Skip to main content
SpringerLink
Log in

Identifying Therapies for Muscle Disease Using Zebrafish

  • Chapter
  • First Online:
Regenerative Medicine for Degenerative Muscle Diseases

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

  • 827 Accesses

Abstract

The zebrafish (Danio rerio) has emerged as a significant animal model not only for studying the mechanisms of muscular dystrophy disease but also for investigating drug therapies for muscular dystrophies. In this chapter, we review recent progress in the use of zebrafish to identify potential drug therapies for two particularly severe forms of muscular dystrophy: Duchenne muscular dystrophy (DMD) and Ullrich congenital muscular dystrophy (UCMD). One common finding across three large-scale chemical screens using the zebrafish dmd model is the identification of phosphodiesterase (PDE) inhibitors as beneficial for the dmd skeletal muscle phenotype. Together with investigations in mouse models and human patients, these studies appear to provide very strong support for PDE inhibitors as possible DMD therapies. We discuss how the zebrafish system has great potential to serve as a preclinical translation model for evaluating optimal drug therapies for DMD and other muscle diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

BM:

Bethlem myopathy

CsA:

Cyclosporin A

DMD:

Duchenne muscular dystrophy

FDA:

United States Food and Drug Administration

MO:

Morpholino

PDE:

Phosphodiesterase

PTP:

Mitochondrial permeability transition pore

SSRI:

Selective serotonin uptake inhibitor

UCMD:

Ullrich congenital muscular dystrophy

References

  1. Dalkilic I, Kunkel LM. Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev. 2003;13:231–8.

    Article  CAS  PubMed  Google Scholar 

  2. Wallace GQ, McNally EM. Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies. Annu Rev Physiol. 2009;71:37–57.

    Article  CAS  PubMed  Google Scholar 

  3. Berger J, Currie PD. Zebrafish models flex their muscles to shed light on muscular dystrophies. Dis Model Mech. 2012;5:726–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gibbs EM, Horstick EJ, Dowling JJ. Swimming into prominence: the zebrafish as a valuable tool for studying human myopathies and muscular dystrophies. FEBS J. 2013;280:4187–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kawahara G, Kunkel LM. Zebrafish based small molecule screens for novel DMD drugs. Drug Discov Today Technol. 2013;10:e91–6.

    Article  Google Scholar 

  6. Maves L. Recent advances using zebrafish animal models for muscle disease drug discovery. Expert Opin Drug Discov. 2014;14:1–13.

    Google Scholar 

  7. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C, DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9:77–93.

    Article  PubMed  Google Scholar 

  8. Hoffman EP, Brown Jr RH, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51:919–28.

    Article  CAS  PubMed  Google Scholar 

  9. Rahimov F, Kunkel LM. The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol. 2013;201:499–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goemans N, Buyse G. Current treatment and management of dystrophinopathies. Curr Treat Options Neurol. 2014;16:287.

    Article  PubMed  Google Scholar 

  11. Bernardi P, Bonaldo P. Mitochondrial dysfunction and defective autophagy in the pathogenesis of collagen VI muscular dystrophies. Cold Spring Harbor Perspect Biol. 2013;5:a011387.

    Article  Google Scholar 

  12. Bushby KM, Collins J, Hicks D. Collagen type VI myopathies. Adv Exp Med Biol. 2014;802:185–99.

    Article  CAS  PubMed  Google Scholar 

  13. Govoni A, Magri F, Brajkovic S, Zanetta C, Faravelli I, Corti S, Bresolin N, Comi GP. Ongoing therapeutic trials and outcome measures for Duchenne muscular dystrophy. Cell Mol Life Sci. 2013;70:4585–602.

    Article  CAS  PubMed  Google Scholar 

  14. Ruegg UT. Pharmacological prospects in the treatment of Duchenne muscular dystrophy. Curr Opin Neurol. 2013;26:577–84.

