Muscle function in A canine model of X-linked myotubular myopathy

Authors

  • Robert W. Grange PhD,

    1. Department of Human Nutrition, Foods and Exercise, College of Agriculture & Life Sciences, Virginia Polytechnic and State University, Blacksburg, Virginia, USA 24060
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  • Jon Doering BS,

    1. Department of Human Nutrition, Foods and Exercise, College of Agriculture & Life Sciences, Virginia Polytechnic and State University, Blacksburg, Virginia, USA 24060
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  • Erin Mitchell DVM,

    1. Wake Forest University Health Sciences, Institute for Regenerative Medicine; 391 Technology Way, Winston-Salem, North Carolina, USA 27101
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  • Melanie N. Holder BS,

    1. Wake Forest University Health Sciences, Institute for Regenerative Medicine; 391 Technology Way, Winston-Salem, North Carolina, USA 27101
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  • Xuan Guan MD,

    1. Wake Forest University Health Sciences, Institute for Regenerative Medicine; 391 Technology Way, Winston-Salem, North Carolina, USA 27101
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  • Melissa Goddard BS,

    1. Wake Forest University Health Sciences, Institute for Regenerative Medicine; 391 Technology Way, Winston-Salem, North Carolina, USA 27101
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  • Christopher Tegeler BS,

    1. Wake Forest University Health Sciences, Institute for Regenerative Medicine; 391 Technology Way, Winston-Salem, North Carolina, USA 27101
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  • Alan H. Beggs PhD,

    1. The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
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  • Martin K. Childers DO, PhD

    Corresponding author
    1. Wake Forest University Health Sciences, Institute for Regenerative Medicine; 391 Technology Way, Winston-Salem, North Carolina, USA 27101
    2. Department of Neurology, School of Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA 27101
    • Wake Forest University Health Sciences, Institute for Regenerative Medicine; 391 Technology Way, Winston-Salem, North Carolina, USA 27101
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Abstract

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. Muscle Nerve 46: 588–591, 2012

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