The central hypothesis proposes that the cytoskeletal protein, dystrophin, reduces muscle damage and dysfunction following stretches of activated muscles. We tested this hypothesis by inducing muscle damage in dogs with inherited dystrophin deficiency, termed golden retriever muscular dystrophy (GRMD). We found that stretches of activated canine muscles in situ resulted in more stretch-induced damage in dystrophin-deficient GRMD than in control muscles. To normalize for effects of dystrophin deficiency in single muscle fibers, we performed in vitro experiments on detergent-treated fibers from GRMD and normal dogs. Treatment of fibers with detergent disrupts the integrity of the sarcolemma. After detergent treatment, we detected no differences in stretch-induced damage between GRMD and control fibers. Thus, these findings support the central hypothesis that dystrophin protects the myofiber from stretch-induced damage.; In GRMD dogs, the cranial sartorius (CS) muscle appears to undergo early damage, followed by marked enlargement. In contrast, the long digital extensor (EDL) muscle undergoes little early damage but subsequently decreases in size. To gain insight into the consequences of this variation in response to the disease, we compared stretch-induced muscle damage between CS and EDL muscles in GRMD dogs. CS fibers were observed to be less susceptible to stretch-induced damage than EDL fibers. Thus, the extent of muscle damage appears to depend on the muscle of origin and its varied pathology to the disease.; We further hypothesized that myosin phosphorylation by myosin light chain kinase (MLCK) increases the extent of stretch-induced damage in activated muscles. To test this hypothesis we compared stretch susceptibility between single skinned rat fibers treated with MLCK versus untreated controls. MLCK-treated fibers incurred more stretch-induced damage than controls. These findings support the hypothesis that myosin phosphorylation by MLCK increases the extent of stretch-induced damage in single rat muscle fibers.; Overall, these experiments indicate that loss of dystrophin is critical in reducing muscle damage in response to physical stress. However, there is considerable muscle-to-muscle variability to stretch in dystrophin-deficient fibers, which appears to result from differences at the level of the myofibrils.
展开▼
