Clinical Features of Skeletal Muscle and Their Underlying Molecular Mechanism

  • Masanori P. TakahashiEmail author


The cardinal features of myotonic dystrophy are muscle stiffness (myotonia) and muscle wasting. RNA gain-of-function has been established as an underlying disease mechanism. Myotonia has been shown to be the result of the missplicing of chloride channel mRNA caused by changes to RNA-binding proteins, including MBNL and CELF. Many types of RNA that play essential roles in skeletal muscle function have been identified as possibly being implicated in muscle wasting. Recently, other mechanisms, such as repeat-associated non-ATG translation, have been proposed, and their contribution to muscle phenotypes is currently the subject of study.


Myotonia Muscle atrophy Splicing Chloride channel Cytoskeletal protein Ca2+ Handling protein 



This work was partly supported by grants from the Ministry of Health, Labour and Welfare of Japan (H28-Nanchitou(Nan)-Ippan-030) and Japan Agency for Medical Research and Development (AMED) (17ek0109259).


  1. 1.
    Streib EW, Sun SF. Distribution of electrical myotonia in myotonic muscular dystrophy. Ann Neurol. 1983;14:80–2.PubMedGoogle Scholar
  2. 2.
    Logigian EL, Ciafaloni E, Quinn LC, Dilek N, Pandya S, Moxley RT, Thornton CA. Severity, type, and distribution of myotonic discharges are different in type 1 and type 2 myotonic dystrophy. Muscle Nerve. 2007;35:479–85.CrossRefGoogle Scholar
  3. 3.
    Ricker K, Meinck HM. Comparison of myotonic discharges in myotonia congenita and dystrophia myotonica. Z Neurol. 1972;201:62–72.PubMedGoogle Scholar
  4. 4.
    Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B, Willer J-C, Tabti N, Fontaine B. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol. 2004;56:650–61.CrossRefGoogle Scholar
  5. 5.
    Fournier E, Viala K, Gervais H, et al. Cold extends electromyography distinction between ion channel mutations causing myotonia. Ann Neurol. 2006;60:356–65.CrossRefGoogle Scholar
  6. 6.
    Cannon SC. Pathomechanisms in channelopathies of skeletal muscle and brain. Annu Rev Neurosci. 2006;29:387–415.CrossRefGoogle Scholar
  7. 7.
    Lipicky RJ, Bryant SH, Salmon JH. Cable parameters, sodium, potassium, chloride, and water content, and potassium efflux in isolated external intercostal muscle of normal volunteers and patients with myotonia congenita. J Clin Invest. 1971;50:2091–103.CrossRefGoogle Scholar
  8. 8.
    Furman RE, Barchi RL. The pathophysiology of myotonia produced by aromatic carboxylic acids. Ann Neurol. 1978;4:357–65.CrossRefGoogle Scholar
  9. 9.
    Renaud JF, Desnuelle C, Schmid-Antomarchi H, Hugues M, Serratrice G, Lazdunski M. Expression of apamin receptor in muscles of patients with myotonic muscular dystrophy. Nature. 1986;319:678–80.CrossRefGoogle Scholar
  10. 10.
    Behrens MI, Jalil P, Serani A, Vergara F, Alvarez O. Possible role of apamin-sensitive K+ channels in myotonic dystrophy. Muscle Nerve. 1994;17:1264–70.CrossRefGoogle Scholar
  11. 11.
    Mounsey JP, Xu P, John JE, Horne LT, Gilbert J, Roses AD, Moorman JR. Modulation of skeletal muscle sodium channels by human myotonin protein kinase. J Clin Invest. 1995;95:2379–84.CrossRefGoogle Scholar
  12. 12.
    Mounsey JP, Mistry DJ, Ai CW, Reddy S, Moorman JR. Skeletal muscle sodium channel gating in mice deficient in myotonic dystrophy protein kinase. Hum Mol Genet. 2000;9:2313–20.CrossRefGoogle Scholar
  13. 13.
