Acute pathophysiological effects of muscle-expressed Dp71 transgene on normal and dystrophic mouse muscle

• Published in: Journal of applied physiology (1985) 2003-11, Vol.95 (5), p.1861-1866
• Main Authors: Wieneke, Sascha, Heimann, Peter, Leibovitz, Sigalit, Nudel, Uri, Jockusch, Harald
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Biological and medical sciences; Dystrophin - analogs & derivatives; Dystrophin - genetics; Female; Fundamental and applied biological sciences. Psychology; Genetics; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle Contraction - physiology; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscular Dystrophy, Animal - pathology; Muscular Dystrophy, Animal - physiopathology; Muscular system; Rodents; Sarcolemma - pathology; Sarcolemma - physiology; Transgenes - physiology
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.00326.2003

1 Developmental Biology and Molecular Pathology, Bielefeld University, D-33501 Bielefeld, Germany; and 2 Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel Submitted 2 April 2003 ; accepted in final form 2 July 2003 products of the dystrophin gene range from the 427-kDa full-length dystrophin to the 70.8-kDa Dp71. Dp427 is expressed in skeletal muscle, where it links the actin cytoskeleton with the extracellular matrix via a complex of dystrophin-associated proteins (DAPs). Dystrophin deficiency disrupts the DAP complex and causes muscular dystrophy in humans and the mdx mouse. Dp71, the major nonmuscle product, consists of the COOH-terminal part of dystrophin, including the binding site for the DAP complex but lacks binding sites for microfilaments. Dp71 transgene (Dp71tg) expressed in mdx muscle restores the DAP complex but does not prevent muscle degeneration. In wild-type (WT) mouse muscle, Dp71tg causes a mild muscular dystrophy. In this study, we tested, using isolated extensor digitorum longus muscles, whether Dp71tg exerts acute influences on force generation and sarcolemmal stress resistance. In WT muscles, there was no effect on isometric twitch and tetanic force generation, but with a cytomegalovirus promotor-driven transgene, contraction with stretch led to sarcolemmal ruptures and irreversible loss of tension. In MDX muscle, Dp71tg reduced twitch and tetanic tension but did not aggravate sarcolemmal fragility. The adverse effects of Dp71 in muscle are probably due to its competition with dystrophin and utrophin (in MDX muscle) for binding to the DAP complex. dystrophin; mdx mouse; sarcolemmal ruptures; eccentric contractions; mechanophysiology Address for reprint requests and other correspondence: H. Jockusch, Developmental Biology & Molecular Pathology, Univ. of Bielefeld, W7, D-33501 Bielefeld, Germany (E-mail: h.jockusch{at}uni-bielefeld.de ).