Loss of Tropomodulin4 in the zebrafish mutant träge causes cytoplasmic rod formation and muscle weakness reminiscent of nemaline myopathy.
Bottom Line: Accordingly, although actin monomers polymerize to form thin filaments in the skeletal muscle of tmod4(trg) mutants, thin filaments often appeared to be dispersed throughout myofibres.Organised myofibrils with the typical striation rarely assemble, leading to severe muscle weakness, impaired locomotion and early death.Myofibrils of tmod4(trg) mutants often featured thin filaments of various lengths, widened Z-disks, undefined H-zones and electron-dense aggregations of various shapes and sizes.
Affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia Joachim.Berger@monash.edu.Show MeSH
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Mentions: As tropomodulins play a major role in thin filament length and dynamics (Gokhin and Fowler, 2013; Littlefield et al., 2001), thin filament organisation was analysed in greater detail. In line with the analysis in animals carrying transgenic Tg(acta1:lifeact-GFP), transmission electron micrographs confirmed that monomeric actin polymerises to form thin filaments in tmod4trg mutants (Fig. 4A,A′). However, filaments were often scattered throughout the myoplasm and rarely assembled into organised myofibrils (Fig. 4C). Instead, most myofibrils appeared disorganised in tmod4trg mutants with undefined H-bands and widened Z-disks (Fig. 4D). Electron-dense aggregations of various sizes and shapes were often detected with a clearly documented lattice pattern, all features of nemaline rods documented in muscle biopsies of NM patients (Fig. 4A,A′). The rare organised myofibrils evident in tmod4trg mutants contained sarcomeres and thin filaments of similar length compared with those of siblings (tmod4trg, 1.75±0.03 μm; siblings, 0.68±0.01 μm). However, thin filaments of different lengths were measured in misorganised myofibrils. Assuming that, in misorganised myofibrils, thin filaments stretch from Z-disk to the rim of the H-zone, thin filaments of various lengths, including 0.6 μm (short) and 0.75 μm (long), were measured (Fig. 4D).
Affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia Joachim.Berger@monash.edu.