Three families of growth factors/hormones have major effects on the differentiation of skeletal muscle cells. Two (FGF and TGF-beta) are potent inhibitors, and the third (IGF) exhibits a biphasic stimulatory action (but is not inhibitory even at high concentrations). All of these affect the expression of myogenin, one of the recently discovered family of myogenesis controlling genes, and FGF and TGF-beta have been shown to inhibit the expression of MyoD1 (and probably myf-5 and herculin) as well. These agents inhibit or stimulate (respectively) all measured aspects of myogenic differentiation--fusion, expression of a set of muscle-specific genes, and attainment of a postmitotic state--in all cells that are capable of these responses, whether cell lines or primary muscle cell cultures. It now seems clear that the myogenesis controlling genes regulate the entire family of muscle-specific proteins. Therefore the demonstration that expression of these genes is controlled (both positively and negatively) by specific growth factors that are now available at high purity and in useful quantities offers the possibility of understanding myogenic differentiation at a level of molecular detail that is very exciting.
It has now been well established that the terminal differentiation of muscle cells in culture is subject to control by hormones and growth factors in the incubation medium. Thus far the most potent and most extensively studied agents are fibroblast growth factor (FGF), the insulinlike growth factors (IGFs), and transforming growth factor-beta (TGF-beta). Independent reports from several laboratories have established that both FGF and TGF-beta are potent inhibitors of differentiation and both appear to act at early stages of commitment to differentiation. Stimulation of differentiation by the IGFs (and by insulin at concentrations in the microgram/ml range) has also been observed and confirmed repeatedly. FGF and IGF are mitogenic for muscle cells, and TGF-beta either has no effect or suppresses cell proliferation, so previous generalizations that mitogens inhibit myogenic differentiation are clearly not valid when results with purified agents in well-defined media are considered. Work with oncogenes and specific toxins is beginning to reveal the mechanisms by which these agents might affect differentiation, and there is reason for optimism that an understanding of the molecular events that control terminal differentiation may be attained in the near future.
Mitogens are generally thought to inhibit myogenesis, and many cell biologists have found it hard to interpret observations that the insulin-like growth factors (IGFs) stimulate both proliferation and differentiation of muscle cells in culture. Our previous studies suggested that the Type I IGF receptor mediates these actions. However, IGF-II and insulin treatment caused myoblasts to differentiate much more extensively, suggesting that more complex mechanisms may be involved. Here we present evidence that the greater mitogenic activity of IGF-I (compared to IGF-II and insulin) delays L6A1 myoblast differentiation. Under conditions in which the mitogenic actions of IGF-I are suppressed, the stimulation of myogenesis by IGF-I approached that by IGF-II: (1) in L6A1 cultures plated at a higher cell density; (2) in L6A1 cultures in which cell proliferation was inhibited by cytosine arabinoside or aphidicolin; and (3) in cultures of primary human muscle cells, which exhibit a smaller mitogenic response to IGF-I. Further evidence that the Type I receptor plays a major role in relaying the signal for differentiation was obtained by using IGF-I and IGF-II analogs. Analogs which have reduced affinity for the Type I receptor showed a dramatic decrease in activity, while an analog with increased affinity for the Type II receptor was no more active than native IGF-I. Our results indicate that both mitogenic and myogenic actions of IGF-I are mediated by the Type I receptor. We conclude that IGF-I delays the onset of myogenesis as a result of its mitogenic actions, and only subsequently stimulates myogenesis. These observations reconcile the apparent conflict between our results with the IGFs and other investigators' reports of effects of other mitogens.
The present study was undertaken to determine the effects of porcine growth hormone (pGH) on glucose transport, to establish which lipogenic enzymes were affected by pGH, and to determine if changes in insulin binding or insulin receptor kinase activity contributed to the diminished insulin responsiveness of adipocytes from pigs treated with pGH. Pigs were treated with pGH daily (70 micrograms/kg body wt.) for 7 days. pGH treatment reduced the basal (non-insulin-stimulated) glucose transport rate by 62% and the insulin-stimulated transport rate by 47%. The decline in glucose transport rate was paralleled by a 64% decrease in fatty acid synthesis. The reduction in the lipogenic rate was associated with a marked decline in the activity of several lipogenic enzymes: glucose-6-phosphate dehydrogenase (50% decrease), 6-phosphogluconate dehydrogenase (11% decrease), malic enzyme (62% decrease) and fatty acid synthase (activity not detectable after pGH treatment). The pGH-dependent decline in insulin responsiveness was not associated with any change in the binding of insulin to intact adipocytes or to plasma membrane preparations. The insulin-stimulated tyrosine kinase activity of the wheat-germ agglutinin-purified receptors from pGH-treated adipocytes was not different from that in control adipocytes, except when high concentrations of insulin were employed. These findings establish that pGH elicits a number of metabolic effects in porcine adipocytes which collectively diminish the rate of lipid synthesis, and thereby contribute to the decrease in lipid deposition observed in pGH-treated pigs. Furthermore, the pGH-dependent impairment in insulin action appears to be mediated at some location distal to the receptor kinase step or in other signal pathway(s) which mediate the biological effects of insulin that are not dependent on activation of insulin receptor tyrosine kinase activity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.