Combinatorial Gene Therapy Strategies for Treating Muscular Dystrophies

  • Catherine E. Winbanks
  • Paul Gregorevic


Muscular dystrophies are commonly associated with progressive loss of muscle mass and strength as a consequence of ongoing myofibril degeneration and wasting. Genetic therapies have been proposed as interventions for disorders where specific monogenic mutations have been linked to the origin of disease. For muscular dystrophies of this nature, a “single-gene therapy” intended to introduce a surrogate “gene” in lieu of the defective endogenous copy (or to ablate a dominant negative state) may prove sufficient to prevent or reverse the development of disease. However, the increasingly severe morphological disruption and depletion of functional muscle fibers observed with disease progression may prove to be difficult to halt or reverse completely depending on the severity of the condition at the time of treatment. Consequently, it may be advantageous to consider coadministration of additional genetic interventions that address not only primary genetic defect, but also exert beneficial effects via other means that minimize degeneration, enhance muscle function, and promote muscle regeneration. Using Duchenne muscular dystrophy (DMD) as a representative neuromuscular condition, this chapter will discuss the potential benefits of combining genetic interventions to prevent or reverse the loss of muscle function, and also treat the primary genetic defect.


Muscular Dystrophy Satellite Cell Duchenne Muscular Dystrophy Expression Cassette Duchenne Muscular Dystrophy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abmayr, S., Gregorevic, P., Allen, J.M., and Chamberlain, J.S. (2005). Phenotypic improvement of dystrophic muscles by rAAV/microdystrophin vectors is augmented by Igf1 codelivery. Mol Ther 12, 441–450.PubMedCrossRefGoogle Scholar
  2. Baghdiguian, S., Martin, M., Richard, I., Pons, F., Astier, C., Bourg, N., Hay, R.T., Chemaly, R., Halaby, G., Loiselet, J., et al. (1999). Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IkappaB alpha/NF-kappaB pathway in limb-girdle muscular dystrophy type 2A. Nat Med 5, 503–511.PubMedCrossRefGoogle Scholar
  3. Bartoli, M., Poupiot, J., Vulin, A., Fougerousse, F., Arandel, L., Daniele, N., Roudaut, C., Noulet, F., Garcia, L., Danos, O., et al. (2007). AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not alpha-sarcoglycan deficiency. Gene Ther 14, 733–740.PubMedCrossRefGoogle Scholar
  4. Barton, E.R., Morris, L., Musaro, A., Rosenthal, N., and Sweeney, H.L. (2002). Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J Cell Biol 157, 137–148.PubMedCrossRefGoogle Scholar
  5. Barton-Davis, E.R., Shoturma, D.I., Musaro, A., Rosenthal, N., and Sweeney, H.L. (1998). Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci U S A 95, 15603–15607.PubMedCrossRefGoogle Scholar
  6. Batchelor, C.L., and Winder, S.J. (2006). Sparks, signals and shock absorbers: how dystrophin loss causes muscular dystrophy. Trends Cell Biol 16, 198–205.PubMedCrossRefGoogle Scholar
  7. Beckmann, J.S., and Spencer, M. (2008). Calpain 3, the “gatekeeper” of proper sarcomere assembly, turnover and maintenance. Neuromuscul Disord 18, 913–921.PubMedCrossRefGoogle Scholar
  8. Benabdallah, B.F., Bouchentouf, M., Rousseau, J., Bigey, P., Michaud, A., Chapdelaine, P., Scherman, D., and Tremblay, J.P. (2008). Inhibiting myostatin with follistatin improves the success of myoblast transplantation in dystrophic mice. Cell Transplant 17, 337–350.PubMedCrossRefGoogle Scholar
  9. Benabdallah, B.F., Bouchentouf, M., and Tremblay, J.P. (2005). Improved success of myoblast transplantation in mdx mice by blocking the myostatin signal. Transplantation 79, 1696–1702.PubMedCrossRefGoogle Scholar
  10. Bodine, S.C., Stitt, T.N., Gonzalez, M., Kline, W.O., Stover, G.L., Bauerlein, R., Zlotchenko, E., Scrimgeour, A., Lawrence, J.C., Glass, D.J., et al. (2001). Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 3, 1014–1019.PubMedCrossRefGoogle Scholar
