Decorin Gene Transfer Promotes Muscle Cell Differentiation and Muscle Regeneration

Abstract

We have shown that decorin, a small leucine-rich proteoglycan, can inhibit transforming growth factor (TGF)-beta1 to prevent fibrous scar formation and improve muscle healing after injury. In the decorin-treated muscle, an enhancement of muscle regeneration is observed through histological examination. In this article, we report our determination of whether decorin has a direct effect on myogenic cells' differentiation. Our results indicate that myoblasts genetically engineered to express decorin (CD cells) differentiated into myotubes at a significantly higher rate than did control myoblasts (C2C12). This enhanced differentiation led to the up-regulation of myogenic genes (Myf5, Myf6, MyoD, and myogenin) in CD cells in vitro. We speculate that the higher rate of differentiation exhibited by the CD cells is due to the up-regulation of follistatin, peroxisome-proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha), p21, and the myogenic genes, and the down-regulation of TGF-beta1 and myostatin. Decorin gene transfer in vivo promoted skeletal muscle regeneration and accelerated muscle healing after injury. These results suggest that decorin not only prevents fibrosis but also improves muscle regeneration and repair.

Inhibiting myostatin reverses muscle fibrosis through apoptosis

“…These include factors and drugs which inhibit TGF-b extracellularly such as TGF-b neutralizing antibodies, the ECM proteoglycan decorin, and latent TGF-b-binding protein 4 (Andreetta et al, 2006;Heydemann et al, 2009;Li et al, 2007). It also includes factors and drugs which may modulate or cross-talk with TGF-b signaling including, in addition to myostatin, IGF-1 and angiotensin II receptor blockers Bedair et al, 2008).…”

Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice

“…TGF-β1 is likely to be an important target of decorin in wound healing, because TGF-β1 plays a key role in scar formation (1)(2)(3)(4)(5), and decorin inhibits TGF-β-dependent responses (4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). CAR-decorin inhibited gene expression of several TGF-β-induced genes that play a role in scar formation (32)(33)(34)(35) by about 50% at day 5 after wounding when TGF-β activity peaks in wounds (5) (Fig.…”

“…The ability of decorin to prevent tissue fibrosis and promote tissue regeneration has been observed in numerous injury models (4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The TGF-β blockade is likely the main factor in the antiscarring activity of decorin, but effects on some other growth factors and on collagen fibrillogenesis may also contribute (13)(14)(15)(16)(17)(18).…”

“…Despite the positive results in animal models (8)(9)(10)(11)(12)(15)(16)(17)(18), decorin has not reached the clinic. One reason is that as a protein therapeutic, it is relatively difficult to manufacture.…”

Efeito da terapia com células-tronco musculares e células-tronco mesenquimais na regeneração do músculo esquelético: modulação por ácido oléico.

“…A laceração é acompanhada por regeneração incompleta, diferentemente do que se observa em modelos de lesão muscular por toxinas onde mesmo sem tratamento o músculo esquelético se recupera espontaneamente (ARSIC et al, 2004;MENETREY et al, 1999). O processo de regeneração muscular em modelos experimentais pode ser estudado em diferentes períodos de tempos após a lesão através de técnicas histológicas e western blotting para marcadores específicos da miogênese e fibrogênese e por testes de função muscular (BORNEMANN e SCHMALBRUCH, 1992;BROCKS et al, 1991;HURME et al, 1991;HURME e KALIMO, 1992;LI et al, 2007;MENETREY et al, 1999;NEGISHI et al, 2005;STRATOS et al, 2007).…”