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Biasing the conformation of Elmo2 reveals that the myoblast fusion process can be exploited for regenerative therapy

ABSTRACT: Myoblast fusion is fundamental for the development of multinucleated myofibers. Evolutionarily conserved proteins required for myoblast fusion include Rac1 and its activator Dock1. Here, we tested the functions of Elmo proteins, Dock1-interacting scaffolds, on myoblast fusion. When Elmo1-/- mice underwent muscle-specific Elmo2 genetic ablation, they exhibited severe myoblast fusion defects. A mutation in the Elmo2 gene that reduced signaling resulted in a decrease in myoblast fusion. Conversely, a mutation in Elmo2 promoting its open conformation increased myoblast fusion during development and in muscle regeneration. Finally, we showed that the dystrophic features of the Dysferlin-null mice, a model of limb-girdle muscular dystrophy type 2B, were reversed when expressing Elmo2 in an open conformation. These data provide direct evidence that the myoblast fusion process could be exploited for regenerative and therapeutic purposes.

ORGANISM(S): Mus musculus

PROVIDER: GSE209546 | GEO | 2022/07/25

REPOSITORIES: GEO

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Cardiac and skeletal muscle gene expression profiles in dysferlin deficient mice

2005-07-10 | GSE2507 | GEO

Transcription profiling of skeletal and cardiac muscles in dysferlin-deficient SJL/J mice and wild type mice to understand the protective mechanisms against dysferlin deficiency in cardiac muscles.

Project description:Dysferlin is expressed in skeletal and cardiac muscle. However, dysferlin deficiency, namely limb girdle muscular dystrophy 2B (LGMD2B) and Myoshi myopathy, results in skeletal muscle weakness and spares the heart. This dichotomy could be caused by differential regulation of protective mechanisms. Therefore, we compared intraindividual mRNA expression profiles between cardiac and skeletal muscle in dysferlin-deficient SJL/J mice and normal C57BL/6 mice. Experiment Overall Design: 20 chips were analyzed. They represent 4 groups of 5 replicates each. Experiment Overall Design: The 4 groups are cardiac (LV) and skeletal muscle of normal and dysferlin deficient mice. Experiment Overall Design: Tissues from normal mice are the controls in comparison to tissues of dysferlin deficient mice.

2007-09-04 | E-GEOD-2507 | biostudies-arrayexpress

Role of annexin A2 in muscle repair

Project description:Repair of injured muscle involves repair of injured myofibers through the involvement of dysferlin and its interacting partners, including annexin. Studies with mice and patients have established that dysferlin deficit leads to chronic inflammation and adipogenic replacement of the diseased muscle. However, longitudinal analysis of annexin deficit on muscle pathology and function is lacking. Here we show that unlike annexin A1, but similar to dysferlin, lack of annexin A2 (AnxA2) causes poor myofiber repair and progressive weakening with age. However, unlike dysferlin-deficient muscle, AnxA2-deficient muscles do not exhibit chronic inflammation or adipogenic replacement. Deletion of AnxA2 in dysferlin deficient mice reduces inflammation, adipogenic replacement, and loss in muscle function caused by dysferlin deficit. These results show that: a) AnxA2 facilitates myofiber repair, b) chronic inflammation and adipogenic replacement of dysferlinopathic muscle requires AnxA2, and c) inhibiting AnxA2-mediated inflammation is a novel therapeutic avenue for dysferlinopathy.

2016-10-04 | GSE87557 | GEO

Mouse myoblast fusion - Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190

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2018-10-24 | PXD002413 | Pride

Gene expression profiling in dysferlinopathies using a dedicated muscle microarray

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2005-07-28 | GSE3022 | GEO

Dock3 is essential for normal myogenic fusion and alters dystrophin-deficiency pathologies

Project description:DOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that function to regulate cell migration, fusion, and overall viability. Previously, we identified a miR-486/Dock3 signaling cascade that was dysregulated in dystrophin-deficient muscle which resulted in the overexpression of DOCK3, however not much else is known about the role of DOCK3 in muscle. In this work, we characterize the functional role of DOCK3 in normal and dystrophic striated muscle. By utilizing the Dock3 global knockout (Dock3 KO) mice, we found reducing Dock3 gene via haploinsufficiency in DMD mice improved muscle histology, however full loss of Dock3 worsened overall muscle function on a dystrophin-deficient background. Consistent with this, Dock3 KO mice have impaired muscle architecture, myoblast fusion defects, and cardiac functional deficits. Moreover, transcriptomic analyses of Dock3 knockout muscles reveal a decrease in factors known for myoblast fusion, suggesting a possible mechanism of action. These studies identify DOCK3 as a novel modulator of muscle fusion and muscle health, and may yield additional therapeutic targets for treating dystrophic muscle symptoms.

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2015-12-10 | E-GEOD-75832 | biostudies-arrayexpress

The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: Role of endogenous toll-like receptor (TLR) ligands

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2013-04-27 | GSE46420 | GEO

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