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Int. J. Mol. Sci. 2017, 18(12), 2629; https://doi.org/10.3390/ijms18122629

Glucocorticoids Improve Myogenic Differentiation In Vitro by Suppressing the Synthesis of Versican, a Transitional Matrix Protein Overexpressed in Dystrophic Skeletal Muscles

1
School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
2
Faculty of Law, The University of Queensland, Brisbane, QLD 4072, Australia
3
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia
*
Author to whom correspondence should be addressed.
Received: 8 November 2017 / Revised: 24 November 2017 / Accepted: 27 November 2017 / Published: 6 December 2017
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)
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Abstract

In Duchenne muscular dystrophy (DMD), a dysregulated extracellular matrix (ECM) directly exacerbates pathology. Glucocorticoids are beneficial therapeutics in DMD, and have pleiotropic effects on the composition and processing of ECM proteins in other biological contexts. The synthesis and remodelling of a transitional versican-rich matrix is necessary for myogenesis; whether glucocorticoids modulate this transitional matrix is not known. Here, versican expression and processing were examined in hindlimb and diaphragm muscles from mdx dystrophin-deficient mice and C57BL/10 wild type mice. V0/V1 versican (Vcan) mRNA transcripts and protein levels were upregulated in dystrophic compared to wild type muscles, especially in the more severely affected mdx diaphragm. Processed versican (versikine) was detected in wild type and dystrophic muscles, and immunoreactivity was highly associated with newly regenerated myofibres. Glucocorticoids enhanced C2C12 myoblast fusion by modulating the expression of genes regulating transitional matrix synthesis and processing. Specifically, Tgfβ1, Vcan and hyaluronan synthase-2 (Has2) mRNA transcripts were decreased by 50% and Adamts1 mRNA transcripts were increased three-fold by glucocorticoid treatment. The addition of exogenous versican impaired myoblast fusion, whilst glucocorticoids alleviated this inhibition in fusion. In dystrophic mdx muscles, versican upregulation correlated with pathology. We propose that versican is a novel and relevant target gene in DMD, given its suppression by glucocorticoids and that in excess it impairs myoblast fusion, a process key for muscle regeneration. View Full-Text
Keywords: Duchenne muscular dystrophy; fibrosis; glucocorticoids; myogenesis; mdx mouse; versican Duchenne muscular dystrophy; fibrosis; glucocorticoids; myogenesis; mdx mouse; versican
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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McRae, N.; Forgan, L.; McNeill, B.; Addinsall, A.; McCulloch, D.; Van der Poel, C.; Stupka, N. Glucocorticoids Improve Myogenic Differentiation In Vitro by Suppressing the Synthesis of Versican, a Transitional Matrix Protein Overexpressed in Dystrophic Skeletal Muscles. Int. J. Mol. Sci. 2017, 18, 2629.

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