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