Significance Dystroglycan (DG) is an extracellular matrix receptor that is linked to the cytoskeleton and critical for the development of skeletal muscle. DG deficiency throughout development is associated with multiple pathological features and muscular dystrophy. However, the direct consequence of DG disruption in mature muscle is not known. Here, we investigate muscles of transgenic mice after genetic knockdown of DG at maturity. The results demonstrate early susceptibility to contraction-induced injury accompanied by reduced passive tension and decreased titin immunostaining, rather than increased necrosis, excitation–contraction uncoupling, or sarcolemmal fragility. These results suggest a need for critical rethinking of both current theories regarding contraction-induced injury in muscular dystrophy and therapeutic strategies.