  11. Bogdanovich, S., Krag, T.O., Barton, E.R., Morris, L.D., Whittemore, L.A., Ahima, R.S., and Khurana, T.S. (2002). Functional improvement of dystrophic muscle by myostatin blockade. Nature 420, 418–421.PubMedCrossRefGoogle Scholar
  12. Brack, A.S., Conboy, M.J., Roy, S., Lee, M., Kuo, C.J., Keller, C., and Rando, T.A. (2007). Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810.PubMedCrossRefGoogle Scholar
  13. Bradley, L., Yaworsky, P.J., and Walsh, F.S. (2008). Myostatin as a therapeutic target for musculoskeletal disease. Cell Mol Life Sci 65, 2119–2124.PubMedCrossRefGoogle Scholar
  14. Brenman, J.E., Chao, D.S., Xia, H., Aldape, K., and Bredt, D.S. (1995). Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell 82, 743–752.PubMedCrossRefGoogle Scholar
  15. Burdi, R., Didonna, M.P., Pignol, B., Nico, B., Mangieri, D., Rolland, J.F., Camerino, C., Zallone, A., Ferro, P., Andreetta, F., et al. (2006). First evaluation of the potential effectiveness in muscular dystrophy of a novel chimeric compound, BN 82270, acting as calpain-inhibitor and anti-oxidant. Neuromuscul Disord 16, 237–248.PubMedCrossRefGoogle Scholar
  16. Burkin, D.J., Wallace, G.Q., Milner, D.J., Chaney, E.J., Mulligan, J.A., and Kaufman, S.J. (2005). Transgenic expression of {alpha}7{beta}1 integrin maintains muscle integrity, increases regenerative capacity, promotes hypertrophy, and reduces cardiomyopathy in dystrophic mice. Am J Pathol 166, 253–263.PubMedGoogle Scholar
  17. Burkin, D.J., Wallace, G.Q., Nicol, K.J., Kaufman, D.J., and Kaufman, S.J. (2001). Enhanced expression of the alpha 7 beta 1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. J Cell Biol 152, 1207–1218.PubMedCrossRefGoogle Scholar
  18. Carlson, M.E., Hsu, M., and Conboy, I.M. (2008). Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. Nature 454, 528–532.PubMedCrossRefGoogle Scholar
  19. Chakravarthy, M.V., Abraha, T.W., Schwartz, R.J., Fiorotto, M.L., and Booth, F.W. (2000a). Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3′-kinase/Akt signaling pathway. J Biol Chem 275, 35942–35952.PubMedCrossRefGoogle Scholar
  20. Chakravarthy, M.V., Davis, B.S., and Booth, F.W. (2000b). IGF-I restores satellite cell proliferative potential in immobilized old skeletal muscle. J Appl Physiol 89, 1365–1379.PubMedGoogle Scholar
  21. Cohn, R.D., and Campbell, K.P. (2000). Molecular basis of muscular dystrophies. Muscle Nerve 23, 1456–1471.PubMedCrossRefGoogle Scholar
  22. Conboy, I.M., Conboy, M.J., Smythe, G.M., and Rando, T.A. (2003). Notch-mediated restoration of regenerative potential to aged muscle. Science 302, 1575–1577.PubMedCrossRefGoogle Scholar
  23. Deconinck, N., Tinsley, J., De Backer, F., Fisher, R., Kahn, D., Phelps, S., Davies, K., and Gillis, J.M. (1997). Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of mice. Nat Med 3, 1216–1221.PubMedCrossRefGoogle Scholar
  24. Dudley, R.W., Danialou, G., Govindaraju, K., Lands, L., Eidelman, D.E., and Petrof, B.J. (2006). Sarcolemmal damage in dystrophin deficiency is modulated by synergistic interactions between mechanical and oxidative/nitrosative stresses. Am J Pathol 168, 1276–1287; quiz 1404-1275.Google Scholar
  25. Eisenberg, I., Alexander, M.S., and Kunkel, L.M. (2009). miRNAS in normal and diseased skeletal muscle. J Cell Mol Med 13, 2–11.PubMedCrossRefGoogle Scholar
  26. Elsherif, L., Huang, M.S., Shai, S.Y., Yang, Y., Li, R.Y., Chun, J., Mekany, M.A., Chu, A.L., Kaufman, S.J., and Ross, R.S. (2008). Combined deficiency of dystrophin and beta1 integrin in the cardiac myocyte causes myocardial dysfunction, fibrosis and calcification. Circ Res 102, 1109–1117.PubMedCrossRefGoogle Scholar
  27. Engert, J.C., Berglund, E.B., and Rosenthal, N. (1996). Proliferation precedes differentiation in IGF-I-stimulated myogenesis. J Cell Biol 135, 431–440.PubMedCrossRefGoogle Scholar
