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.
Highlights
Duchenne muscular dystrophy (DMD) is a fatal hereditary disease affecting ~1:3500 boys, with glucocorticoid therapy being the only treatment with clinical efficacy [1]
We propose that the carefully regulated synthesis and processing of a versican rich transitional matrix is an important factor in differentiating between successful regenerative myogenesis or degeneration and fibrosis
A better understanding of versican function in muscular dystrophy is needed if progress is to be made in targeting the dysregulated extracellular matrix (ECM), which is a hallmark of DMD pathology
Summary
Duchenne muscular dystrophy (DMD) is a fatal hereditary disease affecting ~1:3500 boys, with glucocorticoid therapy being the only treatment with clinical efficacy [1]. Whilst fibrosis is usually thought of as a disease endpoint, it is important to note that endomysial extracellular matrix (ECM) accumulation precedes overt muscle degeneration in DMD [3], and is thought to actively contribute to the degeneration of dystrophic muscles [4,5,6]. Aberrant ECM synthesis and processing is observed in dystrophic muscles from patients with DMD [10] and in mdx mice [11], compromising regenerative myogenesis and exacerbating inflammatory processes [12]. TGF-β is considered to be a key cytokine driving fibrosis in DMD [13], and its levels are elevated in dystrophic muscles and in circulation [14]
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