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.
3261-3279
Vafiadaki, Elizabeth
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Arvanitis, Demetrios A.
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Paplouka, Vasiliki
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Terzis, Gerasimos
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Roumeliotis, Theodoros I.
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Spengos, Konstantinos
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Garbis, Spiros D.
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Manta, Panagiota
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Kranias, Evangelia
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Sanoudou, Despina
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July 2014
Vafiadaki, Elizabeth
55706ac3-0755-4be8-a6c8-68fa567c556d
Arvanitis, Demetrios A.
a80f4115-353e-4da4-a94c-08fe6d315484
Paplouka, Vasiliki
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Terzis, Gerasimos
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Roumeliotis, Theodoros I.
f1284c98-b5eb-483e-9416-594c678e62fd
Spengos, Konstantinos
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Garbis, Spiros D.
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Manta, Panagiota
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Kranias, Evangelia
fd4c4bcf-c0fc-4263-acb0-1da1a3307af1
Sanoudou, Despina
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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), .
(doi:10.1111/febs.12859).
(PMID:24860983)
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
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Local EPrints ID: 395398
URI: http://eprints.soton.ac.uk/id/eprint/395398
ISSN: 1742-464X
PURE UUID: b9f7d99f-d5e4-4580-a4e4-2b93c9e52076
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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
Author:
Panagiota Manta
Author:
Evangelia Kranias
Author:
Despina Sanoudou
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