  28. Ervasti, J.M. (2007). Dystrophin, its interactions with other proteins, and implications for muscular dystrophy. Biochim Biophys Acta 1772, 108–117.PubMedGoogle Scholar
  29. Frascarelli, M., Rocchi, L., and Feola, I. (1988). EMG computerized analysis of localized fatigue in Duchenne muscular dystrophy. Muscle Nerve 11, 757–761.PubMedCrossRefGoogle Scholar
  30. Gehrig, S.M., Ryall, J.G., Schertzer, J.D., and Lynch, G.S. (2008). Insulin-like growth factor-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage. Exp Physiol 93, 1190–1198.PubMedCrossRefGoogle Scholar
  31. Ghosh, A., Yue, Y., Lai, Y., and Duan, D. (2008). A hybrid vector system expands adeno-associated viral vector packaging capacity in a transgene-independent manner. Mol Ther 16, 124–130.PubMedCrossRefGoogle Scholar
  32. Gilbert, R., Nalbantoglu, J., Petrof, B.J., Ebihara, S., Guibinga, G.H., Tinsley, J.M., Kamen, A., Massie, B., Davies, K.E., and Karpati, G. (1999). Adenovirus-mediated utrophin gene transfer mitigates the dystrophic phenotype of mdx mouse muscles. Hum Gene Ther 10, 1299–1310.PubMedCrossRefGoogle Scholar
  33. Gosselin, L.E., Barkley, J.E., Spencer, M.J., McCormick, K.M., and Farkas, G.A. (2003). Ventilatory dysfunction in mdx mice: impact of tumor necrosis factor-alpha deletion. Muscle Nerve 28, 336–343.PubMedCrossRefGoogle Scholar
  34. Gregorevic, P., Blankinship, M.J., Allen, J.M., and Chamberlain, J.S. (2008). Systemic microdystrophin gene delivery improves skeletal muscle structure and function in old dystrophic mdx mice. Mol Ther 16, 657–664.PubMedCrossRefGoogle Scholar
  35. Gregorevic, P., and Chamberlain, J.S. (2003). Gene therapy for muscular dystrophy – a review of promising progress. Expert Opin Biol Ther 3, 803–814.PubMedGoogle Scholar
  36. Gregorevic, P., Plant, D.R., and Lynch, G.S. (2004). Administration of insulin-like growth factor-I improves fatigue resistance of skeletal muscles from dystrophic mdx mice. Muscle Nerve 30, 295–304.PubMedCrossRefGoogle Scholar
  37. Grobet, L., Martin, L.J., Poncelet, D., Pirottin, D., Brouwers, B., Riquet, J., Schoeberlein, A., Dunner, S., Menissier, F., Massabanda, J., et al. (1997). A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 17, 71–74.PubMedCrossRefGoogle Scholar
  38. Grounds, M.D., Radley, H.G., Gebski, B.L., Bogoyevitch, M.A., and Shavlakadze, T. (2008). Implications of cross-talk between tumour necrosis factor and insulin-like growth factor-1 signalling in skeletal muscle. Clin Exp Pharmacol Physiol 35, 846–851.PubMedCrossRefGoogle Scholar
  39. Haidet, A.M., Rizo, L., Handy, C., Umapathi, P., Eagle, A., Shilling, C., Boue, D., Martin, P.T., Sahenk, Z., Mendell, J.R., et al. (2008). Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proc Natl Acad Sci U S A 105, 4318–4322.PubMedCrossRefGoogle Scholar
  40. Handschin, C., Chin, S., Li, P., Liu, F., Maratos-Flier, E., Lebrasseur, N.K., Yan, Z., and Spiegelman, B.M. (2007a). Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem 282, 30014–30021.PubMedCrossRefGoogle Scholar
  41. Handschin, C., Kobayashi, Y.M., Chin, S., Seale, P., Campbell, K.P., and Spiegelman, B.M. (2007b). PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev 21, 770–783.PubMedCrossRefGoogle Scholar
  42. Harper, S.Q., Hauser, M.A., DelloRusso, C., Duan, D., Crawford, R.W., Phelps, S.F., Harper, H.A., Robinson, A.S., Engelhardt, J.F., Brooks, S.V., et al. (2002). Modular flexibility of dystrophin: implications for gene therapy of Duchenne muscular dystrophy. Nat Med 8, 253–261.PubMedCrossRefGoogle Scholar
  43. Hodgetts, S., Radley, H., Davies, M., and Grounds, M.D. (2006). Reduced necrosis of dystrophic muscle by depletion of host neutrophils, or blocking TNFalpha function with Etanercept in mdx mice. Neuromuscul Disord 16, 591–602.PubMedCrossRefGoogle Scholar
  44. Holzbaur, E.L., Howland, D.S., Weber, N., Wallace, K., She, Y., Kwak, S., Tchistiakova, L.A., Murphy, E., Hinson, J., Karim, R., et al. (2006). Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis. Neurobiol Dis 23, 697–707.PubMedCrossRefGoogle Scholar
