Muscular Dystrophy Model

  • Saranyapin PotikanondEmail author
  • Wutigri Nimlamool
  • Jasprien Noordermeer
  • Lee G. Fradkin
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1076)


Muscular dystrophy (MD) is a group of muscle weakness disease involving in inherited genetic conditions. MD is caused by mutations or alteration in the genes responsible for the structure and functioning of muscles. There are many different types of MD which have a wide range from mild symptoms to severe disability. Some types involve the muscles used for breathing which eventually affect life expectancy. This chapter provides an overview of the MD types, its gene mutations, and the Drosophila MD models. Specifically, the Duchenne muscular dystrophy (DMD), the most common form of MD, will be thoroughly discussed including Dystrophin genes, their isoforms, possible mechanisms, and signaling pathways of pathogenesis.


Muscular dystrophy Muscular atrophy Dystrophin-glycoprotein complex Neuromuscular junction Expertise: molecular cell biology Drosophila as a Duchenne muscular dystrophy (DMD) model 


  1. Abu-Baker A, Rouleau GA. Oculopharyngeal muscular dystrophy: recent advances in the understanding of the molecular pathogenic mechanisms and treatment strategies. Biochim Biophys Acta Mol basis Dis. 2007;1772:173–85. Scholar
  2. Akasaka-Manya K, Manya H, Endo T. Mutations of the POMT1 gene found in patients with Walker–Warburg syndrome lead to a defect of protein O-mannosylation. Biochem Biophys Res Commun. 2004;325:75–9. Scholar
  3. Beitel LK, Alvarado C, Mokhtar S, et al. Mechanisms mediating spinal and bulbar muscular atrophy: investigations into polyglutamine-expanded androgen receptor function and dysfunction. Front Neurol. 2013;4:53. Scholar
  4. Berke B, Wittnam J, McNeill E, et al. Retrograde BMP signaling at the synapse: a permissive signal for synapse maturation and activity-dependent plasticity. J Neurosci. 2013;33:17937–50. Scholar
  5. Brzustowicz LM, Lehner T, Castilla LH, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q1 1.2-13.3. Nature. 1990;344:540–1. Scholar
  6. Cerro-Herreros E, Chakraborty M, Pérez-Alonso M, et al. Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic dystrophy type 1-like phenotypes and activate autophagocytosis genes. Sci Rep. 2017;7:2843. Scholar
  7. Chakraborty M, Selma-Soriano E, Magny E, et al. Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction. Dis Model Mech. 2015;8:1569–78. Scholar
  8. Chan YB, Miguel-Aliaga I, Franks C, et al. Neuromuscular defects in a Drosophila survival motor neuron gene mutant. Hum Mol Genet. 2003;12:1367–76.CrossRefPubMedGoogle Scholar
  9. Chang HC-H, Dimlich DN, Yokokura T, et al. Modeling spinal muscular atrophy in Drosophila. PLoS One. 2008;3:e3209. Scholar
  10. Chartier A, Benoit B, Simonelig M. A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1. EMBO J. 2006;25:2253–62. Scholar
  11. Chartier A, Klein P, Pierson S, et al. Mitochondrial dysfunction reveals the role of mRNA Poly(A) tail regulation in Oculopharyngeal muscular dystrophy pathogenesis. PLoS Genet. 2015;11:e1005092. Scholar
  12. Collins MA, Mandigo TR, Camuglia JM, et al. Emery-Dreifuss muscular dystrophy-linked genes and centronuclear myopathy-linked genes regulate myonuclear movement by distinct mechanisms. Mol Biol Cell. 2017.
