Hormones, Growth Factors, and Myogenic Differentiation

Florini, James R.; Ewton, Daina Z.; Magri, K. A.

doi:10.1146/annurev.ph.53.030191.001221

Cited by 393 publications

(205 citation statements)

References 57 publications

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“…For many years it has been accepted that skeletal myoblast differentiation depends on both growth factor depletion and the autocrine secretion of IGFs. 18,19 This would explain the dependence of differentiation on the variables of cell density and time and the inverse relationship of these variables. The greater the cell density the faster the growth factor depletion in GM.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis coincident with the differentiation of skeletal myoblasts is delayed by caspase 3 inhibition and abrogated by MEK-independent constitutive Ras signaling

et al. 2002

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We demonstrate that during 23A2 skeletal myoblast differentiation, between 30 ± 35% of the population apoptose. Both differentiation and apoptosis are controlled by the variables of cell density and time and these variables are inversely related. In response to conditions that permit both differentiation and apoptosis of parental 23A2 myoblasts, myoblasts rendered differentiation-defective by constitutive Ras signaling (A2:HRas myoblasts) do not apoptose. This is not merely a consequence of their differentiation-defective phenotype since myoblasts rendered differentiation-defective by expression of E1A (A2:E1A myoblasts) still apoptose. Although signaling through MEK is important to the survival of proliferating parental 23A2 myoblasts, constitutive signaling through MEK is not responsible for the survival of A2:H-Ras myoblasts. Finally, we demonstrate that caspase 3 is activated and that pharmacological inhibition of caspase 3 activity delays apoptosis without affecting differentiation. Abrogating apoptosis without affecting differentiation could be a useful approach to improve the efficacy of myoblast transfer in the treatment of muscular dystrophies.

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Section: Discussionmentioning

confidence: 99%

Apoptosis coincident with the differentiation of skeletal myoblasts is delayed by caspase 3 inhibition and abrogated by MEK-independent constitutive Ras signaling

et al. 2002

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“…The secreted di erentiation inhibitor is heat stable, suramin sensitive and retained by a 3 kD cuto membrane Skeletal myoblast di erentiation is inhibited by several peptide growth factors (Vaidya et al, 1989;Florini et al, 1991;Olson, 1992). A common property of small peptide growth factors is their resistance to heat denaturation.…”

Section: Mhcmentioning

confidence: 99%

“…Neither FGF-2 nor TGFb is immunologically detected in A2:H-Ras conditioned media FGF-2 and TGFb are the peptide growth factors known to inhibit the di erentiation of skeletal myoblasts (Vaidya et al, 1989;Florini et al, 1991;Olson, 1992). Western analyses using antibodies speci®c for FGF-2 or TGFb were peformed to determine if either of these growth factors are Characterization of the activity in A2:H-Ras conditioned media which inhibits di erentiation.…”

Section: Mhcmentioning

confidence: 99%

“…Clues have come mostly from studying the signaling pathways utilized by molecules which inhibit di erentiation. The actions of the MRFs, and consequently skeletal myoblast di erentiation, are abrogated by culturing myoblasts in fetal serum, FGF2, TGFb, by expression of oncogenes such as Src, Ras, Myc, Fos or Jun or by expression of the E1A protein (Schneider and Olson, 1988;Florini et al, 1991;Olson, 1992;Alema and Tato, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast differentiation