  45. Joulia, D., Bernardi, H., Garandel, V., Rabenoelina, F., Vernus, B., and Cabello, G. (2003). Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatin. Exp Cell Res 286, 263–275.PubMedCrossRefGoogle Scholar
  46. Kambadur, R., Sharma, M., Smith, T.P., and Bass, J.J. (1997). Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res 7, 910–916.PubMedGoogle Scholar
  47. Kanadia, R.N., Shin, J., Yuan, Y., Beattie, S.G., Wheeler, T.M., Thornton, C.A., and Swanson, M.S. (2006). Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc Natl Acad Sci U S A 103, 11748–11753.PubMedCrossRefGoogle Scholar
  48. Kasai, T., Abeyama, K., Hashiguchi, T., Fukunaga, H., Osame, M., and Maruyama, I. (2004). Decreased total nitric oxide production in patients with duchenne muscular dystrophy. J Biomed Sci 11, 534–537.PubMedCrossRefGoogle Scholar
  49. Kobayashi, Y.M., Rader, E.P., Crawford, R.W., Iyengar, N.K., Thedens, D.R., Faulkner, J.A., Parikh, S.V., Weiss, R.M., Chamberlain, J.S., Moore, S.A., et al. (2008). Sarcolemma-localized nNOS is required to maintain activity after mild exercise. Nature 456, 511–515.PubMedCrossRefGoogle Scholar
  50. Kunkel, L.M., and Hoffman, E.P. (1989). Duchenne/Becker muscular dystrophy: a short overview of the gene, the protein, and current diagnostics. Br Med Bull 45, 630–643.PubMedGoogle Scholar
  51. Lai, Y., Thomas, G.D., Yue, Y., Yang, H.T., Li, D., Long, C., Judge, L., Bostick, B., Chamberlain, J.S., Terjung, R.L., et al. (2009). Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J Clin Invest 119, 624–635.PubMedCrossRefGoogle Scholar
  52. Langley, B., Thomas, M., Bishop, A., Sharma, M., Gilmour, S., and Kambadur, R. (2002). Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem 277, 49831–49840.PubMedCrossRefGoogle Scholar
  53. Lee, S.J., and McPherron, A.C. (2001). Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A 98, 9306–9311.PubMedCrossRefGoogle Scholar
  54. Lee, S.J., Reed, L.A., Davies, M.V., Girgenrath, S., Goad, M.E., Tomkinson, K.N., Wright, J.F., Barker, C., Ehrmantraut, G., Holmstrom, J., et al. (2005). Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci U S A 102, 18117–18122.PubMedCrossRefGoogle Scholar
  55. Li, D., Long, C., Yue, Y., and Duan, D. (2009). Sub-physiological sarcoglycan expression contributes to compensatory muscle protection in mdx mice. Hum Mol Genet 18, 1209–1220.PubMedCrossRefGoogle Scholar
  56. Li, J., Sun, W., Wang, B., Xiao, X., and Liu, X.Q. (2008). Protein trans-splicing as a means for viral vector-mediated in vivo gene therapy. Hum Gene Ther 19, 958–964.PubMedCrossRefGoogle Scholar
  57. Li, Z.F., Shelton, G.D., and Engvall, E. (2005). Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethality. Am J Pathol 166, 491–497.PubMedGoogle Scholar
  58. Lin, J., Wu, H., Tarr, P.T., Zhang, C.Y., Wu, Z., Boss, O., Michael, L.F., Puigserver, P., Isotani, E., Olson, E.N., et al. (2002). Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418, 797–801.PubMedCrossRefGoogle Scholar
  59. Lin, X., Miller, J.W., Mankodi, A., Kanadia, R.N., Yuan, Y., Moxley, R.T., Swanson, M.S., and Thornton, C.A. (2006). Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet 15, 2087–2097.PubMedCrossRefGoogle Scholar
  60. Lu, Y., Tian, C., Danialou, G., Gilbert, R., Petrof, B.J., Karpati, G., and Nalbantoglu, J. (2008). Targeting artificial transcription factors to the utrophin A promoter: effects on dystrophic pathology and muscle function. J Biol Chem 283, 34720–34727.PubMedCrossRefGoogle Scholar
  61. Mankodi, A., Urbinati, C.R., Yuan, Q.P., Moxley, R.T., Sansone, V., Krym, M., Henderson, D., Schalling, M., Swanson, M.S., and Thornton, C.A. (2001). Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet 10, 2165–2170.PubMedCrossRefGoogle Scholar
  62. Marsh, D.R., Criswell, D.S., Hamilton, M.T., and Booth, F.W. (1997). Association of insulin-like growth factor mRNA expressions with muscle regeneration in young, adult, and old rats. Am J Physiol 273, R353–R358.Google Scholar
