Submitted on January 10, 2008
Revised on August 21, 2008
Accepted on August 24, 2008
Early Mechanical Dysfunction of the Respiratory Pump in the Muscular Dystrophy with Myositis (Ttnmdm) Model
Michael A Lopez1, Patricia S Pardo1, Gregory A Cox2, and Aladin M Boriek1*
1 Baylor College of Medicine
2 Jackson Laboratory
* To whom correspondence should be addressed. E-mail: boriek{at}bcm.edu.
A complex rearrangement mutation in the mouse titin gene leads to an 83 amino acid deletion in the titin myofilament. Autosomal recessive inheritance of the mutation (Ttnmdm/mdm) leads to a severe early-onset muscular dystrophy and premature death. We hypothesized that the N2A deletion would have a deleterious impact on the force-generating capacity and altered passive mechanical properties of the mdm diaphragm. Two and six week mdm and age-matched control mice were studied. We measured in vitro active isometric contractile and passive length-tension properties to assess muscle function. Micro-computed tomography, myosin heavy chain western, and histology were used to support findings. Our data revealed marked chest wall distortions progressing from 2 to 5 weeks of age. The percent of myofibers with centrally located nuclei in mdm diaphragms was 4% increased at 2 weeks and 17% increased at 6 weeks, compared with age-matched controls. At 6 weeks twitch stress was reduced by 71%, time-to-peak twitch was reduced by 52%, and 1/2 relaxation time was reduced by 57% in mdm diaphragms. Isometric tetanic stress was depressed in both 2 and 6 week-old mdm diaphragms by as much as 64%. Length-tension relationships of the mdm diaphragm from both age groups showed decreased extensibility and increased stiffness. Slow myosin heavy chain expression was aberrantly favored in the mdm diaphragm at 6 weeks of age. Our data strongly support early contractile and passive mechanical aberrations of the respiratory pump resulting from a subtle mutation in the titin N2A region.
