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Author: search.filters.author.Claudio Cabello‐VerrugioHas files: No

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    Angiotensin II receptor type 1 blockade decreases CTGF/CCN2‐mediated damage and fibrosis in normal and dystrophic skeletal muscles
    (2012)
    Claudio Cabello‐Verrugio
    ;
    María Gabriela Morales
    ;
    Daniel Cabrera
    ;
    Carlos P. Vio
    ;
    Enrique Brandan
    <jats:title>Abstract</jats:title><jats:p>Connective tissue growth factor (CTGF/CCN‐2) is mainly involved in the induction of extracellular matrix (ECM) proteins. The levels of CTGF correlate with the degree and severity of fibrosis in many tissues, including dystrophic skeletal muscle. The CTGF overexpression in tibialis anterior skeletal muscle using an adenoviral vector reproduced many of the features observed in dystrophic muscles including muscle damage and regeneration, fibrotic response and decrease in the skeletal muscle strength. The renin–angiotensin system is involved in the genesis and progression of fibrotic diseases through its main fibrotic components angiotensin‐II and its transducer receptor AT‐1. The use of AT‐1 receptor blockers (ARB) has been shown to decrease fibrosis. In this paper, we show the effect of AT‐1 receptor blockade on CTGF‐dependent biological activity in skeletal muscle cells as well as the response to CTGF overexpression in normal skeletal muscle. Our results show that in myoblasts ARB decreased CTGF‐mediated increase of ECM protein levels, extracellular signal regulated kinases 1/2 (ERK‐1/2) phosphorylation and stress fibres formation. In tibialis anterior muscle overexpressing CTGF using an adenovirus, ARB treatment decreased CTGF‐mediated increase of ECM molecules, α‐SMA and ERK‐1/2 phosphorylation levels. Quite remarkable, ARB was able to prevent the loss of contractile force of tibialis anterior muscles overexpressing CTGF. Finally, we show that ARB decreased the levels of fibrotic proteins, CTGF and ERK‐1/2 phosphorylation augmented in a dystrophic skeletal muscle from mdx mice. We propose that ARB is a novel pharmacological tool that can be used to decrease the fibrosis induced by CTGF in skeletal muscle associated with muscular dystrophies.</jats:p>
      2Scopus© Citations 84
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    CTGF/CCN‐2 over‐expression can directly induce features of skeletal muscle dystrophy
    (2011)
    María Gabriela Morales
    ;
    Claudio Cabello‐Verrugio
    ;
    Cristian Santander
    ;
    Daniel Cabrera
    ;
    Roel Goldschmeding
    <jats:title>Abstract</jats:title><jats:p>Muscular dystrophies are diseases characterized by muscle weakness together with cycles of degeneration and regeneration of muscle fibres, resulting in a progressive decrease of muscle mass, diminished muscle force generation and an increase in fibrosis. Fibrotic disorders are the endpoint of many chronic diseases in different tissues, where accumulation of the extracellular matrix (ECM) occurs. Connective tissue growth factor CTGF/CCN2, which is over‐expressed in muscular dystrophies, plays a major role in many progressive scarring conditions. To test the hypothesis that CTGF might not only contribute conversion of already damaged muscle into scar tissue, but that it could by itself also directly contribute to skeletal muscle deterioration, we evaluated the effect of CTGF over‐expression in tibialis anterior muscle of wild‐type mice, using an adenovirus containing the <jats:italic>CTGF</jats:italic> mouse sequence (Ad–mCTGF). CTGF over‐expression induced extensive skeletal muscle damage, which was followed by a massive regeneration of the damaged muscle, as evidenced by increased embryonic myosin and fibres with centrally located nuclei. It also induced strong fibrosis with increased levels of fibronectin, collagen, decorin and α‐smooth muscle actin (α‐SMA). Moreover, CTGF over‐expression caused a decrease of the specific isometric contractile force. Strikingly, when CTGF over‐expression stopped, the entire phenotype proved to be reversible, in parallel with normalization of CTGF levels. Thus, CTGF not merely acts downstream of muscle injury but also contributes directly to the deterioration of skeletal muscle phenotype and function. Moreover, normalization of expression levels led to spontaneous reversal of the CTGF‐induced phenotype and to full recovery of muscle structure. These observations underscore the importance of CTGF in the pathophysiology of muscular dystrophies and suggest that targeting CTGF might have significant potential in the development of novel therapies for Duchenne muscular dystrophy and related diseases. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.</jats:p>
      1Scopus© Citations 101