  63. Mattei, E., Corbi, N., Di Certo, M.G., Strimpakos, G., Severini, C., Onori, A., Desantis, A., Libri, V., Buontempo, S., Floridi, A., et al. (2007). Utrophin up-regulation by an artificial transcription factor in transgenic mice. PLoS One 2, e774.CrossRefGoogle Scholar
  64. McPherron, A.C., Lawler, A.M., and Lee, S.J. (1997). Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387, 83–90.PubMedCrossRefGoogle Scholar
  65. McPherron, A.C., and Lee, S.J. (1997). Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A 94, 12457–12461.PubMedCrossRefGoogle Scholar
  66. Miller, T.M., Kim, S.H., Yamanaka, K., Hester, M., Umapathi, P., Arnson, H., Rizo, L., Mendell, J.R., Gage, F.H., Cleveland, D.W., et al. (2006). Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103, 19546–19551.PubMedCrossRefGoogle Scholar
  67. Milner, D.J., and Kaufman, S.J. (2007). Alpha7beta1 integrin does not alleviate disease in a mouse model of limb girdle muscular dystrophy type 2F. Am J Pathol 170, 609–619.PubMedCrossRefGoogle Scholar
  68. Miura, S., Tomitsuka, E., Kamei, Y., Yamazaki, T., Kai, Y., Tamura, M., Kita, K., Nishino, I., and Ezaki, O. (2006). Overexpression of peroxisome proliferator-activated receptor gamma co-activator-1alpha leads to muscle atrophy with depletion of ATP. Am J Pathol 169, 1129–1139.PubMedCrossRefGoogle Scholar
  69. Mosher, D.S., Quignon, P., Bustamante, C.D., Sutter, N.B., Mellersh, C.S., Parker, H.G., and Ostrander, E.A. (2007). A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet 3, e79.CrossRefGoogle Scholar
  70. Musaro, A., Giacinti, C., Borsellino, G., Dobrowolny, G., Pelosi, L., Cairns, L., Ottolenghi, S., Cossu, G., Bernardi, G., Battistini, L., et al. (2004). Stem cell-mediated muscle regeneration is enhanced by local isoform of insulin-like growth factor 1. Proc Natl Acad Sci U S A 101, 1206–1210.PubMedCrossRefGoogle Scholar
  71. Musaro, A., McCullagh, K., Paul, A., Houghton, L., Dobrowolny, G., Molinaro, M., Barton, E.R., Sweeney, H.L., and Rosenthal, N. (2001). Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27, 195–200.PubMedCrossRefGoogle Scholar
  72. Nakatani, M., Takehara, Y., Sugino, H., Matsumoto, M., Hashimoto, O., Hasegawa, Y., Murakami, T., Uezumi, A., Takeda, S., Noji, S., et al. (2008). Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice. Faseb J 22, 477–487.PubMedCrossRefGoogle Scholar
  73. Narkar, V.A., Downes, M., Yu, R.T., Embler, E., Wang, Y.X., Banayo, E., Mihaylova, M.M., Nelson, M.C., Zou, Y., Juguilon, H., et al. (2008). AMPK and PPARdelta agonists are exercise mimetics. Cell 134, 405–415.PubMedCrossRefGoogle Scholar
  74. Nguyen, H.X., and Tidball, J.G. (2003a). Expression of a muscle-specific, nitric oxide synthase transgene prevents muscle membrane injury and reduces muscle inflammation during modified muscle use in mice. J Physiol 550, 347–356.PubMedCrossRefGoogle Scholar
  75. Nguyen, H.X., and Tidball, J.G. (2003b). Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro. J Physiol 547, 125–132.PubMedCrossRefGoogle Scholar
  76. Nisoli, E., Clementi, E., Paolucci, C., Cozzi, V., Tonello, C., Sciorati, C., Bracale, R., Valerio, A., Francolini, M., Moncada, S., et al. (2003). Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 299, 896–899.PubMedCrossRefGoogle Scholar
  77. Nisoli, E., Falcone, S., Tonello, C., Cozzi, V., Palomba, L., Fiorani, M., Pisconti, A., Brunelli, S., Cardile, A., Francolini, M., et al. (2004). Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc Natl Acad Sci U S A 101, 16507–16512.PubMedCrossRefGoogle Scholar
  78. Odom, G.L., Gregorevic, P., Allen, J.M., Finn, E., and Chamberlain, J.S. (2008). Microutrophin delivery through rAAV6 increases lifespan and improves muscle function in dystrophic dystrophin/utrophin-deficient mice. Mol Ther 16, 1539–1545.PubMedCrossRefGoogle Scholar
