eCite Digital Repository
Hsp72 preserves muscle function and slows progression of severe muscular dystrophy
Citation
Gehrig, SM and van der Poel, C and Sayer, TA and Schertzer, JD and Henstridge, DC and Church, JE and Lamon, S and Russell, AP and Davies, KE and Febbraio, MA and Lynch, GS, Hsp72 preserves muscle function and slows progression of severe muscular dystrophy, Nature, 484, (7394) pp. 394-398. ISSN 0028-0836 (2012) [Refereed Article]
Copyright Statement
Copyright 2012 Macmillan Publishers Limited
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 Ca22+-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.
Item Details
Item Type: | Refereed Article |
---|---|
Keywords: | heat shock protein 72, sarcoplasmic reticulum calcium transporting adenosine triphosphatase, calcium, developmental biology, diabetes, drug, gene expression, ion, muscle, mutation, pathology, male |
Research Division: | Biological Sciences |
Research Group: | Biochemistry and cell biology |
Research Field: | Cell metabolism |
Objective Division: | Health |
Objective Group: | Clinical health |
Objective Field: | Clinical health not elsewhere classified |
UTAS Author: | Henstridge, DC (Dr Darren Henstridge) |
ID Code: | 133334 |
Year Published: | 2012 |
Web of Science® Times Cited: | 193 |
Deposited By: | Health Sciences |
Deposited On: | 2019-06-24 |
Last Modified: | 2019-07-23 |
Downloads: | 0 |
Repository Staff Only: item control page