references: Gene Ther. 2010 Jan;17(1):132-40
references: 19759562
references: J Exp Med. 2008 Mar 17;205(3):565-74
references: 18283119
references: J Immunol. 2006 Dec 15;177(12):8338-47
references: 17142730
references: J Physiol. 2009 Apr 1;587(Pt 7):1535-46
references: 19188252
references: Lancet. 1990 May 26;335(8700):1289
references: 1971366
references: Transpl Int. 2010 Mar 1;23(3):266-76
references: 19804585
references: Genet Test. 1998;2(1):55-60
references: 10464597
references: Nature. 1991 Aug 8;352(6335):536-9
references: 1865908
references: Muscle Nerve. 2010 Jun;41(6):809-18
references: 20151467
references: J Pathol. 2009 Sep;219(1):35-40
references: 19434632