    Franke C, Hatt H, Iaizzo PA, Lehmann-Horn F. Characteristics of Na+ channels and Cl- conductance in resealed muscle fibre segments from patients with myotonic dystrophy. J Physiol. 1990;425:391–405.CrossRefGoogle Scholar
  14. 14.
    Franke C, Iaizzo PA, Hatt H, Spittelmeister W, Ricker K, Lehmann-Horn F. Altered Na+ channel activity and reduced Cl− conductance cause hyperexcitability in recessive generalized myotonia (becker). Muscle Nerve. 1991;14:762–70.CrossRefGoogle Scholar
  15. 15.
    Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D, Krym M, Thornton CA. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science. 2000;289:1769–73.CrossRefGoogle Scholar
  16. 16.
    Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LP. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293:864–7.CrossRefGoogle Scholar
  17. 17.
    Ranum LPW, Cooper TA. RNA-mediated neuromuscular disorders. Annu Rev Neurosci. 2006;29:259–77.CrossRefGoogle Scholar
  18. 18.
    Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, Cannon SC, Thornton CA. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10:35–44.CrossRefGoogle Scholar
  19. 19.
    Charlet BN, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell. 2002;10:45–53.CrossRefGoogle Scholar
  20. 20.
    Kanadia RN, Johnstone KA, Mankodi A, Lungu C, Thornton CA, Esson D, Timmers AM, Hauswirth WW, Swanson MS. A muscleblind knockout model for myotonic dystrophy. Science. 2003;302:1978–80.CrossRefGoogle Scholar
  21. 21.
    Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS. Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J. 2000;19:4439–48.CrossRefGoogle Scholar
  22. 22.
    Kuyumcu-Martinez NM, Wang G-S, Cooper TA. Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell. 2007;28:68–78.CrossRefGoogle Scholar
  23. 23.
    Kimura T, Takahashi MP, Okuda Y, Kaido M, Fujimura H, Yanagihara T, Sakoda S. The expression of ion channel mRNAs in skeletal muscles from patients with myotonic muscular dystrophy. Neurosci Lett. 2000;295:93–6.CrossRefGoogle Scholar
  24. 24.
    Kimura T, Takahashi MP, Fujimura H, Sakoda S. Expression and distribution of a small-conductance calcium-activated potassium channel (SK3) protein in skeletal muscles from myotonic muscular dystrophy patients and congenital myotonic mice. Neurosci Lett. 2003;347:191–5.CrossRefGoogle Scholar
  25. 25.
    Pribnow D, Johnson-Pais T, Bond CT, Keen J, Johnson RA, Janowsky A, Silvia C, Thayer M, Maylie J, Adelman JP. Skeletal muscle and small-conductance calcium-activated potassium channels. Muscle Nerve. 1999;22:742–50.CrossRefGoogle Scholar
  26. 26.
    Ricker K, Koch MC, Lehmann-Horn F, Pongratz D, Otto M, Heine R, Moxley RT. Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology. 1994;44:1448–52.CrossRefGoogle Scholar
  27. 27.
    Matsumura T, Kimura T, Kokunai Y, Nakamori M, Ogata K, Fujimura H, Takahashi MP, Mochizuki H, Sakoda S. Simple questionnaire for screening patients with myotonic dystrophy type 1. Neurol Clin Neurosci. 2014;2:97–103.CrossRefGoogle Scholar
  28. 28.
    Solbakken G, Ørstavik K, Hagen T, Dietrichs E, Naerland T. Major involvement of trunk muscles in myotonic dystrophy type 1. Acta Neurol Scand. 2016;134:467–73.CrossRefGoogle Scholar
  29. 29.
    DiPaolo G, Jimenez-Moreno C, Nikolenko N, Atalaia A, Monckton DG, Guglieri M, Lochmüller H. Functional impairment in patients with myotonic dystrophy type 1 can be assessed by an ataxia rating scale (SARA). J Neurol. 2017;264:701–8.CrossRefGoogle Scholar
  30. 30.
