title: Hsp72 preserves muscle function and slows progression of severe muscular             dystrophy.
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 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.
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology,                     University of Melbourne, Victoria, 3010,                     Australia.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Gehrig
authors.forename: Chris
authors.initials: C
authors.lastname: van der Poel
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Sayer
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schertzer
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.forename: Jarrod E
authors.initials: JE
authors.lastname: Church
authors.forename: Severine
authors.initials: S
authors.lastname: Lamon
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
mesh_terms: D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007738:Kyphosis / Q000188:drug therapy; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D010091:Oximes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats
chemical_list: D050884:HSP72 Heat-Shock Proteins; D010091:Oximes; D010880:Piperidines; D000252:Calcium-Transporting ATPases; C405586:BGP 15