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Loss of Tropomodulin4 in the zebrafish mutant träge causes cytoplasmic rod formation and muscle weakness reminiscent of nemaline myopathy.

Berger J, Tarakci H, Berger S, Li M, Hall TE, Arner A, Currie PD - Dis Model Mech (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia Joachim.Berger@monash.edu.

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The tmod4trg skeletal muscle has impaired force generation. (A) Peak active force at optimal length in tmod4trg is significantly lower than that of siblings (n=6). (B) During single-twitch contraction, the half-time (t1/2) of contraction is similar in tmod4trg and siblings, however, the relaxation time is significantly prolonged in tmod4trg (n=6). (C) Length–active force curves show steeper ascending limb in tmod4trg (red) than in siblings (blue) (n=5). Force is normalised to the maximal active force at optimal length (Lopt), and length is normalised to Lopt. Data are means±s.e.m., **P<0.01, ***P<0.001.
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f5-0071407: The tmod4trg skeletal muscle has impaired force generation. (A) Peak active force at optimal length in tmod4trg is significantly lower than that of siblings (n=6). (B) During single-twitch contraction, the half-time (t1/2) of contraction is similar in tmod4trg and siblings, however, the relaxation time is significantly prolonged in tmod4trg (n=6). (C) Length–active force curves show steeper ascending limb in tmod4trg (red) than in siblings (blue) (n=5). Force is normalised to the maximal active force at optimal length (Lopt), and length is normalised to Lopt. Data are means±s.e.m., **P<0.01, ***P<0.001.

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).


Loss of Tropomodulin4 in the zebrafish mutant träge causes cytoplasmic rod formation and muscle weakness reminiscent of nemaline myopathy.

Berger J, Tarakci H, Berger S, Li M, Hall TE, Arner A, Currie PD - Dis Model Mech (2014)

The tmod4trg skeletal muscle has impaired force generation. (A) Peak active force at optimal length in tmod4trg is significantly lower than that of siblings (n=6). (B) During single-twitch contraction, the half-time (t1/2) of contraction is similar in tmod4trg and siblings, however, the relaxation time is significantly prolonged in tmod4trg (n=6). (C) Length–active force curves show steeper ascending limb in tmod4trg (red) than in siblings (blue) (n=5). Force is normalised to the maximal active force at optimal length (Lopt), and length is normalised to Lopt. Data are means±s.e.m., **P<0.01, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257009&req=5

f5-0071407: The tmod4trg skeletal muscle has impaired force generation. (A) Peak active force at optimal length in tmod4trg is significantly lower than that of siblings (n=6). (B) During single-twitch contraction, the half-time (t1/2) of contraction is similar in tmod4trg and siblings, however, the relaxation time is significantly prolonged in tmod4trg (n=6). (C) Length–active force curves show steeper ascending limb in tmod4trg (red) than in siblings (blue) (n=5). Force is normalised to the maximal active force at optimal length (Lopt), and length is normalised to Lopt. Data are means±s.e.m., **P<0.01, ***P<0.001.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia Joachim.Berger@monash.edu.

Show MeSH
Related in: MedlinePlus