Type beta transforming growth factor is an inhibitor of myogenic differentiation.

Abstract

We have investigated the effect of type (3 transforming growth factor (TGF-() on the differentiation of skeletal muscle myoblasts. TGF-(3 potently (IDso 10 pM) prevents established cell lines and primary cultures of rat and chicken embryo myoblasts from fusing into multinucleated myotubes. Inhibition of morphological differentiation by TGF-,( correlates with inhibition of the expression of muscle-specific fiiRNAs and proteins, strong induction of extracellular matrix type I collagen and fibronectin, and a marked tendency of the treated myoblasts to aggregate into densely multilayered arrays or clusters. Myogenic differentiation can resume after removal of TGF-j3 from the medium. Examination of the time of action of TGF-(3 shows that myoblasts stochastically reach a point beyond which they become insensitive to the inhibitory action of TGF-(8. This resistance of committed myoblasts to the inhibitory action of TGF-.3 is not associated with any measurable change in the number or affinity of TGF-(3 receptors in those cells. The results indicate that TGF-(3 is a potent inhibitor of myogenesis and may regulate muscle development in vivo.Transforming growth factor ,3 (TGF-/3), a hormonally active polypeptide found in normal and transformed tissues, is a potent regulator of cell development (for review, see ref. 1). At picomolar concentrations TGF-P induces anchorageindependent growth of fibroblasts but inhibits the growth of certain tumor-derived as well as normal cells (2-6). In addition to its effects on cell proliferation, TGF-,B inhibits adipogenic differentiation without altering the growth rate of preadipocytes (7). Many cells, the growth or differentiation of which is regulated by TGF-,B, respond to this factor with a marked increase in the production and accumulation of the exetracellular matrix proteins fibronectin (8) and collagen (8,9). 'Available evidence suggests that the induction of an abundant extracellular matrix by TGF-,B mediates cellular responses to this factor such as the stimulation of anchorageindependent proliferation (8). These actions of TGF-P are presumably mediated by specific cell surface receptors: three structurally distinct cell surface glycoproteins that exhibit the properties of high-affinity receptors for TGF-P have been identified in mammalian and avian cells (10-12). It is not known whether all three receptor forms are involved in the mediation of TGF-,B actions or whether one receptor form is a signaling receptor, whereas the others have some other function(s).The widespread distribution of TGF-,3 and its receptors in different cell types and tissues suggests that this factor is involved in an ample spectrum of developmental processes in vivo. To obtain further information on the range of cellular targets for TGF-,B, we have investigated the effects of this factor on the differentiation of skeletal muscle myoblasts.These studies reveal a strong inhibitory action of TGF-,3 on myogenesis. METHODSL6Eq rat skeletal muscle myoblasts (13) were grown in Dulbecco's modified Eagle ...

Characterization of proliferating human skeletal muscle‐derived cells in vitro: Differential modulation of myoblast markers by TGF‐β2

“…TGF-b inhibits myoblast differentiation in some circumstances (Florini et al, 1986;Massague et al, 1986;Olson et al, 1986;Liu et al, 2001;Rousse et al, 2001) but stimulates it in others (Schofield and Wolpert, 1990;Zentella and Massague, 1992;De Angelis et al, 1998). We investigated whether TGF-b suppresses myoblast differentiation specifically in the context of adult HuSkMC proagated in mitogen-rich medium.…”

“…Myoblast differentiation is induced by reduction of serum and other mitogens in the culture medium (Allen et al, 1997), but some spontaneous differentiation will occur even in mitogen-rich cultures, especially at high cell density. Transforming growth factor b (TGF-b) has been reported by a number of investigators to suppress myoblast differentiation, primarily in studies performed on established cell lines under mitogen-poor conditions that inhibit myoblast proliferation (Florini et al, 1986;Massague et al, 1986;Olson et al, 1986;Liu et al, 2001;Rousse et al, 2001). Contradictory findings of TGF-b effects have been reported in the context of mitogen-rich medium used to culture the L6E9 myoblast cell line (Zentella and Massague, 1992), low cell density (De Angelis et al, 1998), and serum-free media (Schofield and Wolpert, 1990).…”

In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury

“…Several members of the TGFβ family (Egerman et al, 2015) are known regulators of muscle regeneration, whose members are secreted by repair macrophages acting in a paracrine manner (Massague, Cheifetz, Endo, & Nadal‐Ginard, 1986; McPherron, Lawler, & Lee, 1997), including GDF3 (Varga et al, 2016). We selected GDF3 for a proof‐of‐concept experiment to evaluate whether the observed impaired phenotypic transition in macrophage phenotype from inflammatory to repair type (Patsalos et al, 2017) can contribute to age‐related delay in muscle regeneration.…”

Amphoterin Stimulates Myogenesis and Counteracts the Antimyogenic Factors Basic Fibroblast Growth Factor and S100B via RAGE Binding

“…Several extracellular factors have been identified that participate in the regulation of myogenesis, some of which promote myoblast differentiation and/or myotube formation, while other factors inhibit these processes. Insulin, insulin-like growth factors (IGF I and IGF II), neuregulin, and nerve growth factor belong to the first category of agents (13-15, 28, 45), while tumor necrosis factor alpha (TNF-␣), basic fibroblast growth factor (bFGF), and transforming growth factor ␤ belong to the second category (12,29,30,35,37,40,42,50,56). However, IGF I and IGF II were reported to promote or inhibit myogenic differentiation depending on the absence or presence of TNF-␣, respectively (16), and down-regulation of nerve growth factor low-affinity receptor was shown to be required for myoblast terminal differentiation (12).…”