MUSCLE FUNCTION IN A CANINE MODEL OF X-LINKED MYOTUBULAR MYOPATHY

Introduction: We established a colony of dogs that harbor an X-linked MTM1 missense mutation. Muscle from affected male dogs exhibits reduction and altered localization of the MTM1 gene product, myotubularin, and provides a model analogous to X-linked myotubular myopathy (XLMTM). Methods: We studied hindlimb muscle function in age-matched canine XLMTM genotypes between ages 9 and 18 weeks. Results: By the end of the study, affected dogs produce only similar to 15% of the torque generated by normals or carriers (0.023 +/- 0.005 vs. 0.152 +/- 0.007 and 0.154 +/- 0.003 N-m/kg body mass, respectively, P < 0.05) and are too weak to stand unassisted. At this age, XLMTM dogs also demonstrate an abnormally low twitch: tetanus ratio, a right-shifted torque-frequency relationship and an increase in torque during repetitive stimulation (P < 0.05). Conclusions: We hypothesize that muscle weakness results from impaired excitation-contraction (E-C) coupling. Interventions that improve E-C coupling might be translated from the XLMTM dog model to patients. Muscle Nerve 46: 588-591, 2012