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

Abstract

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.

Follistatin: A Novel Therapeutic for the Improvement of Muscle Regeneration

“…One piece of data that corroborates these antifibrotic effects is the reduction of CTGF on day 5 by FST treatment. CTGF has been known to play a direct role in contributing to muscle dystrophy, and has been shown to be regulated by activin A in hepatocytes (Gressner et al, 2008;Morales et al, 2011). In future experiments, these gene changes could be monitored in other models of fibrosis where FST is tested.…”

The complex of PAMAM-OH dendrimer with Angiotensin (1–7) prevented the disuse-induced skeletal muscle atrophy in mice

“…Muscle strength was determined as described previously. [31][32][33] Briefly, the optimum muscle length (Lo) and stimulation voltage were determined from micromanipulations of muscle length to produce the maximum isometric twitch force using a S48 rNa isolation, reverse transcription, and quantitative real-time polymerase chain reaction (Pcr)…”

CTGF Mediates Smad-Dependent Transforming Growth Factor β Signaling To Regulate Mesenchymal Cell Proliferation during Palate Development

“…CTGF is a matricellular protein involved in the regulation of cell survival, proliferation, adhesion, migration, and ECM production (13). Interestingly, TGF-␤ is able to induce Ctgf expression in diverse cell types, predominantly in fibrotic disorders (14)(15)(16)(17), and Ctgf contains a TGF-␤ response element in its promoter (18). At the protein level, CTGF possesses four domains that interact with growth factors, ECM proteins, low-density lipoprotein (LDL)-receptor related proteins (LRP), and integrins (13,(19)(20)(21).…”