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

Lopez MA, Pardo PS, Cox GA, Boriek AM. Early mechanical dysfunction of the diaphragm in the muscular dystrophy with myositis (Ttn) model. Am J Physiol Cell Physiol 295: C1092–C1102, 2008. First published August 27, 2008; doi:10.1152/ajpcell.16.2008.—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) 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 2and 6-wk mdm diaphragms by as much as 64%. Length-tension relationships of the 2and 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.