Muscle Function in a Canine Model of X-linked Myotubular Myopathy

Muscle Nerve. 2012 Oct;46(4):588-91. doi: 10.1002/mus.23463.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dogs
  • Male
  • Muscle, Skeletal / physiopathology*
  • Mutation, Missense
  • Myopathies, Structural, Congenital / genetics*
  • Myopathies, Structural, Congenital / physiopathology*
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • X Chromosome / genetics*

Substances

  • Protein Tyrosine Phosphatases, Non-Receptor
  • myotubularin