Abstract
Transforming growth factor beta 1 (TGF-beta 1) is an inhibitor of skeletal muscle myoblast differentiation. Myoblast differentiation is dependent on the expression of certain myogenic differentiation genes and is affected by cell interaction with the extracellular matrix. We have searched for events in the differentiation process of L6E9 rat myoblasts that may be involved in the inhibitory action of TGF-beta 1. Elevated expression of the myogenic differentiation gene, myogenin, which is thought to play a central role in the differentiation process, occurs 10 h after the shift of L6E9 myoblasts to differentiation medium. Elevation of myogenin mRNA is blocked by TGF-beta 1 added at the time of the shift. This effect is preceded by, and might be related to, a rapid up-regulation of junB mRNA observed in TGF-beta 1-treated L6E9 myoblasts. However, TGF-beta 1 can also block myogenic differentiation in cells transfected with the myogenin gene under the control of a constitutive SV40 viral promoter. The nature of a mechanism that could mediate the inhibitory action of TGF-beta 1 without blocking myogenin mRNA expression is suggested by the observations that (a) TGF-beta 1 upregulates type I collagen expression and deposition in L6E9 myoblasts, (b) a fibrillar type I collagen layer inhibits L6E9 myoblast differentiation, and (c) inhibition of L6E9 myoblast differentiation by a type I collagen layer occurs without a block in myogenin expression. Thus, the data suggest that inhibition of L6E9 myoblast differentiation by TGF-beta 1 may be accomplished by at least two mechanisms acting in concert. One mechanism leads to a block in the expression of myogenin whereas the other mechanism may involve TGF-beta 1-induced changes in cell adhesion that either block the action of myogenic differentiation gene products or prevent the function of other as yet unknown components of the myogenic differentiation pathway.
Highlights
Myoblast differentiation is dependent on the expression of certain myogenic differentiation genes and is affected by cell interaction with the extracellular matrix
We have searched for events in the differentiation process of LaEg rat myoblasts that may be involved in the inhibitory action of TGF-/31
Elevated expression of the myogenic differentiation gene, myogenin, which is thought to play a central role in the differentiation process, occurs 10 h after the shift of LaE9 myoblasts to differentiation medium
Summary
Transforming growth factor 81 (TGF-j31) is an inhibitor of skeletal muscle myoblast differentiation. The mechanism by which TGF-fis inhibit myoblast differentiation is unknown, but it has been noted that an early and persistent response of myoblasts and many other cell types to TGF-@ is a marked elevation in the expression of extracellular matrix components including fibronectin, collagen, proteoglycans, protease inhibitors, and cell adhesion receptors [8,9,10,11,12,13,14]. We provide evidence that TGF-/3 action on LsE9 rat skeletal muscle myoblasts might be accomplished by two parallel pathways that involve, respectively, decreased expression of the myogenic differentiation gene, myogenin, and changes in extracellular matrix that inhibits myoblast differentiation without blocking myogenin mRNA expression
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