  79. Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., and Sunada, Y. (2006). Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition. J Clin Invest 116, 2924–2934.PubMedCrossRefGoogle Scholar
  80. Otto, A., Schmidt, C., Luke, G., Allen, S., Valasek, P., Muntoni, F., Lawrence-Watt, D., and Patel, K. (2008). Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration. J Cell Sci 121, 2939–2950.PubMedCrossRefGoogle Scholar
  81. Parsons, S.A., Millay, D.P., Sargent, M.A., McNally, E.M., and Molkentin, J.D. (2006). Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy. Am J Pathol 168, 1975–1985.PubMedCrossRefGoogle Scholar
  82. Percival, J.M., Anderson, K.N., Gregorevic, P., Chamberlain, J.S., and Froehner, S.C. (2008). Functional deficits in nNOSmu-deficient skeletal muscle: myopathy in nNOS knockout mice. PLoS One 3, e3387.CrossRefGoogle Scholar
  83. Philip, B., Lu, Z., and Gao, Y. (2005). Regulation of GDF-8 signaling by the p38 MAPK. Cell Signal 17, 365–375.PubMedCrossRefGoogle Scholar
  84. Pierno, S., Nico, B., Burdi, R., Liantonio, A., Didonna, M.P., Cippone, V., Fraysse, B., Rolland, J.F., Mangieri, D., Andreetta, F., et al. (2007). Role of tumour necrosis factor alpha, but not of cyclo-oxygenase-2-derived eicosanoids, on functional and morphological indices of dystrophic progression in mdx mice: a pharmacological approach. Neuropathol Appl Neurobiol 33, 344–359.PubMedCrossRefGoogle Scholar
  85. Polesskaya, A., Seale, P., and Rudnicki, M.A. (2003). Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell 113, 841–852.PubMedCrossRefGoogle Scholar
  86. Qiao, C., Li, J., Zheng, H., Bogan, J., Yuan, Z., Zhang, C., Bogan, D., Kornegay, J., and Xiao, X. (2008). Hydrodynamic limb vein injection of AAV8 canine myostatin propeptide gene in normal dogs enhances muscle growth. Hum Gene Ther 20, 1–10.Google Scholar
  87. Radley, H.G., Davies, M.J., and Grounds, M.D. (2008). Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment. Neuromuscul Disord 18, 227–238.PubMedCrossRefGoogle Scholar
  88. Reay, D.P., Bilbao, R., Koppanati, B.M., Cai, L., O’Day, T.L., Jiang, Z., Zheng, H., Watchko, J.F., and Clemens, P.R. (2008). Full-length dystrophin gene transfer to the mdx mouse in utero. Gene Ther 15, 531–536.PubMedCrossRefGoogle Scholar
  89. Rezniczek, G.A., Konieczny, P., Nikolic, B., Reipert, S., Schneller, D., Abrahamsberg, C., Davies, K.E., Winder, S.J., and Wiche, G. (2007). Plectin 1f scaffolding at the sarcolemma of dystrophic (mdx) muscle fibers through multiple interactions with beta-dystroglycan. J Cell Biol 176, 965–977.PubMedCrossRefGoogle Scholar
  90. Rios, R., Carneiro, I., Arce, V.M., and Devesa, J. (2002). Myostatin is an inhibitor of myogenic differentiation. Am J Physiol Cell Physiol 282, C993–C999.Google Scholar
  91. Rommel, C., Bodine, S.C., Clarke, B.A., Rossman, R., Nunez, L., Stitt, T.N., Yancopoulos, G.D., and Glass, D.J. (2001). Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 3, 1009–1013.PubMedCrossRefGoogle Scholar
  92. Rooney, J.E., Welser, J.V., Dechert, M.A., Flintoff-Dye, N.L., Kaufman, S.J., and Burkin, D.J. (2006). Severe muscular dystrophy in mice that lack dystrophin and alpha7 integrin. J Cell Sci 119, 2185–2195.PubMedCrossRefGoogle Scholar
  93. Rosenberg, M.I., Georges, S.A., Asawachaicharn, A., Analau, E., and Tapscott, S.J. (2006). MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206. J Cell Biol 175, 77–85.PubMedCrossRefGoogle Scholar
  94. Russell-Jones, D.L., Umpleby, A.M., Hennessy, T.R., Bowes, S.B., Shojaee-Moradie, F., Hopkins, K.D., Jackson, N.C., Kelly, J.M., Jones, R.H., and Sonksen, P.H. (1994). Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans. Am J Physiol 267, E591–E598.Google Scholar
  95. Sandalon, Z., Bruckheimer, E.M., Lustig, K.H., and Burstein, H. (2007). Long-term suppression of experimental arthritis following intramuscular administration of a pseudotyped AAV2/1-TNFR:Fc Vector. Mol Ther 15, 264–269.PubMedCrossRefGoogle Scholar