    Bouchard J-P, Cossette L, Bassez G, Puymirat J. Natural history of skeletal muscle involvement in myotonic dystrophy type 1: a retrospective study in 204 cases. J Neurol. 2015;262:285–93.CrossRefGoogle Scholar
  31. 31.
    Hammarén E, Kjellby-Wendt G, Lindberg C. Muscle force, balance and falls in muscular impaired individuals with myotonic dystrophy type 1: a five-year prospective cohort study. Neuromuscul Disord. 2015;25:141–8.CrossRefGoogle Scholar
  32. 32.
    Schoser B. Myotonic dystrophies type 1 and 2. In: Goebel CAS HH, Weller RO, editors. Muscle disease pathology and genetics. 2nd ed. Chichester: Wiley-Blackwell; 2013. p. 273–83.CrossRefGoogle Scholar
  33. 33.
    Dubowitz V, Sewry CA, Oldfors A, Lane RJM. Muscular dystrophies and allied disorders V: facioscapulohumeral, myotonic and oculopharyngeal muscular dystrophies. In: Dubowitz V, Sewry CA, Oldfors A, editors. Muscle biopsy: a practical approach: Saunders; 2013. p. 345–57.Google Scholar
  34. 34.
    Tohgi H, Kawamorita A, Utsugisawa K, Yamagata M, Sano M. Muscle histopathology in myotonic dystrophy in relation to age and muscular weakness. Muscle Nerve. 1994;17:1037–43.CrossRefGoogle Scholar
  35. 35.
    Tanabe Y, Nonaka I. Congenital myotonic dystrophy. Changes in muscle pathology with ageing. J Neurol Sci. 1987;77:59–68.CrossRefGoogle Scholar
  36. 36.
    Kimura T, Nakamori M, Lueck JD, Pouliquin P, Aoike F, Fujimura H, Dirksen RT, Takahashi MP, Dulhunty AF, Sakoda S. Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1. Hum Mol Genet. 2005;14:2189–200.CrossRefGoogle Scholar
  37. 37.
    Tang ZZ, Yarotskyy V, Wei L, Sobczak K, Nakamori M, Eichinger K, Moxley RT, Dirksen RT, Thornton CA. Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of CaV1.1 calcium channel. Hum Mol Genet. 2012;21:1312–24.CrossRefGoogle Scholar
  38. 38.
    Hino S-I, Kondo S, Sekiya H, et al. Molecular mechanisms responsible for aberrant splicing of SERCA1 in myotonic dystrophy type 1. Hum Mol Genet. 2007;16:2834–43.CrossRefGoogle Scholar
  39. 39.
    Kimura T, Lueck JD, Harvey PJ, Pace SM, Ikemoto N, Casarotto MG, Dirksen RT, Dulhunty AF. Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling. Cell Calcium. 2009;45:264–74.CrossRefGoogle Scholar
  40. 40.
    Zhao Y, Ogawa H, Yonekura S-I, Mitsuhashi H, Mitsuhashi S, Nishino I, Toyoshima C, Ishiura S. Functional analysis of SERCA1b, a highly expressed SERCA1 variant in myotonic dystrophy type 1 muscle. Biochim Biophys Acta Mol basis Dis. 2015;1852:2042–7.CrossRefGoogle Scholar
  41. 41.
    Benders AAGM, Wevers RA, Veerkamp JH. Ion transport in human skeletal muscle cells: disturbances in myotonic dystrophy and Brody’s disease. Acta Physiol Scand. 1996;156:355–67.CrossRefGoogle Scholar
  42. 42.
    Santoro M, Piacentini R, Masciullo M, Bianchi MLE, Modoni A, Podda MV, Ricci E, Silvestri G, Grassi C. Alternative splicing alterations of Ca2+ handling genes are associated with Ca2+ signal dysregulation in myotonic dystrophy type 1 (DM1) and type 2 (DM2) myotubes. Neuropathol Appl Neurobiol. 2014;40:464–76.CrossRefGoogle Scholar
  43. 43.
