Abstract

Glucocorticoids are clinically used in Duchenne muscular dystrophy although their mechanism of action is largely unclear. Part of their effect in dystrophic muscle can be mediated by the enhancement of utrophin expression; however the impact of this increase on dystrophin–glycoprotein complex (DGC) is unknown. In the present work we assessed the effect of a chronic treatment with α-methyl-prednisolone (PDN) (4–6 weeks at 1 mg/kg day) in the exercised mdx mouse model, on the expression of utrophin and key proteins of the DGC in skeletal muscle. We found a significant increase in expression of utrophin, α and β dystroglycan and DGC-bound aquaporin (AQP)-4 at both mRNA and protein level in PDN-treated muscles. Interestingly, this was paralleled by a normalization of phosphorylation state of β-dystroglycan and an increase in laminin. Immunohistochemistry supported the correct sarcolemmal localization of the proteins. On pathology-related signs, PDN increased mdx mouse force in vivo, while ex vivo it ameliorated calcium homeostasis and reduced signs of myofiber degeneration; however plasma creatine kinase and susceptibility to eccentric contraction were not ameliorated. In parallel we also assessed the impact of PDN treatment on blood–brain barrier (BBB), based on its serious impairment in mdx mice and on the clinical use of glucocorticoids in disorders characterized by leaky BBB. Interestingly, we found a restoration of key BBB markers at level of endothelium (ZO-1 and occludin), pericytes (desmin) and glial cells (glial fibrillary acidic protein, GFAP) in PDN-treated mdx mice. In parallel, an increase of mRNA and protein content of DGC (α–β dystroglycan complex Dp 71, AQP4), and a rescue of the phosphorylation state of AQP4 and β dystroglycan were found. Then PDN exerts a positive action on DGC in both muscle and brain, disclosing a novel mechanism of action whose impact on therapeutic effect deserves to be better investigated (Supported by Duchenne Parent Project NL).

Autore Pugliese

• De Luca Annamaria , Ribatti Domenico

Tutti gli autori

• DE LUCA A.;NICO B.;RIBATTI D.

Titolo volume/Rivista

Non Disponibile

Anno di pubblicazione

2012

ISSN

0960-8966

ISBN

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Numero di citazioni Wos

Nessuna citazione

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Settori ERC

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