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.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.Importantly, Gomori trichrome staining and the lattice pattern of the detected cytoplasmic rods, together with the reactivity of rods with phalloidin and an antibody against actinin, is reminiscent of nemaline rods found in nemaline myopathy, suggesting that misregulation of thin filament length causes cytoplasmic rod formation in tmod4(trg) mutants.
Affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia Joachim.Berger@monash.edu.Show MeSH
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Mentions: To further investigate the functional deficits in the skeletal muscle of tmod4trg homozygotes and to quantify their muscle weakness, mechanical experiments were performed using a specialized force transducer (Li et al., 2013). Isometric force and length–active force relations were determined in the trunk muscle of tmod4trg mutants and siblings at 5 dpf. The muscles were stimulated to give single twitch contractions at different lengths. Consistent with reduced amounts of myofibril, the tmod4trg trunk muscles generated an isometric strength of 0.064±0.004 mN that was significantly less compared to that of their siblings, which generated 0.884±0.069 mN (P<0.001, n=6) (Fig. 5A). To determine whether the lower active force emanated from smaller muscle size, the CSA was measured at 5 dpf. Consistent with measurements at 3 dpf, the muscle of tmod4trg mutants was only very slightly reduced in size; the CSA of sibling muscle was 0.0324±0.0007 mm2 and that of tmod4trg mutants was 0.0315±0.0004 mm2 (equalling a reduction to 97±1%, P<0.01, n=4). Thus, the markedly lower active force evident in tmod4trg mutants cannot be explained by a decrease in CSA (Fig. 5A).
Affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia Joachim.Berger@monash.edu.