Contraction-Mediated Damage in mdx Mice Trabeculae: A Model for Cardiomyopathy in Duchene Muscular Dystrophy

Abstract

Duchene muscular dystrophy (DMD) is an inherited and progressive disease of striated muscle deterioration. Studies on skeletal muscle using an eccentric contraction model have provided great insight of the contraction-mediated damage in skeletal muscle in DMD. Because of different contraction mechanics in the cardiac vs. skeletal muscle, the protocols used to gain understanding in skeletal muscle pathology cannot be readily applied to the myocardium. To investigate contraction-mediated damage in dystrophin-deficient myocardium under physiological conditions, we developed an in vitro model of myocardial mechanics-induced injury. We employed computer-programmed protocols to trigger consecutive lengthening ramps during the twitch contraction at 4 Hz in age matched (young and adult) mdx and wild type mice right ventricular trabeculae. These ultra-thin muscles possess all major cardiac cell types and their contractile behavior very closely mimics that of the whole heart. In the first group of experiments, 10 lengthening contractions of various (1-10%) magnitude of stretch were performed in trabeculae from 10 week old mdx and wild type mice. In the second group, 100 lengthening contractions at each magnitude were conducted in trabeculae from 20 weeks old mice. The peak isometric active developed tension (Fdev, in mN/mm2), diastolic tension (Fdia), and force kinetics were measured throughout the protocol, and the rate of decline of these parameters can be taken as a relative measurement of how susceptible the myocardium is to lengthening-induced dysfunction. Our results indicate dystrophin deficient myocardium in older mdx mice is more sensitive to severe mechanical stress compared to age-matched wild type controls. This suggests that lengthening contraction in myocardium is an appropriate model to study contraction-mediated damage in DMD associated cardiomyopathy.