Weyman

Wolfman

1997

Oncogene

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Expression of oncogenic H-Ras in 23A2 myoblasts (A2:H-Ras cells) is su cient to induce both a transformed phenotype and a di erentiation-defective phenotype. Because oncogenic Ras is known to induce the secretion of several di erent growth factors involved in maintaining the transformed phenotype of both ®broblast and epithelial cells, we explored the possibility that expression of oncogenic Ras in 23A2 myoblasts might lead to the secretion of a factor which inhibits di erentiation. The di erentiation of 23A2 myoblasts was inhibited (i) by coculture with an equal number of A2:H-Ras cells, (ii) by culture with an equal number of A2:H-Ras cells in the same tissue culture medium on an insert which allowed equilibration of molecules smaller than 1 micron, and (iii) by culture in media previously conditioned by A2:H-Ras cells. Similar results were obtained when 23A2 myoblasts expressing oncogenic NRas were substituted for A2:H-Ras cells in each assay. No inhibition of di erentiation was observed, however, when di erentiation-defective E1A-expressing 23A2 cells or C3H10T1/2 ®broblasts were substituted for A2:HRas cells. The di erentiation inhibitor(s) in media conditioned by A2:H-Ras cells is heat stable, larger than 3 kD, and sensitive to the non-speci®c growth factor antagonist, suramin. Western analyses failed to detect either FGF-2 or TGFb (the known inhibitors of myoblast di erentiation) in media conditioned by A2:H-Ras cells. Furthermore, while FGF-2 is a potent activator of MAP kinase and TGFb is a potent inhibitor of mink lung epithelial cell (CCL64) growth, conditioned media from A2:H-Ras cells does not activate MAP kinase and does not inhibit the growth of CCL64 cells. These results indicate that expression of oncogenic Ras induces the secretion of a novel inhibitor of skeletal myoblast di erentiation. Furthermore, these results are the ®rst to implicate an autocrine/paracrine mechanism in the inhibition of di erentiation by oncogenic Ras.

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“…Insulin-like growth factor-I (IGF-I) is therefore unique among growth factors as it stimulates both proliferation and differentiation of skeletal-muscle cells in culture [1][2][3][4][5][6][7]. In normal cell division, most cell lines require IGF-I, i.e.…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor (IGF-I) induces myotube hypertrophy associated with an increase in anaerobic glycolysis in a clonal skeletal-muscle cell model

Semsarian

Sutrave

Richmond

et al. 1999

Biochemical Journal

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Insulin-like growth factor-I (IGF-I) is an important autocrine/paracrine mediator of skeletal-muscle growth and development. To develop a definitive cultured cell model of skeletal-muscle hypertrophy, C2C12 cells were stably transfected with IGF-I and clonal lines developed and evaluated. Quantitative morphometric analysis showed that IGF-I-transfected myotubes had a larger area (2381±60 µm2 versus 1429±39 µm2; P< 0.0001) and a greater maximum width (21.4±0.6 µm versus 13.9±0.3 µm; P< 0.0001) than control C2C12 myotubes, independent of the number of cell nuclei per myotube. IGF-I-transfected myotubes had higher levels of protein synthesis but no difference in DNA synthesis when compared with control myotubes, indicating the development of hypertrophy rather than hyperplasia. Both lactate dehydrogenase and alanine aminotransferase activities were increased (3- and 5-fold respectively), and total lactate levels were higher (2.3-fold) in IGF-I-transfected compared with control myotubes, indicating an increase in anaerobic glycolysis in the hypertrophied myotubes. However, expression of genes involved in skeletal-muscle growth or hypertrophy in vivo, e.g. myocyte nuclear factor and myostatin, was not altered in the IGF-I myotubes. Finally, myotube hypertrophy could also be induced by treatment of C2C12 cells with recombinant IGF-I or by growing C2C12 cells in conditioned media from IGF-I-transfected cells. This quantitative model should be uniquely useful for elucidating the molecular mechanisms of skeletal-muscle hypertrophy.

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Hormones, Growth Factors, and Myogenic Differentiation

Cited by 393 publications

References 57 publications

Apoptosis coincident with the differentiation of skeletal myoblasts is delayed by caspase 3 inhibition and abrogated by MEK-independent constitutive Ras signaling

Apoptosis coincident with the differentiation of skeletal myoblasts is delayed by caspase 3 inhibition and abrogated by MEK-independent constitutive Ras signaling

Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast differentiation

Insulin-like growth factor (IGF-I) induces myotube hypertrophy associated with an increase in anaerobic glycolysis in a clonal skeletal-muscle cell model

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