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 P., Davies, Kay E., Febbraio, Mark A. and Lynch, Gordon S. 2012, HSP72 preserves muscle function and slows progression of severe muscular dystrophy, Nature, vol. 484, no. 7394, pp. 394-398, doi: 10.1038/nature10980.

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Title HSP72 preserves muscle function and slows progression of severe muscular dystrophy
Author(s) Gehrig, Stefan M.
van der Poel, Chris
Sayer, Timothy A.
Schertzer, Jonathan D.
Henstridge, Darren C.
Church, Jarrod E.
Lamon, SeverineORCID iD for Lamon, Severine orcid.org/0000-0002-3271-6551
Russell, Aaron P.ORCID iD for Russell, Aaron P. orcid.org/0000-0002-7323-9501
Davies, Kay E.
Febbraio, Mark A.
Lynch, Gordon S.
Journal name Nature
Volume number 484
Issue number 7394
Start page 394
End page 398
Total pages 5
Publisher Nature Publishing Group
Place of publication London, U. K.
Publication date 2012-04-19
ISSN 0028-0836
Keyword(s) disease
Summary 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.
Language eng
DOI 10.1038/nature10980
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Grant ID NHMRC 479536
Copyright notice ©2012, Macmillan Publishers Limited
Persistent URL http://hdl.handle.net/10536/DRO/DU:30045282

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