  96. Sander, M., Chavoshan, B., Harris, S.A., Iannaccone, S.T., Stull, J.T., Thomas, G.D., and Victor, R.G. (2000). Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 97, 13818–13823.PubMedCrossRefGoogle Scholar
  97. Sandri, M., Lin, J., Handschin, C., Yang, W., Arany, Z.P., Lecker, S.H., Goldberg, A.L., and Spiegelman, B.M. (2006). PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A 103, 16260–16265.PubMedCrossRefGoogle Scholar
  98. Schertzer, J.D., Gehrig, S.M., Ryall, J.G., and Lynch, G.S. (2007). Modulation of insulin-like growth factor (IGF)-I and IGF-binding protein interactions enhances skeletal muscle regeneration and ameliorates the dystrophic pathology in mdx mice. Am J Pathol 171, 1180–1188.PubMedCrossRefGoogle Scholar
  99. Schertzer, J.D., and Lynch, G.S. (2006). Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury. Gene Ther 13, 1657–1664.PubMedCrossRefGoogle Scholar
  100. Schertzer, J.D., Ryall, J.G., and Lynch, G.S. (2006). Systemic administration of IGF-I enhances oxidative status and reduces contraction-induced injury in skeletal muscles of mdx dystrophic mice. Am J Physiol Endocrinol Metab 291, E499–E505.CrossRefGoogle Scholar
  101. Schertzer, J.D., van der Poel, C., Shavlakadze, T., Grounds, M.D., and Lynch, G.S. (2008). Muscle-specific overexpression of IGF-I improves E-C coupling in skeletal muscle fibers from dystrophic mdx mice. Am J Physiol Cell Physiol 294, C161–C168.CrossRefGoogle Scholar
  102. Schuelke, M., Wagner, K.R., Stolz, L.E., Hubner, C., Riebel, T., Komen, W., Braun, T., Tobin, J.F., and Lee, S.J. (2004). Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 350, 2682–2688.PubMedCrossRefGoogle Scholar
  103. Shavlakadze, T., White, J., Hoh, J.F., Rosenthal, N., and Grounds, M.D. (2004). Targeted expression of insulin-like growth factor-I reduces early myofiber necrosis in dystrophic mdx mice. Mol Ther 10, 829–843.PubMedCrossRefGoogle Scholar
  104. Shavlakadze, T., Winn, N., Rosenthal, N., and Grounds, M.D. (2005). Reconciling data from transgenic mice that overexpress IGF-I specifically in skeletal muscle. Growth Horm IGF Res 15, 4–18.PubMedCrossRefGoogle Scholar
  105. Shiao, T., Fond, A., Deng, B., Wehling-Henricks, M., Adams, M.E., Froehner, S.C., and Tidball, J.G. (2004). Defects in neuromuscular junction structure in dystrophic muscle are corrected by expression of a NOS transgene in dystrophin-deficient muscles, but not in muscles lacking alpha- and beta1-syntrophins. Hum Mol Genet 13, 1873–1884.PubMedCrossRefGoogle Scholar
  106. Song, Y.H., Godard, M., Li, Y., Richmond, S.R., Rosenthal, N., and Delafontaine, P. (2005). Insulin-like growth factor I-mediated skeletal muscle hypertrophy is characterized by increased mTOR-p70S6K signaling without increased Akt phosphorylation. J Investig Med 53, 135–142.PubMedCrossRefGoogle Scholar
  107. Spencer, M.J., and Mellgren, R.L. (2002). Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology. Hum Mol Genet 11, 2645–2655.PubMedCrossRefGoogle Scholar
  108. Stitt, T.N., Drujan, D., Clarke, B.A., Panaro, F., Timofeyva, Y., Kline, W.O., Gonzalez, M., Yancopoulos, G.D., and Glass, D.J. (2004). The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14, 395–403.PubMedCrossRefGoogle Scholar
  109. Thomas, G.D., Sander, M., Lau, K.S., Huang, P.L., Stull, J.T., and Victor, R.G. (1998). Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc Natl Acad Sci U S A 95, 15090–15095.PubMedCrossRefGoogle Scholar
  110. Thomas, M., Langley, B., Berry, C., Sharma, M., Kirk, S., Bass, J., and Kambadur, R. (2000). Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J Biol Chem 275, 40235–40243.PubMedCrossRefGoogle Scholar
  111. Tidball, J.G., and Wehling-Henricks, M. (2005). Damage and inflammation in muscular dystrophy: potential implications and relationships with autoimmune myositis. Curr Opin Rheumatol 17, 707–713.PubMedCrossRefGoogle Scholar
  112. Tidball, J.G., and Wehling-Henricks, M. (2007). The role of free radicals in the pathophysiology of muscular dystrophy. J Appl Physiol 102, 1677–1686.PubMedCrossRefGoogle Scholar