  13. D’Angelo MG, Lorusso ML, Civati F, et al. Neurocognitive profiles in Duchenne muscular dystrophy and gene mutation site. Pediatr Neurol. 2011;45:292–9. Scholar
  14. de Haro M, Al-Ramahi I, De Gouyon B, et al. MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. Hum Mol Genet. 2006;15:2138–45. Scholar
  15. Deconinck AE, Rafael JA, Skinner JA, et al. Utrophin-Dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell. 1997;90:717–27. Scholar
  16. Dialynas G, Speese S, Budnik V, et al. The role of Drosophila Lamin C in muscle function and gene expression. Development. 2010;137:3067–77. Scholar
  17. Dimachkie MM, Barohn RJ. Distal myopathies. Neurol Clin. 2014;32(817–42):x. Scholar
  18. Duff RM, Tay V, Hackman P, et al. Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. Am J Hum Genet. 2011;88:729–40. Scholar
  19. Ferri G, Huichalaf CH, Caccia R, Gabellini D. Direct interplay between two candidate genes in FSHD muscular dystrophy. Hum Mol Genet. 2015;24:1256–66. Scholar
  20. Funderburk SF, Shatkina L, Mink S, et al. Specific N-terminal mutations in the human androgen receptor induce cytotoxicity. Neurobiol Aging. 2009;30:1851–64. Scholar
  21. Garcia-Lopez A, Monferrer L, Garcia-Alcover I, et al. Genetic and chemical modifiers of a CUG toxicity model in Drosophila. PLoS One. 2008;3:e1595. Scholar
  22. Gourdon G, Meola G. Myotonic dystrophies: state of the art of new therapeutic developments for the CNS. Front Cell Neurosci. 2017;11:101. Scholar
  23. Grewal PK, Todd LC, van der Maarel S, et al. FRG1, a gene in the FSH muscular dystrophy region on human chromosome 4q35, is highly conserved in vertebrates and invertebrates. Gene. 1998;216:13–9.CrossRefPubMedGoogle Scholar
  24. Haines N, Seabrooke S, Stewart BA. Dystroglycan and protein O-mannosyltransferases 1 and 2 are required to maintain integrity of Drosophila larval muscles. Mol Biol Cell. 2007;18:4721–30. Scholar
  25. Hanel ML, Sun C-YJ, Jones TI, et al. Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a dynamic nuclear and sarcomeric protein. Differentiation. 2011;81:107–18. Scholar
  26. Helbling-Leclerc A, Bonne G, Schwartz K. Emery-Dreifuss muscular dystrophy. Eur J Hum Genet. 2002;10:157–61. Scholar
  27. Houseley JM, Wang Z, Brock GJR, et al. Myotonic dystrophy associated expanded CUG repeat muscleblind positive ribonuclear foci are not toxic to Drosophila. Hum Mol Genet. 2005;14:873–83. Scholar
  28. Ichimiya T, Manya H, Ohmae Y, et al. The twisted abdomen phenotype of Drosophila POMT1 and POMT2 mutants coincides with their heterophilic protein O-mannosyltransferase activity. J Biol Chem. 2004;279:42638–47. Scholar
  29. Jones TI, Parilla M, Jones PL. Transgenic Drosophila for investigating DUX4 and FRG1, two genes associated with Facioscapulohumeral muscular dystrophy (FSHD). PLoS One. 2016;11:e0150938. Scholar
  30. Kleopa KA, Drousiotou A, Mavrikiou E, et al. Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy. Hum Mol Genet. 2006;15:1623–8. Scholar
  31. Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33:831–46. Scholar
  32. Kühn U, Nemeth A, Meyer S, Wahle E. The RNA binding domains of the nuclear poly(A)-binding protein. J Biol Chem. 2003;278:16916–25. Scholar
  33. Lee G, Schwarz TL. Filamin, a synaptic organizer in Drosophila, determines glutamate receptor composition and membrane growth. Elife. 2016.
