Original Article

Coordinate Control of Muscle Cell Survival by Distinct Insulin-like Growth Factor Activated Signaling Pathways

Correspondence to: Peter Rotwein, Oregon Health Sciences University, Molecular Medicine Division, 3181 S.W. Sam Jackson Park Road, Mail code: NRC3, Portland, OR 97201-3098. Tel:(503) 494-0536 Fax:(503) 494-7368 E-mail:rotweinp{at}ohsu.edu.

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.

Key Words: insulin-like growth factors, p21, MyoD, phosphatidyl inositol 3-kinase, Akt

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Nakanishi, K., Dohmae, N., Morishima, N. (2007). Endoplasmic reticulum stress increases myofiber formation in vitro. FASEB J. 21: 2994-3003 [Abstract] [Full Text]  
• Wilson, E. M., Rotwein, P. (2007). Selective Control of Skeletal Muscle Differentiation by Akt1. J. Biol. Chem. 282: 5106-5110 [Abstract] [Full Text]  
• Wilson, E. M., Rotwein, P. (2006). Control of MyoD Function during Initiation of Muscle Differentiation by an Autocrine Signaling Pathway Activated by Insulin-like Growth Factor-II. J. Biol. Chem. 281: 29962-29971 [Abstract] [Full Text]  
• Kuninger, D., Wright, A., Rotwein, P. (2006). Muscle cell survival mediated by the transcriptional coactivators p300 and PCAF displays different requirements for acetyltransferase activity. Am. J. Physiol. Cell Physiol. 291: C699-C709 [Abstract] [Full Text]  
• Pampusch, M S, Xi, G, Kamanga-Sollo, E, Loseth, K J, Hathaway, M R, Dayton, W R, White, M E (2005). Production of recombinant porcine IGF-binding protein-5 and its effect on proliferation of porcine embryonic myoblast cultures in the presence and absence of IGF-I and Long-R3-IGF-I. J Endocrinol 185: 197-206 [Abstract] [Full Text]  
• Ljubimov, A. V., Caballero, S., Aoki, A. M., Pinna, L. A., Grant, M. B., Castellon, R. (2004). Involvement of Protein Kinase CK2 in Angiogenesis and Retinal Neovascularization. IOVS 45: 4583-4591 [Abstract] [Full Text]  
• Short, K. R., Nygren, J., Bigelow, M. L., Nair, K. S. (2004). Effect of Short-Term Prednisone Use on Blood Flow, Muscle Protein Metabolism, and Function. J. Clin. Endocrinol. Metab. 89: 6198-6207 [Abstract] [Full Text]  
• Dasarathy, S., Dodig, M., Muc, S. M., Kalhan, S. C., McCullough, A. J. (2004). Skeletal muscle atrophy is associated with an increased expression of myostatin and impaired satellite cell function in the portacaval anastamosis rat. Am. J. Physiol. Gastrointest. Liver Physiol. 287: G1124-G1130 [Abstract] [Full Text]  
• Wilson, E. M., Tureckova, J., Rotwein, P. (2004). Permissive Roles of Phosphatidyl Inositol 3-Kinase and Akt in Skeletal Myocyte Maturation. Mol. Biol. Cell 15: 497-505 [Abstract] [Full Text]  
• Morris, R. T., Spangenburg, E. E., Booth, F. W. (2004). Responsiveness of cell signaling pathways during the failed 15-day regrowth of aged skeletal muscle. J. Appl. Physiol. 96: 398-404 [Abstract] [Full Text]  
• Kataoka, Y., Matsumura, I., Ezoe, S., Nakata, S., Takigawa, E., Sato, Y., Kawasaki, A., Yokota, T., Nakajima, K., Felsani, A., Kanakura, Y. (2003). Reciprocal Inhibition between MyoD and STAT3 in the Regulation of Growth and Differentiation of Myoblasts. J. Biol. Chem. 278: 44178-44187 [Abstract] [Full Text]  