  113. Tinsley, J., Deconinck, N., Fisher, R., Kahn, D., Phelps, S., Gillis, J.M., and Davies, K. (1998). Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nat Med 4, 1441–1444.PubMedCrossRefGoogle Scholar
  114. Vainzof, M., de Paula, F., Tsanaclis, A.M., and Zatz, M. (2003). The effect of calpain 3 deficiency on the pattern of muscle degeneration in the earliest stages of LGMD2A. J Clin Pathol 56, 624–626.PubMedCrossRefGoogle Scholar
  115. Vlachopapadopoulou, E., Zachwieja, J.J., Gertner, J.M., Manzione, D., Bier, D.M., Matthews, D.E., and Slonim, A.E. (1995). Metabolic and clinical response to recombinant human insulin-like growth factor I in myotonic dystrophy – a clinical research center study. J Clin Endocrinol Metab 80, 3715–3723.PubMedCrossRefGoogle Scholar
  116. Wagner, K.R., McPherron, A.C., Winik, N., and Lee, S.J. (2002). Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann Neurol 52, 832–836.PubMedCrossRefGoogle Scholar
  117. Wang, Y.X., Zhang, C.L., Yu, R.T., Cho, H.K., Nelson, M.C., Bayuga-Ocampo, C.R., Ham, J., Kang, H., and Evans, R.M. (2004). Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2, e294.CrossRefGoogle Scholar
  118. Watchko, J., O’Day, T., Wang, B., Zhou, L., Tang, Y., Li, J., and Xiao, X. (2002). Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. Hum Gene Ther 13, 1451–1460.PubMedCrossRefGoogle Scholar
  119. Wehling, M., Spencer, M.J., and Tidball, J.G. (2001). A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. J Cell Biol 155, 123–131.PubMedCrossRefGoogle Scholar
  120. Wehling-Henricks, M., Jordan, M.C., Roos, K.P., Deng, B., and Tidball, J.G. (2005). Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium. Hum Mol Genet 14, 1921–1933.PubMedCrossRefGoogle Scholar
  121. Wheeler, T.M., Lueck, J.D., Swanson, M.S., Dirksen, R.T., and Thornton, C.A. (2007). Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Invest 117, 3952–3957.PubMedGoogle Scholar
  122. Wheeler, T.M., and Thornton, C.A. (2007). Myotonic dystrophy: RNA-mediated muscle disease. Curr Opin Neurol 20, 572–576.PubMedCrossRefGoogle Scholar
  123. White, J.D., Davies, M., and Grounds, M.D. (2001). Leukaemia inhibitory factor increases myoblast replication and survival and affects extracellular matrix production: combined in vivo and in vitro studies in post-natal skeletal muscle. Cell Tissue Res 306, 129–141.PubMedCrossRefGoogle Scholar
  124. White, J.D., Davies, M., McGeachie, J., and Grounds, M.D. (2002). An evaluation of leukaemia inhibitory factor as a potential therapeutic agent in the treatment of muscle disease. Neuromuscul Disord 12, 909–916.PubMedCrossRefGoogle Scholar
  125. Whittemore, L.A., Song, K., Li, X., Aghajanian, J., Davies, M., Girgenrath, S., Hill, J.J., Jalenak, M., Kelley, P., Knight, A., et al. (2003). Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun 300, 965–971.PubMedCrossRefGoogle Scholar
  126. Wineinger, M.A., Walsh, S.A., and Abresch, R.T. (1998). The effect of age and temperature on mdx muscle fatigue. Muscle Nerve 21, 1075–1077.PubMedCrossRefGoogle Scholar
  127. Wolf, E., Kramer, R., Polejaeva I., Thoenen, H., Brem, G., (1994). Efficient generation of chimaeric mice using embryonic stem cells after long-term culture in the presence of ciliary neurotrophic factor. Transgenic Res 3(3), 152–158.Google Scholar
  128. Yang, W., Chen, Y., Zhang, Y., Wang, X., Yang, N., and Zhu, D. (2006). Extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway is involved in myostatin-regulated differentiation repression. Cancer Res 66, 1320–1326.PubMedCrossRefGoogle Scholar
  129. Zhu, X., Hadhazy, M., Wehling, M., Tidball, J.G., and McNally, E.M. (2000). Dominant negative myostatin produces hypertrophy without hyperplasia in muscle. FEBS Lett 474, 71–75.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Laboratory for Muscle Research and Therapeutics DevelopmentBakerIDI Heart & Diabetes InstituteMelbourneAustralia

Personalised recommendations