    Article  CAS  PubMed  Google Scholar 

  15. Fairclough RJ, Wood MJ, Davies KE. Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nat Rev Genet. 2013;14:373–8.

    Article  CAS  PubMed  Google Scholar 

  16. Seto JT, Bengtsson NE, Chamberlain JS. Therapy of genetic disorders-novel therapies for Duchenne muscular dystrophy. Curr Pediatr Rep. 2014;2:102–12.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kornegay JN, Spurney CF, Nghiem PP, Brinkmeyer-Langford CL, Hoffman EP, Nagaraju K. Pharmacologic management of Duchenne muscular dystrophy: target identification and preclinical trials. ILAR J. 2014;55:119–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ljubicic V, Jasmin BJ. AMP-activated protein kinase at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy. Trends Mol Med. 2013;19:614–24.

    Article  CAS  PubMed  Google Scholar 

  19. Telfer WR, Busta AS, Bonnemann CG, Feldman EL, Dowling JJ. Zebrafish models of collagen VI-related myopathies. Hum Mol Genet. 2010;19:2433–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lin YY. Muscle diseases in the zebrafish. Neuromuscul Disord. 2012;22:673–84.

    Article  PubMed  Google Scholar 

  21. Santoriello C, Zon LI. Hooked! Modeling human disease in zebrafish. J Clin Invest. 2012;122:2337–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zon LI, Peterson RT. In vivo drug discovery in the zebrafish. Nat Rev Drug Discov. 2005;4:35–44.

    Article  CAS  PubMed  Google Scholar 

  23. Felsenfeld AL, Walker C, Westerfield M, Kimmel C, Streisinger G. Mutations affecting skeletal muscle myofibril structure in the zebrafish. Development. 1990;108:443–59.

    CAS  PubMed  Google Scholar 

  24. Kawahara G, Karpf JA, Myers JA, Alexander MS, Guyon JR, Kunkel LM. Drug screening in a zebrafish model of Duchenne muscular dystrophy. Proc Natl Acad Sci USA. 2011;108:5331–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Johnson NM, Farr, GH 3rd, Maves L. The HDAC inhibitor TSA ameliorates a zebrafish model of Duchenne muscular dystrophy. PLoS Curr. 2013;5. pii: ecurrents.md.8273cf41db10e2d15dd3ab827cb4b027

    Google Scholar 

  26. Smith LL, Beggs AH, Gupta VA. Analysis of skeletal muscle defects in larval zebrafish by birefringence and touch-evoke escape response assays. J Vis Exp. 2013;82, e50925.

    Google Scholar 

  27. Bassett DI, Bryson-Richardson RJ, Daggett DF, Gautier P, Keenan DG, Currie PD. Dystrophin is required for the formation of stable muscle attachments in the zebrafish embryo. Development. 2003;130:5851–60.

    Article  CAS  PubMed  Google Scholar 

  28. Goody MF, Kelly MW, Reynolds CJ, Khalil A, Crawford BD, Henry CA. NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy. PLoS Biol. 2012;10, e1001409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Berger J, Sztal T, Currie PD. Quantification of birefringence readily measures the level of muscle damage in zebrafish. Biochem Biophys Res Commun. 2012;423:785–8.

    Article  CAS  PubMed  Google Scholar 

  30. Winder SJ, Lipscomb L, Angela Parkin C, Juusola M. The proteasomal inhibitor MG132 prevents muscular dystrophy in zebrafish. PLoS Curr. 2011;3:RRRN1286.

    Article  Google Scholar 

  31. Kimmel CB, Patterson J, Kimmel RO. The development and behavioral characteristics of the startle response in the zebra fish. Dev Psychobiol. 1974;7:47–60.

    Article  CAS  PubMed  Google Scholar 

  32. Saint-Amant L, Drapeau P. Time course of the development of motor behaviors in the zebrafish embryo. J Neurobiol. 1998;37:622–32.

    Article  CAS  PubMed  Google Scholar 

  33. Dowling JJ, Arbogast S, Hur J, Nelson DD, McEvoy A, Waugh T, Marty I, Lunardi J, Brooks SV, Kuwada JY, Ferreiro A. Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. Brain. 2012;135:1115–27.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hirata H, Watanabe T, Hatakeyama J, Sprague SM, Saint-Amant L, Nagashima A, Cui WW, Zhou W, Kuwada JY. Zebrafish relatively relaxed mutants have a ryanodine receptor defect, show slow swimming and provide a model of multi-minicore disease. Development. 2007;134:2771–81.