• Hribal, M. L., Nakae, J., Kitamura, T., Shutter, J. R., Accili, D. (2003). Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors. J. Cell Biol. 162: 535-541 [Abstract] [Full Text]  
• Ricchi, P., Palma, A. D., Matola, T. D., Apicella, A., Fortunato, R., Zarrilli, R., Acquaviva, A. M. (2003). Aspirin Protects Caco-2 Cells from Apoptosis after Serum Deprivation through the Activation of a Phosphatidylinositol 3-Kinase/AKT/p21Cip/WAF1Pathway. Mol. Pharmacol. 64: 407-414 [Abstract] [Full Text]  
• Ostrovsky, O., Bengal, E. (2003). The Mitogen-activated Protein Kinase Cascade Promotes Myoblast Cell Survival by Stabilizing the Cyclin-dependent Kinase Inhibitor, p21WAF1 Protein. J. Biol. Chem. 278: 21221-21231 [Abstract] [Full Text]  
• Takahashi, A., Kureishi, Y., Yang, J., Luo, Z., Guo, K., Mukhopadhyay, D., Ivashchenko, Y., Branellec, D., Walsh, K. (2002). Myogenic Akt Signaling Regulates Blood Vessel Recruitment during Myofiber Growth. Mol. Cell. Biol. 22: 4803-4814 [Abstract] [Full Text]  
• Barton, E. R., Morris, L., Musaro, A., Rosenthal, N., Sweeney, H. L. (2002). Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J. Cell Biol. 157: 137-148 [Abstract] [Full Text]  
• Rossig, L., Badorff, C., Holzmann, Y., Zeiher, A. M., Dimmeler, S. (2002). Glycogen Synthase Kinase-3 Couples AKT-dependent Signaling to the Regulation of p21Cip1 Degradation. J. Biol. Chem. 277: 9684-9689 [Abstract] [Full Text]  
• Wakino, S., Kintscher, U., Liu, Z., Kim, S., Yin, F., Ohba, M., Kuroki, T., Schonthal, A. H., Hsueh, W. A., Law, R. E. (2001). Peroxisome Proliferator-activated Receptor gamma Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cdelta Pathway in Vascular Smooth Muscle Cells. J. Biol. Chem. 276: 47650-47657 [Abstract] [Full Text]  
• Tureckova, J., Wilson, E. M., Cappalonga, J. L., Rotwein, P. (2001). Insulin-like Growth Factor-mediated Muscle Differentiation. COLLABORATION BETWEEN PHOSPHATIDYLINOSITOL 3-KINASE-Akt-SIGNALING PATHWAYS AND MYOGENIN. J. Biol. Chem. 276: 39264-39270 [Abstract] [Full Text]  
• Palmer, S., Groves, N., Schindeler, A., Yeoh, T., Biben, C., Wang, C.-C., Sparrow, D. B., Barnett, L., Jenkins, N. A., Copeland, N. G., Koentgen, F., Mohun, T., Harvey, R. P. (2001). The Small Muscle-specific Protein Csl Modifies Cell Shape and Promotes Myocyte Fusion in an Insulin-like Growth Factor 1-dependent Manner. J. Cell Biol. 153: 985-998 [Abstract] [Full Text]  
• Kang, Q., Cao, Y., Zolkiewska, A. (2001). Direct Interaction between the Cytoplasmic Tail of ADAM 12 and the Src Homology 3 Domain of p85alpha Activates Phosphatidylinositol 3-Kinase in C2C12 Cells. J. Biol. Chem. 276: 24466-24472 [Abstract] [Full Text]  
• Rossig, L., Badorff, C., Holzmann, Y., Zeiher, A. M., Dimmeler, S. (2002). Glycogen Synthase Kinase-3 Couples AKT-dependent Signaling to the Regulation of p21Cip1 Degradation. J. Biol. Chem. 277: 9684-9689 [Abstract] [Full Text]  
• Barton, E. R., Morris, L., Musaro, A., Rosenthal, N., Sweeney, H. L. (2002). Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J. Cell Biol. 157: 137-148 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents