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Molecular and Cellular Biology, May 2000, p. 3256-3265, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Dual Control of Muscle Cell Survival by Distinct Growth Factor-Regulated Signaling Pathways

Margaret A. Lawlor, Xiuhong Feng, Daniel R. Everding, Kerry Sieger, Claire E. H. Stewart, and Peter Rotwein*

Molecular Medicine Division, Oregon Health Sciences University, Portland, Oregon 97201-3098

Received 9 September 1999/Returned for modification 27 October 1999/Accepted 19 January 2000

In addition to their ability to stimulate cell proliferation, polypeptide growth factors are able to maintain cell survival under conditions that otherwise lead to apoptotic death. Growth factors control cell viability through regulation of critical intracellular signal transduction pathways. We previously characterized C2 muscle cell lines that lacked endogenous expression of insulin-like growth factor II (IGF-II). These cells did not differentiate but underwent apoptotic death in low-serum differentiation medium. Death could be prevented by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we analyze the signaling pathways involved in growth factor-mediated myoblast survival. PDGF treatment caused sustained activation of extracellular-regulated kinases 1 and 2 (ERK1 and -2), while IGF-I only transiently induced these enzymes. Transient transfection of a constitutively active Mek1, a specific upstream activator of ERKs, maintained myoblast viability in the absence of growth factors, while inhibition of Mek1 by the drug UO126 blocked PDGF-mediated but not IGF-stimulated survival. Although both growth factors activated phosphatidylinositol 3-kinase (PI3-kinase) to similar extents, only IGF-I treatment led to sustained stimulation of its downstream kinase, Akt. Transient transfection of a constitutively active PI3-kinase or an inducible Akt promoted myoblast viability in the absence of growth factors, while inhibition of PI3-kinase activity by the drug LY294002 selectively blocked IGF- but not PDGF-mediated muscle cell survival. In aggregate, these observations demonstrate that distinct growth factor-regulated signaling pathways independently control myoblast survival. Since IGF action also stimulates muscle differentiation, these results suggest a means to regulate myogenesis through selective manipulation of different signal transduction pathways.

* Corresponding author. Mailing address: Oregon Health Sciences University, Molecular Medicine Division, 3181 S.W. Sam Jackson Park Road, Mail code NRC3, Portland, OR 97201-3098. Phone: (503) 494-0536. Fax: (503) 494-7368. E-mail: rotweinp{at}ohsu.edu.

Molecular and Cellular Biology, May 2000, p. 3256-3265, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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