Hsp72 preserves muscle function and slows progression of severe muscular dystrophy

Stefan M Gehrig, Chris van der Poel, Timothy A. Sayer, Jonathan D Schertzer, Darren C. Henstridge, Jarrod E. Church, Severine Lamon, Aaron Paul Russell, Kay E Davies, Mark A. Febbraio, Gordon S Lynch

Research output: Contribution to journalArticleResearchpeer-review

137 Citations (Scopus)

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 dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca2+, which activates inflammatory and muscle degenerative pathways. 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 death, 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.

Original languageEnglish
Pages (from-to)394-398
Number of pages5
JournalNature
Volume484
Issue number7394
DOIs
Publication statusPublished - 19 Apr 2012
Externally publishedYes

Cite this

Gehrig, S. M., van der Poel, C., Sayer, T. A., Schertzer, J. D., Henstridge, D. C., Church, J. E., ... Lynch, G. S. (2012). Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. Nature, 484(7394), 394-398. https://doi.org/10.1038/nature10980
Gehrig, Stefan M ; van der Poel, Chris ; Sayer, Timothy A. ; Schertzer, Jonathan D ; Henstridge, Darren C. ; Church, Jarrod E. ; Lamon, Severine ; Russell, Aaron Paul ; Davies, Kay E ; Febbraio, Mark A. ; Lynch, Gordon S. / Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. In: Nature. 2012 ; Vol. 484, No. 7394. pp. 394-398.
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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 dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca2+, which activates inflammatory and muscle degenerative pathways. 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 death, 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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Gehrig, SM, van der Poel, C, Sayer, TA, Schertzer, JD, Henstridge, DC, Church, JE, Lamon, S, Russell, AP, Davies, KE, Febbraio, MA & Lynch, GS 2012, 'Hsp72 preserves muscle function and slows progression of severe muscular dystrophy', Nature, vol. 484, no. 7394, pp. 394-398. https://doi.org/10.1038/nature10980

Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. / Gehrig, Stefan M; van der Poel, Chris; Sayer, Timothy A.; Schertzer, Jonathan D; Henstridge, Darren C.; Church, Jarrod E.; Lamon, Severine; Russell, Aaron Paul; Davies, Kay E; Febbraio, Mark A.; Lynch, Gordon S.

In: Nature, Vol. 484, No. 7394, 19.04.2012, p. 394-398.

Research output: Contribution to journalArticleResearchpeer-review

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Gehrig SM, van der Poel C, Sayer TA, Schertzer JD, Henstridge DC, Church JE et al. Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. Nature. 2012 Apr 19;484(7394):394-398. https://doi.org/10.1038/nature10980