Key result
Affected dogs with the X-linked MTM1 mutation produced only ~15% of the torque generated by normal or carrier dogs.
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Severe torque deficit in canine MTM1 model should not yet alter human practice; leaves open translational validation.
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 ∼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.
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Grange et al. (2012) studied X-linked myotubular myopathy (XLMTM). X-linked MTM1 missense mutation vs. Normal or carrier dogs was evaluated on Torque generated by hindlimb muscle (N-m/kg body mass) (p=<0.05). Affected dogs with the X-linked MTM1 mutation produced only ~15% of the torque generated by normal or carrier dogs.
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