Early mechanical dysfunction of the diaphragm in the muscular dystrophy with myositis (Ttnmdm) model.

Academic Article


  • A complex rearrangement mutation in the mouse titin gene leads to an in-frame 83-amino acid deletion in the N2A region of titin. Autosomal recessive inheritance of the titin muscular dystrophy with myositis (Ttn(mdm/mdm)) mutation leads to a severe early-onset muscular dystrophy and premature death. We hypothesized that the N2A deletion would negatively impact the force-generating capacity and passive mechanical properties of the mdm diaphragm. We measured in vitro active isometric contractile and passive length-tension properties to assess muscle function at 2 and 6 wk of age. Micro-CT, myosin heavy chain Western blotting, and histology were used to assess diaphragm structure. Marked chest wall distortions began at 2 wk and progressively worsened until 5 wk. The percentage of myofibers with centrally located nuclei in mdm mice was significantly (P < 0.01) increased at 2 and 6 wk by 4% and 17%, respectively, compared with controls. At 6 wk, mdm diaphragm twitch stress was significantly (P < 0.01) reduced by 71%, time to peak twitch was significantly (P < 0.05) reduced by 52%, and half-relaxation time was significantly (P < 0.05) reduced by 57%. Isometric tetanic stress was significantly (P < 0.05) depressed in 2- and 6-wk mdm diaphragms by as much as 64%. Length-tension relationships of the 2- and 6-wk mdm diaphragms showed significantly (P < 0.05) decreased extensibility and increased stiffness. Slow myosin heavy chain expression was aberrantly favored in the mdm diaphragm at 6 wk. Our data strongly support early contractile and passive mechanical aberrations of the respiratory pump in mdm mice.
  • Authors


  • Animals, Blotting, Western, Connectin, Diaphragm, Disease Models, Animal, Mice, Mice, Mutant Strains, Muscle Contraction, Muscle Proteins, Muscle Strength, Muscular Dystrophy, Animal, Mutation, Myofibrils, Myosin Heavy Chains, Myositis, Protein Kinases, Time Factors, Tomography, X-Ray Computed
  • Digital Object Identifier (doi)

    Author List

  • Lopez MA; Pardo PS; Cox GA; Boriek AM
  • Start Page

  • C1092
  • End Page

  • C1102
  • Volume

  • 295
  • Issue

  • 5