  34. Lemmers RJ, Miller DG, van der Maarel SM. Facioscapulohumeral muscular dystrophy. Seattle: University of Washington; 1993.Google Scholar
  35. Machuca-Tzili L, Thorpe H, Robinson TE, et al. Flies deficient in Muscleblind protein model features of myotonic dystrophy with altered splice forms of Z-band associated transcripts. Hum Genet. 2006;120:487–99. Scholar
  36. Manya H, Chiba A, Yoshida A, et al. Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc Natl Acad Sci U S A. 2004;101:500–5. Scholar
  37. Martín-Blanco E, García-Bellido A. Mutations in the rotated abdomen locus affect muscle development and reveal an intrinsic asymmetry in Drosophila. Proc Natl Acad Sci U S A. 1996;93:6048–52.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Meola G, Cardani R. Myotonic dystrophy type 2: an update on clinical aspects, genetic and pathomolecular mechanism. J Neuromuscul Dis. 2015;2:S59–71. Scholar
  39. Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron. 2005;48:885–95. Scholar
  40. Morel V, Lepicard S, N. Rey A, et al (2014) Drosophila Nesprin-1 controls glutamate receptor density at neuromuscular junctions. Cell Mol Life Sci 71:3363–3379. doi: Scholar
  41. Muntoni F, Brockington M, Brown SC. Glycosylation eases muscular dystrophy. Nat Med. 2004;10:676–7. Scholar
  42. Parent A. Duchenne De Boulogne: a pioneer in neurology and medical photography. Can J Neurol Sci. 2005;32:369–77.CrossRefPubMedGoogle Scholar
  43. Pegoraro E, Hoffman EP. Limb-Girdle muscular dystrophy overview. Seattle: University of Washington; 1993.Google Scholar
  44. Philips AV, Timchenko LT, Cooper TA. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science. 1998;280:737–41.CrossRefPubMedGoogle Scholar
  45. Picchio L, Plantie E, Renaud Y, et al. Novel Drosophila model of myotonic dystrophy type 1: phenotypic characterization and genome-wide view of altered gene expression. Hum Mol Genet. 2013;22:2795–810. Scholar
  46. Pilgram GS, Potikanond S, Baines RA, et al. The roles of the dystrophin-associated glycoprotein complex at the synapse. Mol Neurobiol. 2010;41:1–21. Scholar
  47. Rajendra TK, Gonsalvez GB, Walker MP, et al. A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle. J Cell Biol. 2007;176:831–41. Scholar
  48. Rajgor D, Shanahan CM. Nesprins: from the nuclear envelope and beyond. Expert Rev Mol Med. 2013;15:e5. Scholar
  49. Rocha CT, Hoffman EP. Limb-girdle and congenital muscular dystrophies: current diagnostics, management, and emerging technologies. Curr Neurol Neurosci Rep. 2010;10:267–76. Scholar
  50. Ryder S, Leadley RM, Armstrong N, et al. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J Rare Dis. 2017;12:79. Scholar
  51. Shcherbata HR, Yatsenko AS, Patterson L, et al. Dissecting muscle and neuronal disorders in a Drosophila model of muscular dystrophy. EMBO J. 2007;26:481–93. Scholar
  52. Skordis LA, Dunckley MG, Burglen L, et al. Characterisation of novel point mutations in the survival motor neuron gene SMN, in three patients with SMA. Hum Genet. 2001;108:356–7.CrossRefPubMedGoogle Scholar
  53. Snider L, Geng LN, Lemmers RJLF, et al. Facioscapulohumeral dystrophy: incomplete suppression of a Retrotransposed gene. PLoS Genet. 2010;6:e1001181. Scholar
  54. Sparks SE, Quijano-Roy S, Harper A, et al. Congenital muscular dystrophy overview. Seattle: University of Washington; 1993.Google Scholar
  55. Statland J, Tawil R. Facioscapulohumeral muscular dystrophy. Neurol Clin. 2014;32(721–8):ix. Scholar