    Nakamori M, Kimura T, Fujimura H, Takahashi MP, Sakoda S. Altered mRNA splicing of dystrophin in type 1 myotonic dystrophy. Muscle Nerve. 2007;36:251–7.CrossRefGoogle Scholar
  44. 44.
    Nakamori M, Sobczak K, Puwanant A, et al. Splicing biomarkers of disease severity in myotonic dystrophy. Ann Neurol. 2013;74:862–72.CrossRefGoogle Scholar
  45. 45.
    Rau F, Lainé J, Ramanoudjame L, et al. Abnormal splicing switch of DMD’s penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nat Commun. 2015;6:7205.CrossRefGoogle Scholar
  46. 46.
    Nakamori M, Kimura T, Kubota T, Matsumura T, Sumi H, Fujimura H, Takahashi MP, Sakoda S. Aberrantly spliced alpha-dystrobrevin alters alpha-syntrophin binding in myotonic dystrophy type 1. Neurology. 2008;70:677–85.CrossRefGoogle Scholar
  47. 47.
    Lee E, Marcucci M, Daniell L, Pypaert M, Weisz OA, Ochoa G-C, Farsad K, Wenk MR, De Camilli P. Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle. Science. 2002;297:1193–6.CrossRefGoogle Scholar
  48. 48.
    Fugier C, Klein AF, Hammer C, et al. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat Med. 2011;17:720–5.CrossRefGoogle Scholar
  49. 49.
    Nicot A-S, Toussaint A, Tosch V, et al. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet. 2007;39:1134–9.CrossRefGoogle Scholar
  50. 50.
    Romero NB. Centronuclear myopathies: a widening concept. Neuromuscul Disord. 2010;20:223–8.CrossRefGoogle Scholar
  51. 51.
    Buj-Bello A, Furling D, Tronchère H, Laporte J, Lerouge T, Butler-Browne GS, Mandel J-L. Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells. Hum Mol Genet. 2002;11:2297–307.CrossRefGoogle Scholar
  52. 52.
    Lin X, Miller JW, Mankodi A, Kanadia RN, Yuan Y, Moxley RT, Swanson MS, Thornton CA. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet. 2006;15:2087–97.CrossRefGoogle Scholar
  53. 53.
    Kino Y, Washizu C, Kurosawa M, Oma Y, Hattori N, Ishiura S, Nukina N. Nuclear localization of MBNL1: splicing-mediated autoregulation and repression of repeat-derived aberrant proteins. Hum Mol Genet. 2015;24:740–56.CrossRefGoogle Scholar
  54. 54.
    Adereth Y, Dammai V, Kose N, Li R, Hsu T. RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1. Nat Cell Biol. 2005;7:1240–7.CrossRefGoogle Scholar
  55. 55.
    Masuda A, Andersen HS, Doktor TK, Okamoto T, Ito M, Andresen BS, Ohno K. CUGBP1 and MBNL1 preferentially bind to 3’ UTRs and facilitate mRNA decay. Sci Rep. 2012;2:209.CrossRefGoogle Scholar
  56. 56.
    Wang ET, Cody NAL, Jog S, et al. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell. 2012;150:710–24.CrossRefGoogle Scholar
  57. 57.
    Du H, Cline MS, Osborne RJ, et al. Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat Struct Mol Biol. 2010;17:187–93.CrossRefGoogle Scholar
  58. 58.
    Timchenko NA, Cai ZJ, Welm AL, Reddy S, Ashizawa T, Timchenko LT. RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGBP1. J Biol Chem. 2001;276:7820–6.CrossRefGoogle Scholar
  59. 59.
    Timchenko NA, Patel R, Iakova P, Cai Z-J, Quan L, Timchenko LT. Overexpression of CUG triplet repeat-binding protein, CUGBP1, in mice inhibits myogenesis. J Biol Chem. 2004;279:13129–39.CrossRefGoogle Scholar
  60. 60.
