Hsp72 preserves muscle function and slows progression of severe muscular dystrophy

Increasing the expression of intramuscular heat shock protein 72 preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy, suggesting a promising way forward for the treatment of muscular dystrophy. Hsp72 in muscular dystrophy The absence of the membrane-stabilizing protein dystrophin in patients with Duchenne muscular dystrophy results in a highly fragile muscle-cell membrane, abnormal handling of cytoplasmic calcium ions and muscle degeneration. Gehrig et al . tested the idea that enhanced intramuscular expression of heat shock protein 72 (Hsp72) might reduce the pathophysiology of muscular dystrophy in two mouse models. They found that treatment with BGP-15 — an Hsp72 inducer in clinical trials for diabetes — improved muscle function and whole body strength in mdx dystrophic mice. Activity of sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase was reduced in both mouse models, and was restored by BGP-15. This work raises the prospect that BGP-15 and other therapies targeting Hsp72 might be beneficial in people with muscular dystrophy. 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 1 , 2 , 3 . Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca 2+ , which activates inflammatory and muscle degenerative pathways 4 , 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 death 7 , 8 , 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 fun