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dc.contributor.authorGehrig, SM
dc.contributor.authorvan der Poel, C
dc.contributor.authorSayer, TA
dc.contributor.authorSchertzer, JD
dc.contributor.authorHenstridge, DC
dc.contributor.authorChurch, JE
dc.contributor.authorLamon, S
dc.contributor.authorRussell, AP
dc.contributor.authorDavies, KE
dc.contributor.authorFebbraio, MA
dc.contributor.authorLynch, GS
dc.identifierpii: nature10980
dc.identifier.citationGehrig, S. M., van der Poel, C., Sayer, T. A., Schertzer, J. D., Henstridge, D. C., Church, J. E., Lamon, S., Russell, A. P., Davies, K. E., Febbraio, M. A. & Lynch, G. S. (2012). Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. NATURE, 484 (7394), pp.394-398.
dc.descriptionC1 - Journal Articles Refereed
dc.description.abstractDuchenne 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 Ca(2+), 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 Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) 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.
dc.subjectNeurology and Neuromuscular Diseases; Inherited Diseases (incl. Gene Therapy)
dc.titleHsp72 preserves muscle function and slows progression of severe muscular dystrophy
dc.typeJournal Article
melbourne.peerreviewPeer Reviewed
melbourne.affiliationThe University of Melbourne
melbourne.contributor.authorCHURCH, JARROD
melbourne.contributor.authorLynch, Gordon
melbourne.contributor.authorGEHRIG, STEFAN
melbourne.contributor.authorSayer, Timothy
melbourne.contributor.authorVAN DER POEL, CHRISTOPHER
melbourne.contributor.authorSCHERTZER, JONATHAN
melbourne.contributor.authorSayer, Tim
melbourne.identifier.fundernameidNHMRC, 1009114
melbourne.fieldofresearch320905 Neurology and neuromuscular diseases
melbourne.seocode200199 Clinical health not elsewhere classified
melbourne.accessrightsThis item is currently not available from this repository

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