Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Hsp72 preserves muscle function and slows progression of severe muscular dystrophy

Nature volume 484, pages 394–398 (2012)Cite this article

Subjects

Abstract

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin1,2,3. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca2+, which activates inflammatory and muscle degenerative pathways4,5,6. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death7,8, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca2+) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Transgenic Hsp72 overexpression increases muscle strength, decreases muscle breakdown and improves diaphragm muscle histological parameters in mdx mice.
Figure 2: Maximal SERCA activity is decreased in mouse models of dystrophy; Hsp72 binding improves SERCA function.
Figure 3: Pharmacological induction of Hsp72 ameliorates muscular dystrophy in mdx mice.
Figure 4: Treatment with BGP-15 decreases kyphosis (spinal curvature), improves muscle function and prolongs lifespan in severely dystrophic dko mice.

Similar content being viewed by others

References

  1. Emery, A. E. The muscular dystrophies. Lancet 359, 687–695 (2002)

    Article  CAS  Google Scholar 

  2. Ervasti, J. M. & Campbell, K. P. Membrane organization of the dystrophin–glycoprotein complex. Cell 66, 1121–1131 (1991)

    Article  CAS  Google Scholar 

  3. Koenig, M., Monaco, A. P. & Kunkel, L. M. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 53, 219–228 (1988)

    Article  CAS  Google Scholar 

  4. Blake, D. J., Weir, A., Newey, S. E. & Davies, K. E. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol. Rev. 82, 291–329 (2002)

    Article  CAS  Google Scholar 

  5. Straub, V., Rafael, J. A., Chamberlain, J. S. & Campbell, K. P. Animal models for muscular dystrophy show different patterns of sarcolemmal disruption. J. Cell Biol. 139, 375–385 (1997)

    Article  CAS  Google Scholar 

  6. Turner, P. R., Westwood, T., Regen, C. M. & Steinhardt, R. A. Increased protein degradation results from elevated free calcium levels found in muscle from mdx mice. Nature 335, 735–738 (1988)

    Article  ADS  CAS  Google Scholar 

  7. Grady, R. M. et al. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell 90, 729–738 (1997)

    Article  CAS  Google Scholar 

  8. Deconinck, A. E. et al. Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90, 717–727 (1997)

    Article  CAS  Google Scholar 

  9. Gervasio, O. L., Whitehead, N. P., Yeung, E. W., Phillips, W. D. & Allen, D. G. TRPC1 binds to caveolin-3 and is regulated by Src kinase—role in Duchenne muscular dystrophy. J. Cell Sci. 121, 2246–2255 (2008)

    Article  CAS  Google Scholar 

  10. Fong, P. Y., Turner, P. R., Denetclaw, W. F. & Steinhardt, R. A. Increased activity of calcium leak channels in myotubes of Duchenne human and mdx mouse origin. Science 250, 673–676 (1990)

    Article  ADS  CAS  Google Scholar 

  11. Bellinger, A. M. et al. Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nature Med. 15, 325–330 (2009)

    Article  CAS  Google Scholar 

  12. Nicolas-Metral, V., Raddatz, E., Kucera, P. & Ruegg, U. T. Mdx myotubes have normal excitability but show reduced contraction–relaxation dynamics. J. Muscle Res. Cell Motil. 22, 69–75 (2001)

    Article  CAS  Google Scholar 

  13. Tutdibi, O., Brinkmeier, H., Rudel, R. & Fohr, K. J. Increased calcium entry into dystrophin-deficient muscle fibres of MDX and ADR-MDX mice is reduced by ion channel blockers. J. Physiol. (Lond.) 515, 859–868 (1999)

    Article  CAS  Google Scholar 

  14. Goonasekera, S. A. et al. Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle. J. Clin. Invest. 121, 1044–1052 (2011)

    Article  CAS  Google Scholar 

  15. Morine, K. J., Sleeper, M. M., Barton, E. R. & Sweeney, H. L. Overexpression of SERCA1a in the mdx diaphragm reduces susceptibility to contraction-induced damage. Hum. Gene Ther. 12, 1735–1739 (2010)

    Article  Google Scholar 

  16. Porter, J. D. et al. A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice. Hum. Mol. Genet. 11, 263–272 (2002)

    Article  CAS  Google Scholar 

  17. Acharyya, S. et al. Interplay of IKK/NF-κB signaling in macrophages and myofibres promotes muscle degeneration in Duchenne muscular dystrophy. J. Clin. Invest. 117, 889–901 (2007)

    Article  CAS  Google Scholar 

  18. Kolodziejczyk, S. M. et al. Activation of JNK1 contributes to dystrophic muscle pathogenesis. Curr. Biol. 11, 1278–1282 (2001)