    Article  CAS  PubMed  Google Scholar 

  35. Horstick EJ, Gibbs EM, Li X, Davidson AE, Dowling JJ. Analysis of embryonic and larval zebrafish skeletal myofibers from dissociated preparations. J Vis Exp. 2013;81, e50259.

    Google Scholar 

  36. Kawahara G, Gasperini MJ, Myers JA, Widrick JJ, Eran A, Serafini PR, Alexander MS, Pletcher MT, Morris CA, Kunkel LM. Dystrophic muscle improvement in zebrafish via increased heme oxygenase signaling. Hum Mol Genet. 2014;23:1869–78.

    Article  CAS  PubMed  Google Scholar 

  37. Granato M, van Eeden FJ, Schach U, Trowe T, Brand M, Furutani-Seiki M, Haffter P, Hammerschmidt M, Heisenberg CP, Jiang YJ, Kane DA, Kelsh RN, Mullins MC, Odenthal J, Nüsslein-Volhard C. Genes controlling and mediating locomotion behavior of the zebrafish embryo and larva. Development. 1996;123:399–413.

    Google Scholar 

  38. Blackburn PR, Campbell JM, Clark KJ, Ekker SC. The CRISPR system--keeping zebrafish gene targeting fresh. Zebrafish. 2013;10:116–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Campbell JM, Hartjes KA, Nelson TJ, Xu X, Ekker SC. New and TALENted genome engineering toolbox. Circ Res. 2013;113:571–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kettleborough RN, Busch-Nentwich EM, Harvey SA, Dooley CM, de Bruijn E, van Eeden F, Sealy I, White RJ, Herd C, Nijman IJ, Fényes F, Mehroke S, Scahill C, Gibbons R, Wali N, Carruthers S, Hall A, Yen J, Cuppen E, Stemple DL. A systematic genome-wide analysis of zebrafish protein-coding gene function. Nature. 2013;496:494–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bradford Y, Conlin T, Dunn N, Fashena D, Frazer K, Howe DG, Knight J, Mani P, Martin R, Moxon SA, Paddock H, Pich C, Ramachandran S, Ruef BJ, Ruzicka L, Bauer Schaper H, Schaper K, Shao X, Singer A, Sprague J, Sprunger B, Van Slyke C, Westerfield M. ZFIN: enhancements and updates to the Zebrafish Model Organism Database. Nucleic Acids Res. 2011;39:D822–9.

    Article  CAS  PubMed  Google Scholar 

  42. Berger J, Berger S, Hall TE, Lieschke GJ, Currie PD. Dystrophin-deficient zebrafish feature aspects of the Duchenne muscular dystrophy pathology. Neuromuscul Disord. 2010;20:826–32.

    Article  PubMed  Google Scholar 

  43. Waugh TA, Horstick E, Hur J, Jackson SW, Davidson AE, Li X, Dowling JJ. Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy. Hum Mol Genet. 2014;23:4651–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Guyon JR, Mosley AN, Zhou Y, O'Brien KF, Sheng X, Chiang K, Davidson AJ, Volinski JM, Zon LI, Kunkel LM. The dystrophin associated protein complex in zebrafish. Hum Mol Genet. 2003;12:601–15.

    Article  CAS  PubMed  Google Scholar 

  45. Steffen LS, Guyon JR, Vogel ED, Beltre R, Pusack TJ, Zhou Y, Zon LI, Kunkel LM. Zebrafish orthologs of human muscular dystrophy genes. BMC Genomics. 2007;8:79.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Li M, Andersson-Lendahl M, Sejersen T, Arner A. Muscle dysfunction and structural defects of dystrophin-null sapje mutant zebrafish larvae are rescued by ataluren treatment. FASEB J. 2014;28:1593–9.

