CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy

María Gabriela Morales, Claudio Cabello-Verrugio, Cristian Santander, Daniel Cabrera, Roel Goldschmeding, Enrique Brandan

Resultado de la investigación: Article

63 Citas (Scopus)

Resumen

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 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.

Idioma originalEnglish
Páginas (desde-hasta)490-501
Número de páginas12
PublicaciónJournal of Pathology
Volumen225
N.º4
DOI
EstadoPublished - dic 2011

Huella dactilar

Skeletal Muscle
Muscles
Muscular Dystrophies
Phenotype
Cicatrix
Regeneration
Fibrosis
Decorin
Connective Tissue Growth Factor
Duchenne Muscular Dystrophy
Muscle Weakness
Muscular Diseases
Myosins
Fibronectins
Adenoviridae
Extracellular Matrix
Smooth Muscle
Actins
Chronic Disease
Collagen

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Citar esto

Morales, M. G., Cabello-Verrugio, C., Santander, C., Cabrera, D., Goldschmeding, R., & Brandan, E. (2011). CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy. Journal of Pathology, 225(4), 490-501. https://doi.org/10.1002/path.2952
Morales, María Gabriela ; Cabello-Verrugio, Claudio ; Santander, Cristian ; Cabrera, Daniel ; Goldschmeding, Roel ; Brandan, Enrique. / CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy. En: Journal of Pathology. 2011 ; Vol. 225, N.º 4. pp. 490-501.
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Morales, MG, Cabello-Verrugio, C, Santander, C, Cabrera, D, Goldschmeding, R & Brandan, E 2011, 'CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy', Journal of Pathology, vol. 225, n.º 4, pp. 490-501. https://doi.org/10.1002/path.2952

CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy. / Morales, María Gabriela; Cabello-Verrugio, Claudio; Santander, Cristian; Cabrera, Daniel; Goldschmeding, Roel; Brandan, Enrique.

En: Journal of Pathology, Vol. 225, N.º 4, 12.2011, p. 490-501.

Resultado de la investigación: Article

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AU - Morales, María Gabriela

AU - Cabello-Verrugio, Claudio

AU - Santander, Cristian

AU - Cabrera, Daniel

AU - Goldschmeding, Roel

AU - Brandan, Enrique

PY - 2011/12

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N2 - 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 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.

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