    Article  CAS  Google Scholar 

  19. Monici, M. C., Aguennouz, M., Mazzeo, A., Messina, C. & Vita, G. Activation of nuclear factor-κB in inflammatory myopathies and Duchenne muscular dystrophy. Neurology 60, 993–997 (2003)

    Article  CAS  Google Scholar 

  20. Senf, S. M., Dodd, S. L., McClung, J. M. & Judge, A. R. Hsp70 overexpression inhibits NF-κB and Foxo3a transcriptional activities and prevents skeletal muscle atrophy. FASEB J. 22, 3836–3845 (2008)

    Article  CAS  Google Scholar 

  21. Park, H. S., Lee, J. S., Huh, S. H., Seo, J. S. & Choi, E. J. Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J. 20, 446–456 (2001)

    Article  CAS  Google Scholar 

  22. Chung, J. et al. HSP72 protects against obesity-induced insulin resistance. Proc. Natl Acad. Sci. USA 105, 1739–1744 (2008)

    Article  ADS  CAS  Google Scholar 

  23. Tupling, A. R. et al. HSP70 binds to the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1a) and prevents thermal inactivation. J. Biol. Chem. 279, 52382–52389 (2004)

    Article  CAS  Google Scholar 

  24. Bornman, L., Polla, B. S., Lotz, B. P. & Gericke, G. S. Expression of heat-shock/stress proteins in Duchenne muscular dystrophy. Muscle Nerve 18, 23–31 (1995)

    Article  CAS  Google Scholar 

  25. Lou, J. S., Weiss, M. D. & Carter, G. T. Assessment and management of fatigue in neuromuscular disease. Am. J. Hosp. Palliat. Care 27, 145–157 (2010)

    Article  Google Scholar 

  26. Finsterer, J. Cardiopulmonary support in Duchenne muscular dystrophy. Lung 184, 205–215 (2006)

    Article  Google Scholar 

  27. Stedman, H. H. et al. The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature 352, 536–539 (1991)

    Article  ADS  CAS  Google Scholar 

  28. Briguet, A., Courdier-Fruh, I., Foster, M., Meier, T. & Magyar, J. P. Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse. Neuromuscul. Disord. 14, 675–682 (2004)

    Article  Google Scholar 

  29. Literati-Nagy, B. et al. Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: a proof of concept randomized double-blind clinical trial. Horm. Metab. Res. 41, 374–380 (2009)

    Article  CAS  Google Scholar 

  30. Morimoto, R. I. Cells in stress: transcriptional activation of heat shock genes. Science 259, 1409–1410 (1993)

    Article  ADS  CAS  Google Scholar 

  31. Marber, M. S. et al. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J. Clin. Invest. 95, 1446–1456 (1995)

    Article  CAS  Google Scholar 

  32. Taleb, M. et al. Hsp70 inhibits aminoglycoside-induced hair cell death and is necessary for the protective effect of heat shock. J. Assoc. Res. Otolaryngol. 9, 277–289 (2008)

    Article  Google Scholar 

  33. Literati-Nagy, B. et al. Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine-induced metabolic disorders. Brain Res. Bull. 20, 340–344 (2010)

    Article  Google Scholar 

  34. Saegusa, Y. & Tabata, H. Usefulness of infrared thermometry in determining body temperature in mice. J. Vet. Med. Sci. 65, 1365–1367 (2003)

    Article  Google Scholar 

  35. Gregorevic, P., Plant, D. R., Leeding, K. S., Bach, L. A. & Lynch, G. S. Improved contractile function of the mdx dystrophic mouse diaphragm muscle after insulin-like growth factor-I administration. Am. J. Pathol. 161, 2263–2272 (2002)

    Article  CAS  Google Scholar 

  36. Schertzer, J. D., Ryall, J. G. & Lynch, G. S. Systemic administration of IGF-I enhances oxidative status and reduces contraction-induced injury in skeletal muscles of mdx dystrophic mice. Am. J. Physiol. 291, 499–505 (2006)

    Google Scholar 

  37. Schertzer, J. D., Gehrig, S. M., Ryall, J. G. & Lynch, G. S. 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 (2007)

    Article  CAS  Google Scholar 

  38. Gehrig, S. M., Koopman, R., Naim, T., Tjoakarfa, C. & Lynch, G. S. Making fast-twitch dystrophic muscles bigger protects them from contraction injury and attenuates the dystrophic pathology. Am. J. Pathol. 176, 29–33 (2010)

    Article  CAS  Google Scholar 

  39. Briguet, A., Courdier-Fruh, I., Foster, M., Meier, T. & Magyar, J. P. Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse. Neuromuscul. Disord. 14, 675–682 (2004)

