Dystrophin protects the sarcolemma from stresses developed during muscle contraction.

Abstract

The protein dystrophin, normally found on the cytoplasmic surface of skeletal muscle cell membranes, is absent in patients with Duchenne muscular dystrophy as well as mdx (X-linked muscular dystrophy) mice. Although its primary structure has been determined, the precise functional role of dystrophin remains the subject of speculation. In the present study, we demonstrate that dystrophin-deficient muscle fibers of the mdx mouse exhibit an increased susceptibility to contraction-induced sarcolemmal rupture. The level of sarcolemmal damage is directly correlated with the magnitude of mechanical stress placed upon the membrane during contraction rather than the number of activations of the muscle. These findings strongly support the proposition that the primary function of dystrophin is to provide mechanical reinforcement to the sarcolemma and thereby protect it from the membrane stresses developed during muscle contraction. Furthermore, the methodology used in this study should prove useful in assessing the efficacy of dystrophin gene therapy in the mdx mouse.

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice

“…AdV-Dys efficacy in protecting adult mdx muscle from contraction-induced mechanical stress It was previously demonstrated that dystrophin-deficient myofibers exhibit an abnormally increased susceptibility to contraction-induced injury that is reflected by an accelerated loss of isometric force-generating capacity following the imposition of high-stress eccentric contractions. 5 Therefore, we also determined the effects of AdV-Dys administration on the vulnerability of mdx soleus muscles to this form of damage. As depicted in Figure 7, both AdV-Dys and control mdx muscles exhibited reductions in force-generating capacity over the course of the eccentric contraction protocol.…”

“…After completing contractility measurements in the soleus muscles, mice were killed by anesthetic overdose and the diaphragm was removed en bloc with its intact rib cage as previously described. 5,29 Contractility measurements were then made in random order on muscle strips obtained from each side of the diaphragm.…”

“…One end of each muscle was securely anchored to a platform near the base of the chamber, while the opposite tendon was tied to the lever arm of a force transducer/length servomotor system (model 300B dual mode; Cambridge Technology, Watertown, MA, USA). 5,29 The latter was mounted on a mobile micrometer stage (Newport Instruments, Toronto, Canada) to allow incremental adjustments of muscle length. Electrical field stimulation was induced via platinum plate electrodes placed into the bath on both sides of the muscle.…”

“…3 Dystrophin is a large cytoskeletal protein that is normally present on the cytoplasmic aspect of the myofiber surface membrane. 3 Current evidence suggests that myofibers lacking dystrophin are abnormally susceptible to contraction-induced sarcolemmal damage, 4,5 which secondarily leads to muscle fiber dysfunction, 6,7 necrosis and eventual replacement of the lost fibers by adipose and connective tissue. Therefore, the muscle weakness found in DMD patients is due to both myofiber loss and impaired contractile function in the surviving myofiber population.…”

Cytoplasmic γ-actin expression in diverse animal models of muscular dystrophy

“…However, GRMD dogs suffer a severe and rapidly progressing muscle disease with premature lethality more closely resembling DMD in humans while mdx mice exhibit a milder phenotype with no dramatic reduction in lifespan [3]. Thus, it appears that compensatory cytoskeletal remodeling is not as effective in dystrophin-deficient dogs compared to mice, which may be due to the greater mechanical stresses imposed on the sarcolemma of larger animals with correspondingly larger myofibers [30,41]. More interestingly, we demonstrated that daily treatment with prednisone correlated with a significant elevation in γ cyto -actin levels in GRMD skeletal muscle as compared to muscle from non-treated GRMD dogs.…”