Overexpression of HSP72 attenuates skeletal muscle pathophysiology in mdx dystrophic mice

S.M. Gehrig,¹ C. Van Der Poel,¹ D.C. Henstridge,² J.D. Schertzer,¹ R. Koopman,¹ T. Naim,¹ M.A. Febbraio² and G.S. Lynch,¹ ¹Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, VIC 3010, Australia and ²Cellular and Molecular Metabolism Laboratory, Baker IDI, PO Box 6492, St Kilda Road Central, VIC 8008, Australia.

An absence of dystrophin in muscle fibres results in fragility, membrane tears, Ca²⁺ influx and an elevated cytoplasmic [Ca²⁺], resulting in the activation of degenerative pathways. Chronic degeneration and ineffective regeneration results in fibrotic infiltration leading to functional impairments in DMD patients and in muscles from dystrophin-deficient mdx mice. Heat-shock protein 72 (HSP72) has potential to protect contractile function and improve Ca²⁺ handling in cardiac muscle. We tested the hypothesis that HSP72 overexpression would ameliorate the pathophysiology of skeletal muscles of mdx dystrophic mice. Contractile properties of isolated diaphragm muscle preparations from mdx mice overexpressing HSP72 (mdx^HSP72) and mdx littermate control mice (n≥5) were determined according to methods we have described previously. HSP72 overexpression improved normalised force of isolated diaphragm muscle strips (P < 0.05), reduced collagen infiltration (P < 0.05), and improved the minimal Ferets variance coefficient, indicative of a reduced dystrophic muscle fibre pathology (P < 0.05). Serum creatine kinase levels were significantly lower in mdx^HSP72 mice compared with mdx littermate controls (P < 0.05), indicating a general reduction in muscle degeneration. The findings reveal that overexpression of HSP72 protein improved the dystrophic muscle pathology.