    Article  Google Scholar 

  40. Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254 (1976)

    Article  CAS  Google Scholar 

  41. Schertzer, J. D. et al. β2-Agonist administration increases sarcoplasmic reticulum Ca2+-ATPase activity in aged rat skeletal muscle. Am. J. Physiol. 288, 526–533 (2005)

    Google Scholar 

  42. Plant, D. R. & Lynch, G. S. Depolarization-induced contraction and SR function in mechanically skinned muscle fibres from dystrophic mdx mice. Am. J. Physiol. 285, C522–C528 (2003)

    Article  CAS  Google Scholar 

  43. Murphy, K. T. et al. Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function. FASEB J. 24, 4433–4442 (2010)

    Article  CAS  Google Scholar 

  44. Green, M. C. A rapid method for clearing and staining specimens for the demonstration of bone. Ohio J. Sci. 52, 31–33 (1952)

    Google Scholar 

Download references

Acknowledgements

We thank R. Koopman, J. G. Ryall and G. I. Lancaster for comments; J. Trieu, B. G. Gleeson, T. Naim and A. Chee for technical support; and C. Angelini and the Neuromuscular bank of tissues and DNA samples – Telethon Network of Genetic Biobanks for the provision of human muscle specimens. We thank N-Gene R&D Inc. USA for providing the BGP-15 compound. This study was supported in part by research grants from the National Health and Medical Research Council (NHMRC; project numbers 1009114 to G.S.L. and 472650 and 1004441 to M.A.F.), Association Française contre les Myopathies (France, to G.S.L.) and the Muscular Dystrophy Association (USA, to G.S.L.). M.A.F. is a Senior Principal Research Fellow of the NHMRC. A.P.R. was supported by a NHMRC Biomedical career Development Award. S.L. was supported by a postdoctoral fellowship from the Swiss National Science Foundation. S.M.G. was supported by a National Heart Foundation Postgraduate Scholarship (Australia). D.C.H. was supported by a National Heart Foundation Post-Doctoral Fellowship.

Author information

Author notes

  1. Chris van der Poel, Jonathan D. Schertzer & Jarrod E. Church

    Present address: Present addresses: Department of Human Biosciences, Faculty of Health Sciences, La Trobe University, Bundoora, 3086, Victoria, Australia (C.v.d.P. and J.E.C.); Department of Biochemistry and Biomedical Sciences and Department of Pediatrics, McMaster University, Hamilton, Ontario, L8S 4L8, Canada (J.D.S.).,

Authors and Affiliations

  1. Department of Physiology, Basic and Clinical Myology Laboratory, University of Melbourne, Victoria, 3010, Australia

    Stefan M. Gehrig, Chris van der Poel, Timothy A. Sayer, Jonathan D. Schertzer, Jarrod E. Church & Gordon S. Lynch

  2. Cellular and Molecular Metabolism Laboratory, Baker-IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, Victoria, 8008, Australia ,

    Darren C. Henstridge & Mark A. Febbraio

  3. Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, 3125, Australia ,

    Severine Lamon & Aaron P. Russell

  4. Department of Physiology, MRC Functional Genomics Unit, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK,

    Kay E. Davies

Authors
  1. Stefan M. Gehrig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chris van der Poel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Timothy A. Sayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan D. Schertzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Darren C. Henstridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jarrod E. Church
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Severine Lamon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aaron P. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kay E. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark A. Febbraio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gordon S. Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.M.G., J.D.S., C.v.d.P., M.A.F. and G.S.L. conceived and designed the experiments. S.M.G., T.A.S., C.v.d.P., D.C.H. and J.E.C. performed the experiments. M.A.F. and K.E.D. facilitated experiments through the provision of mice and experimental compounds. A.P.R. and S.L. performed experiments on muscle samples from patients with DMD and from controls. S.M.G., D.C.H., M.A.F., C.v.d.P. and G.S.L. analysed the data. S.M.G. and G.S.L. wrote the manuscript. All authors checked for scientific content and contributed to the final drafting of the manuscript.

Corresponding author

Correspondence to Gordon S. Lynch.

Ethics declarations

Competing interests

M.A.F. is a scientific consultant for N-Gene R&D Inc. USA, who supplied the BGP-15 compound. He has a position on a patent held by N-Gene R&D Inc. D.C.H., G.S.L. and S.M.G. have positions on a patent held by N-Gene R&D Inc. The remaining authors declare no competing interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-8 and Supplementary Table 1. (PDF 1465 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gehrig, S., van der Poel, C., Sayer, T. et al. Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. Nature 484, 394–398 (2012). https://doi.org/10.1038/nature10980

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10980

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research