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Muscle lim protein isoform negatively regulates striated muscle actin dynamics and differentiation

Muscle lim protein isoform negatively regulates striated muscle actin dynamics and differentiation
Muscle lim protein isoform negatively regulates striated muscle actin dynamics and differentiation
Muscle lim protein (MLP) has emerged as a critical regulator of striated muscle physiology and pathophysiology. Mutations in cysteine and glycine-rich protein 3 (CSRP3), the gene encoding MLP, have been directly associated with human cardiomyopathies, whereas aberrant expression patterns are reported in human cardiac and skeletal muscle diseases. Increasing evidence suggests that MLP has an important role in both myogenic differentiation and myocyte cytoarchitecture, although the full spectrum of its intracellular roles has not been delineated. We report the discovery of an alternative splice variant of MLP, designated as MLP-b, showing distinct expression in neuromuscular disease and direct roles in actin dynamics and muscle differentiation. This novel isoform originates by alternative splicing of exons 3 and 4. At the protein level, it contains the N-terminus first half LIM domain of MLP and a unique sequence of 22 amino acids. Physiologically, it is expressed during early differentiation, whereas its overexpression reduces C2C12 differentiation and myotube formation. This may be mediated through its inhibition of MLP/cofilin-2-mediated F-actin dynamics. In differentiated striated muscles, MLP-b localizes to the sarcomeres and binds directly to Z-disc components, including ?-actinin, T-cap and MLP. The findings of the present study unveil a novel player in muscle physiology and pathophysiology that is implicated in myogenesis as a negative regulator of myotube formation, as well as in differentiated striated muscles as a contributor to sarcomeric integrity.
1742-464X
3261-3279
Vafiadaki, Elizabeth
55706ac3-0755-4be8-a6c8-68fa567c556d
Arvanitis, Demetrios A.
a80f4115-353e-4da4-a94c-08fe6d315484
Paplouka, Vasiliki
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Terzis, Gerasimos
5955a7e5-c3bd-4c66-83d8-347a54b4a925
Roumeliotis, Theodoros I.
f1284c98-b5eb-483e-9416-594c678e62fd
Spengos, Konstantinos
4a9f455a-f17a-4d93-9832-f1e1ec90decb
Garbis, Spiros D.
7067fd19-50c9-4d42-9611-f370289470bd
Manta, Panagiota
d3385ff7-116b-49f5-b8b1-20448467e0a2
Kranias, Evangelia
fd4c4bcf-c0fc-4263-acb0-1da1a3307af1
Sanoudou, Despina
eea6e657-1543-4588-8cf1-703cd5507fbe
Vafiadaki, Elizabeth
55706ac3-0755-4be8-a6c8-68fa567c556d
Arvanitis, Demetrios A.
a80f4115-353e-4da4-a94c-08fe6d315484
Paplouka, Vasiliki
3028ea08-5ab6-47e1-ac27-1e3e6f242bbc
Terzis, Gerasimos
5955a7e5-c3bd-4c66-83d8-347a54b4a925
Roumeliotis, Theodoros I.
f1284c98-b5eb-483e-9416-594c678e62fd
Spengos, Konstantinos
4a9f455a-f17a-4d93-9832-f1e1ec90decb
Garbis, Spiros D.
7067fd19-50c9-4d42-9611-f370289470bd
Manta, Panagiota
d3385ff7-116b-49f5-b8b1-20448467e0a2
Kranias, Evangelia
fd4c4bcf-c0fc-4263-acb0-1da1a3307af1
Sanoudou, Despina
eea6e657-1543-4588-8cf1-703cd5507fbe

Vafiadaki, Elizabeth, Arvanitis, Demetrios A., Paplouka, Vasiliki, Terzis, Gerasimos, Roumeliotis, Theodoros I., Spengos, Konstantinos, Garbis, Spiros D., Manta, Panagiota, Kranias, Evangelia and Sanoudou, Despina (2014) Muscle lim protein isoform negatively regulates striated muscle actin dynamics and differentiation. Febs Journal, 281 (14), 3261-3279. (doi:10.1111/febs.12859). (PMID:24860983)

Record type: Article

Abstract

Muscle lim protein (MLP) has emerged as a critical regulator of striated muscle physiology and pathophysiology. Mutations in cysteine and glycine-rich protein 3 (CSRP3), the gene encoding MLP, have been directly associated with human cardiomyopathies, whereas aberrant expression patterns are reported in human cardiac and skeletal muscle diseases. Increasing evidence suggests that MLP has an important role in both myogenic differentiation and myocyte cytoarchitecture, although the full spectrum of its intracellular roles has not been delineated. We report the discovery of an alternative splice variant of MLP, designated as MLP-b, showing distinct expression in neuromuscular disease and direct roles in actin dynamics and muscle differentiation. This novel isoform originates by alternative splicing of exons 3 and 4. At the protein level, it contains the N-terminus first half LIM domain of MLP and a unique sequence of 22 amino acids. Physiologically, it is expressed during early differentiation, whereas its overexpression reduces C2C12 differentiation and myotube formation. This may be mediated through its inhibition of MLP/cofilin-2-mediated F-actin dynamics. In differentiated striated muscles, MLP-b localizes to the sarcomeres and binds directly to Z-disc components, including ?-actinin, T-cap and MLP. The findings of the present study unveil a novel player in muscle physiology and pathophysiology that is implicated in myogenesis as a negative regulator of myotube formation, as well as in differentiated striated muscles as a contributor to sarcomeric integrity.

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Accepted/In Press date: 22 May 2014
e-pub ahead of print date: 11 June 2014
Published date: July 2014
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 395398
URI: http://eprints.soton.ac.uk/id/eprint/395398
ISSN: 1742-464X
PURE UUID: b9f7d99f-d5e4-4580-a4e4-2b93c9e52076
ORCID for Spiros D. Garbis: ORCID iD orcid.org/0000-0002-1050-0805

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Date deposited: 27 May 2016 14:38
Last modified: 15 Mar 2024 00:39

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Contributors

Author: Elizabeth Vafiadaki
Author: Demetrios A. Arvanitis
Author: Vasiliki Paplouka
Author: Gerasimos Terzis
Author: Theodoros I. Roumeliotis
Author: Konstantinos Spengos
Author: Spiros D. Garbis ORCID iD
Author: Panagiota Manta
Author: Evangelia Kranias
Author: Despina Sanoudou

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