1. ¹Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
2. ²Department of Neurology, University of Washington, Seattle, Washington, USA

Correspondence: DeWayne Townsend, 7712 Medical Science II, 1301 East Catherine Street, Ann Arbor, Michigan 48109-0622, USA. E-mail: dtown@umich.edu

Received 7 November 2006; Accepted 11 February 2007; Published online 17 April 2007.

Abstract

Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration resulting from the loss of the cytoskeletal protein dystrophin. Most patients develop significant cardiomyopathy, with heart failure being the second leading cause of death in DMD. Compared with the extensive studies on skeletal muscle defects and potential therapy in DMD, very little attention has been directed at the increasing incidence of heart failure in DMD. Here we show that a single systemic injection of recombinant adeno-associated virus (rAAV2/6) harboring micro-dystrophin leads to extensive cardiac transduction, with micro-dystrophin correctly localized at the periphery of the cardiac myocytes and functionally associated with the sarcolemmal membrane. Significantly, micro-dystrophin gene transfer corrected the baseline end-diastolic volume defect in the mdx mouse heart and prevented cardiac pump failure induced by dobutamine stress testing in vivo, although several parameters of systolic function were not corrected. These results demonstrate that systemic gene delivery of micro-dystrophin can restore ventricular distensibility and protect the mdx myocardium from pump dysfunction during adrenergic stimulation in vivo.