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Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation

Myofibrils within skeletal muscle are composed of sarcomeres that generate force by contraction when their myosin-rich thick filaments slide past actin-based thin filaments. Although mutations in components of the sarcomere are a major cause of human disease, the highly complex process of sarcomere...

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Autores principales: Berger, Joachim, Berger, Silke, Mok, Yu Shan G., Li, Mei, Tarakci, Hakan, Currie, Peter D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870547/
https://www.ncbi.nlm.nih.gov/pubmed/35148320
http://dx.doi.org/10.1371/journal.pgen.1010066
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author Berger, Joachim
Berger, Silke
Mok, Yu Shan G.
Li, Mei
Tarakci, Hakan
Currie, Peter D.
author_facet Berger, Joachim
Berger, Silke
Mok, Yu Shan G.
Li, Mei
Tarakci, Hakan
Currie, Peter D.
author_sort Berger, Joachim
collection PubMed
description Myofibrils within skeletal muscle are composed of sarcomeres that generate force by contraction when their myosin-rich thick filaments slide past actin-based thin filaments. Although mutations in components of the sarcomere are a major cause of human disease, the highly complex process of sarcomere assembly is not fully understood. Current models of thin filament assembly highlight a central role for filament capping proteins, which can be divided into three protein families, each ascribed with separate roles in thin filament assembly. CapZ proteins have been shown to bind the Z-disc protein α-actinin to form an anchoring complex for thin filaments and actin polymerisation. Subsequent thin filaments extension dynamics are thought to be facilitated by Leiomodins (Lmods) and thin filament assembly is concluded by Tropomodulins (Tmods) that specifically cap the pointed end of thin filaments. To study thin filament assembly in vivo, single and compound loss-of-function zebrafish mutants within distinct classes of capping proteins were analysed. The generated lmod3- and capza1b-deficient zebrafish exhibited aspects of the pathology caused by variations in their human orthologs. Although loss of the analysed main capping proteins of the skeletal muscle, capza1b, capza1a, lmod3 and tmod4, resulted in sarcomere defects, residual organised sarcomeres were formed within the assessed mutants, indicating that these proteins are not essential for the initial myofibril assembly. Furthermore, detected similarity and location of myofibril defects, apparent at the peripheral ends of myofibres of both Lmod3- and CapZα-deficient mutants, suggest a function in longitudinal myofibril growth for both proteins, which is molecularly distinct to the function of Tmod4.
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spelling pubmed-88705472022-02-25 Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation Berger, Joachim Berger, Silke Mok, Yu Shan G. Li, Mei Tarakci, Hakan Currie, Peter D. PLoS Genet Research Article Myofibrils within skeletal muscle are composed of sarcomeres that generate force by contraction when their myosin-rich thick filaments slide past actin-based thin filaments. Although mutations in components of the sarcomere are a major cause of human disease, the highly complex process of sarcomere assembly is not fully understood. Current models of thin filament assembly highlight a central role for filament capping proteins, which can be divided into three protein families, each ascribed with separate roles in thin filament assembly. CapZ proteins have been shown to bind the Z-disc protein α-actinin to form an anchoring complex for thin filaments and actin polymerisation. Subsequent thin filaments extension dynamics are thought to be facilitated by Leiomodins (Lmods) and thin filament assembly is concluded by Tropomodulins (Tmods) that specifically cap the pointed end of thin filaments. To study thin filament assembly in vivo, single and compound loss-of-function zebrafish mutants within distinct classes of capping proteins were analysed. The generated lmod3- and capza1b-deficient zebrafish exhibited aspects of the pathology caused by variations in their human orthologs. Although loss of the analysed main capping proteins of the skeletal muscle, capza1b, capza1a, lmod3 and tmod4, resulted in sarcomere defects, residual organised sarcomeres were formed within the assessed mutants, indicating that these proteins are not essential for the initial myofibril assembly. Furthermore, detected similarity and location of myofibril defects, apparent at the peripheral ends of myofibres of both Lmod3- and CapZα-deficient mutants, suggest a function in longitudinal myofibril growth for both proteins, which is molecularly distinct to the function of Tmod4. Public Library of Science 2022-02-11 /pmc/articles/PMC8870547/ /pubmed/35148320 http://dx.doi.org/10.1371/journal.pgen.1010066 Text en © 2022 Berger et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Berger, Joachim
Berger, Silke
Mok, Yu Shan G.
Li, Mei
Tarakci, Hakan
Currie, Peter D.
Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation
title Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation
title_full Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation
title_fullStr Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation
title_full_unstemmed Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation
title_short Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation
title_sort genetic dissection of novel myopathy models reveals a role of capzα and leiomodin 3 during myofibril elongation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870547/
https://www.ncbi.nlm.nih.gov/pubmed/35148320
http://dx.doi.org/10.1371/journal.pgen.1010066
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