The non-muscle ADF/cofilin-1 controls sarcomeric actin filament integrity and force production in striated muscle laminopathies.

Actin Cytoskeleton / metabolism Adolescent Adult Animals Cell Line Child Cofilin 1 / metabolism Destrin / metabolism Humans Lamin Type A / genetics Laminopathies / genetics Male Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism Muscle, Striated / metabolism Muscular Dystrophy, Emery-Dreifuss / genetics Mutation Phosphorylation Sarcomeres / metabolism Signal Transduction Young Adult

ERK1/2 signaling cofilin-1 muscular dystrophy sarcomeric organization skeletal muscle

Journal

Cell reports

ISSN: 2211-1247

Titre abrégé: Cell Rep

Pays: United States

ID NLM: 101573691

Informations de publication

Date de publication:
24 08 2021

Historique:

received: 23 03 2020

revised: 09 06 2021

accepted: 04 08 2021

entrez: 25 8 2021

pubmed: 26 8 2021

medline: 15 2 2022

Statut: ppublish

Résumé

Cofilins are important for the regulation of the actin cytoskeleton, sarcomere organization, and force production. The role of cofilin-1, the non-muscle-specific isoform, in muscle function remains unclear. Mutations in LMNA encoding A-type lamins, intermediate filament proteins of the nuclear envelope, cause autosomal Emery-Dreifuss muscular dystrophy (EDMD). Here, we report increased cofilin-1 expression in LMNA mutant muscle cells caused by the inability of proteasome degradation, suggesting a protective role by ERK1/2. It is known that phosphorylated ERK1/2 directly binds to and catalyzes phosphorylation of the actin-depolymerizing factor cofilin-1 on Thr25. In vivo ectopic expression of cofilin-1, as well as its phosphorylated form on Thr25, impairs sarcomere structure and force generation. These findings present a mechanism that provides insight into the molecular pathogenesis of muscular dystrophies caused by LMNA mutations.

Identifiants

DOI: 10.1016/j.celrep.2021.109601 PMID: 34433058 PMC: PMC8411111

pubmed: 34433058

pii: S2211-1247(21)01039-1

doi: 10.1016/j.celrep.2021.109601

pmc: PMC8411111

pii:

doi:

Substances chimiques

Cofilin 1 0

DSTN protein, human 0

Destrin 0

LMNA protein, human 0

Lamin Type A 0

Mitogen-Activated Protein Kinase 1 EC 2.7.11.24

Mitogen-Activated Protein Kinase 3 EC 2.7.11.24

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

109601

Subventions

Organisme : Biotechnology and Biological Sciences Research Council

Pays : United Kingdom

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of interests H.J.W. is on the scientific advisory board and owns equity in AlloMek Therapeutics. The remaining authors declare no competing interests.

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