    Salisbury E, Sakai K, Schoser B, Huichalaf C, Schneider-Gold C, Nguyen H, Wang G-L, Albrecht JH, Timchenko LT. Ectopic expression of cyclin D3 corrects differentiation of DM1 myoblasts through activation of RNA CUG-binding protein, CUGBP1. Exp Cell Res. 2008;314:2266–78.CrossRefGoogle Scholar
  61. 61.
    Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, Woodgett J, Killian J, Timchenko NA, Timchenko LT. GSK3β mediates muscle pathology in myotonic dystrophy. J Clin Invest. 2012;122:4461–72.CrossRefGoogle Scholar
  62. 62.
    About AMO-02. Accessed 31 Jan 2017.
  63. 63.
    Cho DH, Thienes CP, Mahoney SE, Analau E, Filippova GN, Tapscott SJ. Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol Cell. 2005;20:483–9.CrossRefGoogle Scholar
  64. 64.
    Filippova GN, Thienes CP, Penn BH, Cho DH, Hu YJ, Moore JM, Klesert TR, Lobanenkov VV, Tapscott SJ. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat Genet. 2001;28:335–43.CrossRefGoogle Scholar
  65. 65.
    Zu T, Gibbens B, Doty NS, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011;108:260–5.CrossRefGoogle Scholar
  66. 66.
    Cleary JD, Ranum LPW. Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders. Curr Opin Genet Dev. 2014;26:6–15.CrossRefGoogle Scholar
  67. 67.
    Kearse MG, Todd PK. Repeat-associated non-AUG translation and its impact in neurodegenerative disease. Neurotherapeutics. 2014;11:721–31.CrossRefGoogle Scholar
  68. 68.
    Yamashita Y, Matsuura T, Shinmi J, et al. Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy. J Hum Genet. 2012;57:368–74.CrossRefGoogle Scholar
  69. 69.
    Orengo JP, Chambon P, Metzger D, Mosier DR, Snipes GJ, Cooper TA. Expanded CTG repeats within the DMPK 3’ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy. Proc Natl Acad Sci U S A. 2008;105:2646–51.CrossRefGoogle Scholar
  70. 70.
    Ohsawa N, Koebis M, Suo S, Nishino I, Ishiura S. Alternative splicing of PDLIM3/ALP, for α-actinin-associated LIM protein 3, is aberrant in persons with myotonic dystrophy. Biochem Biophys Res Commun. 2011;409:64–9.CrossRefGoogle Scholar
  71. 71.
    Koebis M, Ohsawa N, Kino Y, Sasagawa N, Nishino I, Ishiura S. Alternative splicing of myomesin 1 gene is aberrantly regulated in myotonic dystrophy type 1. Genes Cells. 2011;16:961–72.CrossRefGoogle Scholar
  72. 72.
    Rinaldi F, Terracciano C, Pisani V, et al. Aberrant splicing and expression of the non muscle myosin heavy-chain gene MYH14 in DM1 muscle tissues. Neurobiol Dis. 2012;45:264–71.CrossRefGoogle Scholar
  73. 73.
    Wagner SD, Struck AJ, Gupta R, Farnsworth DR, Mahady AE, Eichinger K, Thornton CA, Wang ET, Berglund JA. Dose-dependent regulation of alternative splicing by MBNL proteins reveals biomarkers for myotonic dystrophy. PLoS Genet. 2016;12:e1006316.CrossRefGoogle Scholar
  74. 74.
    Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001;29:40–7.CrossRefGoogle Scholar
  75. 75.
    Nakamori M, Takahashi MP. Myotonic dystrophy. In: Translational research in muscular dystrophy. Tokyo: Springer; 2016. p. 39–61.CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Clinical Neurophysiology, Department of Functional Diagnostic ScienceOsaka University Graduate School of MedicineSuitaJapan

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