DSpace Repository :: Browsing by Author "Cabello-Verrugio, Claudio"

Browsing by Author "Cabello-Verrugio, Claudio"

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Angiotensin II receptor type 1 blockade decreases CTGF/CCN2-mediated damage and fibrosis in normal and dystrophic skeletal muscles
(John Wiley & Sons, 2012) Cabello-Verrugio, Claudio; Morales, Maria; Cabrera, Daniel; Vio, Carlos; Brandan, Enrique
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.
Angiotensin II-induced pro-fibrotic effects require p38MAPK activity and transforming growth factor beta 1 expression in skeletal muscle cells
(Elsevier, 2012) Morales, Maria; Vazquez, Yaneisi; Acuña, Maria; Rivera, Juan; Simon, Felipe; Salas, Jose; Ruf, Joel; Brandan, Enrique; Cabello-Verrugio, Claudio
Fibrotic disorders are typically characterised by excessive connective tissue and extracellular matrix (ECM) deposition that preclude the normal healing of different tissues. Several skeletal muscle dystrophies are characterised by extensive fibrosis. Among the factors involved in skeletal muscle fibrosis is angiotensin II (Ang-II), a key protein of the renin-angiotensin system (RAS). We previously demonstrated that myoblasts responded to Ang-II by increasing the ECM protein levels mediated by AT-1 receptors, implicating an Ang-II-induced reactive oxygen species (ROS) by a NAD(P)H oxidase-dependent mechanism. In this paper, we show that in myoblasts, Ang-II induced the increase of transforming growth factor beta 1 (TGF-β1) and connective tissue growth factor (CTGF) expression through its AT-1 receptor. This effect is dependent of the NAD(P)H oxidase (NOX)-induced ROS, as indicated by a decrease of the expression of both pro-fibrotic factors when the ROS production was inhibited via the NOX inhibitor apocynin. The increase in pro-fibrotic factors levels was paralleled by enhanced p38MAPK and ERK1/2 phosphorylation in response to Ang-II. However, only the p38MAPK activity was critical for the Ang-II-induced fibrotic effects, as indicated by the decrease in the Ang-II-induced TGF-β1 and CTGF expression and fibronectin levels by SB-203580, an inhibitor of the p38MAPK, but not by U0126, an inhibitor of ERK1/2 phosphorylation. Furthermore, we showed that the Ang-II-dependent p38MAPK activation, but not the ERK1/2 phosphorylation, was necessary for the NOX-derived ROS. In addition, we demonstrated that TGF-β1 expression was required for the Ang-II-induced pro-fibrotic effects evaluated by using SB-431542, an inhibitor of TGF-βRI kinase activity, and by knocking down TGF-β1 levels by shRNA technique. These results strongly suggest that the fibrotic response to Ang-II is mediated by the AT-1 receptor and requires the p38MAPK phosphorylation, NOX-induced ROS, and TGF-β1 expression increase mediated by Ang-II in skeletal muscle cells.
CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy
(2011) Morales, Maria Gabriela; Cabello-Verrugio, Claudio; Santander, Cristian; Cabrera, Daniel; Goldschmeding, Roel; Brandan, Enrique
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 CTGF 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 a-smooth muscle actin (alpha-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 (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Fibrotic response induced by angiotensin-II requires NAD(P)H oxidase-induced reactive oxygen species (ROS) in skeletal muscle cells
(2011) Cabello-Verrugio, Claudio; Acuña, Maria José; Morales, Maria Gabriela; Becerra, Alvaro; Simon, Felipe; Brandan, Enrique
Fibrotic disorders are typified by excessive connective tissue and extracellular matrix (ECM) deposition that precludes normal healing processes in different tissues. Angiotensin-II (Ang-II) is involved in the fibrotic response. Several muscular dystrophies are characterized by extensive fibrosis. However, the exact role of Ang-II in skeletal muscle fibrosis is unknown. Here we show that myoblasts responded to Ang-II by increasing protein levels of connective tissue growth factor (CTGF/CCN2), collagen-III and fibronectin. These Ang-II-induced pro-fibrotic effects were mediated by AT-1 receptors. Remarkably, Ang-II induced reactive oxygen species (ROS) via a NAD(P)H oxidase-dependent mechanism, as shown by inhibition of ROS production via the NAD(P)H oxidase inhibitors diphenylene iodonium (DPI) and apocynin. This increase in ROS is critical for Ang-II-induced fibrotic effects, as indicated by the decrease in Ang-II-induced CTGF and fibronectin levels by DPI and apocynin. We also show that Ang-II-induced ROS production and fibrosis require PKC activity as indicated by the generic PKC inhibitor chelerythrine. These results strongly suggest that the fibrotic response induced by Ang-II is mediated by AT-I receptor and requires NAD(P)H-induced ROS in skeletal muscle cells. (C) 2011 Elsevier Inc. All rights reserved.
High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis
(Hindawi Publishing Corp., 2016) Abrigo, Johanna; Rivera, Juan Carlos; Aravena, Javier; Cabrera, Daniel; Simon, Felipe; Ezquer, Fernando; Ezquer, Marcelo; Cabello-Verrugio, Claudio
Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs) are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes.
The Internal Region Leucine-rich Repeat 6 of Decorin Interacts with Low Density Lipoprotein Receptor-related Protein-1, Modulates Transforming Growth Factor (TGF)-beta-dependent Signaling, and Inhibits TGF-beta-dependent Fibrotic Response in Skeletal Muscles
(American Society for Biochemistry and Molecular Biology, 2012) Cabello-Verrugio, Claudio; Santander, Cristian; Cofre, Catalina; Acuña, Maria; Melo, Francisco; Brandan, Enrique
Decorin is a small proteoglycan, composed of 12 leucine-rich repeats (LRRs) that modulates the activity of transforming growth factor type β (TGF-β) and other growth factors, and thereby influences proliferation and differentiation in a wide array of physiological and pathological processes, such as fibrosis, in several tissues and organs. Previously we described two novel modulators of the TGF-β-dependent signaling pathway: LDL receptor-related protein (LRP-1) and decorin. Here we have determined the regions in decorin that are responsible for interaction with LRP-1 and are involved in TGF-β-dependent binding and signaling. Specifically, we used decorin deletion mutants, as well as peptides derived from internal LRR regions, to determine the LRRs responsible for these decorin functions. Our results indicate that LRR6 and LRR5 participate in the interaction with LRP-1 and TGF-β as well as in its dependent signaling. Furthermore, the internal region (LRR6i), composed of 11 amino acids, is responsible for decorin binding to LRP-1 and subsequent TGF-β-dependent signaling. Furthermore, using an in vivo approach, we also demonstrate that the LRR6 region of decorin can inhibit TGF-β mediated action in response to skeletal muscle injury.

Browsing by Author "Cabello-Verrugio, Claudio"

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