    Article  CAS  PubMed  Google Scholar 

  47. Adamo CM, Dai DF, Percival JM, Minami E, Willis MS, Patrucco E, Froehner SC, Beavo JA. Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy. Proc Natl Acad Sci USA. 2010;107:19079–83.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Asai A, Sahani N, Kaneki M, Ouchi Y, Martyn JA, Yasuhara SE. Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy. PLoS ONE. 2007;2, e806.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Percival JM, Whitehead NP, Adams ME, Adamo CM, Beavo JA, Froehner SC. Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy. J Pathol. 2012;228:77–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Nelson MD, Rader F, Tang X, Tavyev J, Nelson SF, Miceli MC, Elashoff RM, Sweeney HL, Victor RG. PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology. 2014;82:2085–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Leung DG, Herzka DA, Thompson WR, He B, Bibat G, Tennekoon G, Russell SD, Schuleri KH, Lardo AC, Kass DA, Thompson RE, Judge DP, Wagner KR. Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. Ann Neurol. 2014;76:541–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Witting N, Kruuse C, Nyhuus B, Prahm KP, Citirak G, Lundgaard SJ, von Huth S, Vejlstrup N, Lindberg U, Krag TO, Vissing J. Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy. Ann Neurol. 2014;76:550–7.

    Article  CAS  PubMed  Google Scholar 

  53. Bonaldo P, Braghetta P, Zanetti M, Piccolo S, Volpin D, Bressan GM. Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet. 1998;7:2135–40.

    Article  CAS  PubMed  Google Scholar 

  54. Irwin WA, Bergamin N, Sabatelli P, Reggiani C, Megighian A, Merlini L, Braghetta P, Columbaro M, Volpin D, Bressan GM, Bernardi P, Bonaldo P. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet. 2003;35:367–71.

    Article  CAS  PubMed  Google Scholar 

  55. Grumati P, Coletto L, Sabatelli P, Cescon M, Angelin A, Bertaggia E, Blaauw B, Urciuolo A, Tiepolo T, Merlini L, Maraldi NM, Bernardi P, Sandri M, Bonaldo P. Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med. 2010;16:1313–20.

    Article  CAS  PubMed  Google Scholar 

  56. Zulian A, Rizzo E, Schiavone M, Palma E, Tagliavini F, Blaauw B, Merlini L, Maraldi NM, Sabatelli P, Braghetta P, Bonaldo P, Argenton F, Bernardi P. NIM811, a cyclophilin inhibitor without immunosuppressive activity, is beneficial in collagen VI congenital muscular dystrophy models. Hum Mol Genet. 2014;23:5353–63.

    Article  CAS  PubMed  Google Scholar 

  57. Janssen PM, Murray JD, Schill KE, Rastogi N, Schultz EJ, Tran T, Raman SV, Rafael-Fortney JA. Prednisolone attenuates improvement of cardiac and skeletal contractile function and histopathology by lisinopril and spironolactone in the mdx mouse model of Duchenne muscular dystrophy. PLoS ONE. 2014;9, e88360.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Funding for work on zebrafish skeletal muscle disease in the Maves lab comes from the Seattle Children’s Research Institute Myocardial Regeneration Initiative and NIH R03 AR065760. EP was supported by the University of Washington School of Medicine Medical Student Research Training Program.

Author information

Authors and Affiliations

  1. Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, 1900 Ninth Avenue, Seattle, WA, 98101, USA

    Elizabeth U. Parker & Lisa Maves

  2. Department of Pediatrics, University of Washington, Seattle, WA, USA

    Lisa Maves

Authors
  1. Elizabeth U. Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa Maves
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lisa Maves .

Editor information

Editors and Affiliations

  1. Department of Rehabilitation Medicine, University of Washington Department of Rehabilitation Medicine, WINSTON SALEM, North Carolina, USA

    Martin K. Childers

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this chapter

Cite this chapter

Parker, E.U., Maves, L. (2016). Identifying Therapies for Muscle Disease Using Zebrafish. In: Childers, M. (eds) Regenerative Medicine for Degenerative Muscle Diseases. Stem Cell Biology and Regenerative Medicine. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3228-3_10

Download citation

Publish with us

Policies and ethics

Search

Navigation