  56. Taghli-Lamallem O, Akasaka T, Hogg G, et al. Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype. Aging Cell. 2008;7:237–49. Scholar
  57. Takeyama K, Ito S, Yamamoto A, et al. Androgen-dependent neurodegeneration by Polyglutamine-expanded human androgen receptor in Drosophila. Neuron. 2002;35:855–64. Scholar
  58. Thijssen PE, Balog J, Yao Z, et al. DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy. Skelet Muscle. 2014;4:19. Scholar
  59. Tracy K, Velentzas PD, Baehrecke EH. Ral GTPase and the exocyst regulate autophagy in a tissue-specific manner. EMBO Rep. 2016;17:110–21. Scholar
  60. Trollet C, Gidaro T, Klein P, et al. Oculopharyngeal muscular dystrophy. Seattle: University of Washington; 1993.Google Scholar
  61. Turner C, Hilton-Jones D. Myotonic dystrophy. Curr Opin Neurol. 2014;27:599–606. Scholar
  62. Uchino R, Nonaka Y, Horigome T, et al. Loss of Drosophila A-type Lamin C initially causes tendon abnormality including disintegration of cytoskeleton and nuclear lamina in muscular defects. Dev Biol. 2013;373:216–27. Scholar
  63. Udd B. Distal muscular dystrophies. Curr Neurol Neurosci Rep. 2014;14:434.
  64. Ueyama M, Akimoto Y, Ichimiya T, et al. Increased apoptosis of myoblasts in Drosophila model for the Walker-Warburg syndrome. PLoS One. 2010;5:e11557. Scholar
  65. Vajsar J, Schachter H. Walker-Warburg syndrome. Orphanet J Rare Dis. 2006;1:29. Scholar
  66. van der Plas MC, Pilgram GS, Plomp JJ, et al. Dystrophin is required for appropriate retrograde control of neurotransmitter release at the Drosophila neuromuscular junction. J Neurosci. 2006;26:333–44. 26/1/333 [pii]. Scholar
  67. van der Plas MC, Pilgram GSK, de Jong AWM, et al. Drosophila Dystrophin is required for integrity of the musculature. Mech Dev. 2007;124:617–30. Scholar
  68. Wairkar YP, Fradkin LG, Noordermeer JN, DiAntonio A. Synaptic defects in a Drosophila model of congenital muscular dystrophy. J Neurosci. 2008;28:3781–9. 28/14/3781 [pii]. Scholar
  69. Weill L, Belloc E, Bava F-A, Méndez R. Translational control by changes in poly(A) tail length: recycling mRNAs. Nat Struct Mol Biol. 2012;19:577–85. Scholar
  70. Wuebbles RD, Long SW, Hanel ML, Jones PL. Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int J Clin Exp Pathol. 2010;3:386–400.PubMedPubMedCentralGoogle Scholar
  71. Yenigun VB, Sirito M, Amcheslavky A, et al. (CCUG) n RNA toxicity in a Drosophila model of myotonic dystrophy type 2 (DM2) activates apoptosis. Dis Model Mech. 2017;10:993–1003. Scholar
  72. Yu Z, Goodman LD, Shieh S-Y, et al. A fly model for the CCUG-repeat expansion of myotonic dystrophy type 2 reveals a novel interaction with MBNL1. Hum Mol Genet. 2015;24:954–62. Scholar
  73. Zhang Q, Ragnauth C, Greener MJ, Shanahan CM, Roberts RG. The nesprins are giant actin-binding proteins orthologous to Drosophila melanogaster muscle protein MSP-300. Genomics. 2002;80:473–81. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Saranyapin Potikanond
    • 1
    Email author
  • Wutigri Nimlamool
    • 1
  • Jasprien Noordermeer
    • 2
  • Lee G. Fradkin
    • 3
  1. 1.Department of Pharmacology, Faculty of MedicineChiang Mai UniversityChiang MaiThailand
  2. 2.Department of Molecular BiologyLeiden University Medical Center (LUMC)LeidenThe Netherlands
  3. 3.Department of NeurobiologyUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations