Coordinate control of muscle cell survival by distinct insulin-like growth factor activated signaling pathways

Margaret A. Lawlor, Peter Rotwein

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Peptide growth factors control diverse cellular functions by regulating distinct signal transduction pathways. In cultured myoblasts, insulin-like growth factors (IGFs) stimulate differentiation and promote hypertrophy. IGFs also maintain muscle cell viability. We previously described C2 skeletal muscle lines lacking expression of IGF-II. These cells did not differentiate, but underwent progressive apoptotic death when incubated in differentiation medium. Viability could be sustained and differentiation enabled by IGF analogues that activated the IGF-I receptor; survival was dependent on stimulation of phosphatidylinositol 3-kinase (PI3-kinase). We now find that IGF action promotes myoblast survival through two distinguishable PI3-kinase-regulated pathways that culminate in expression of the cyclin-dependent kinase inhibitor, p21. Incubation with IGF-I or transfection with active PI3-kinase led to rapid induction of MyoD and p21, and forced expression of either protein maintained viability in the absence of growth factors. Ectopic expression of MyoD induced p21, and inhibition of p21 blocked MyoD-mediated survival, thus defining one PI3-kinase-dependent pathway as leading first to MyoD, and then to p21 and survival. Unexpectedly, loss of MyoD expression did not impede IGF-mediated survival, revealing a second pathway involving activation by PI3-kinase of Akt, and subsequent induction of p21. Since inhibition of p21 caused death even in the presence of IGF-I, these results establish a central role for p21 as a survival factor for muscle cells. Our observations also define a MyoD-independent pathway for regulating p21 in muscle, and demonstrate that distinct mechanisms help ensure appropriate expression of this key protein during differentiation.

Original languageEnglish (US)
Pages (from-to)1131-1140
Number of pages10
JournalJournal of Cell Biology
Volume151
Issue number6
DOIs
StatePublished - Dec 11 2000

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Phosphatidylinositol 3-Kinase
Somatomedins
Muscle Cells
Cell Survival
Myoblasts
Insulin-Like Growth Factor I
Intercellular Signaling Peptides and Proteins
Cyclin-Dependent Kinase Inhibitor p21
IGF Type 1 Receptor
Insulin-Like Growth Factor II
Hypertrophy
Transfection
Signal Transduction
Skeletal Muscle
Proteins
Muscles
Peptides

Keywords

  • Akt
  • Insulin-like growth factors
  • MyoD
  • p21
  • Phosphatidyl inositol 3-kinase

ASJC Scopus subject areas

  • Cell Biology

Cite this

Coordinate control of muscle cell survival by distinct insulin-like growth factor activated signaling pathways. / Lawlor, Margaret A.; Rotwein, Peter.

In: Journal of Cell Biology, Vol. 151, No. 6, 11.12.2000, p. 1131-1140.

Research output: Contribution to journalArticle

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