Abstract
Insulin receptor substrate (IRS)-1 is a major substrate of insulin-like growth factor (IGF)-I receptors. It is well-known that IGF-I and II play essential roles in myogenesis progression. Herein, we report an unexpected phenomenon that IRS-1-overexpressing L6 myoblasts are eliminated from normal cell layers at the beginning of differentiation. Initially, the IRS protein level and apoptosis were examined during myogenic differentiation in L6 myoblasts. We found that the IRS-1 protein level decreased, whereas active caspase 3 increased around 1 day after induction of differentiation. The addition of a pan-caspase inhibitor, Z-VAD-FMK, inhibited differentiation-induced suppression of the IRS-1 protein level. Apoptosis was not enhanced in L6 myoblasts stably expressing high levels of IRS-1 (L6-IRS-1). However, when L6-IRS-1 was cultured with control cells (L6-mock), we observed that L6-IRS-1 was eliminated from the cell layer. We have recently reported that, in L6-IRS-1, internalization of the IGF-I receptor was delayed and IGF signal activation was sustained for a longer period than in L6-mock. When cells stably expressing IRS-1 3YA mutant, which could not maintain the IGF signals, were cultured with normal cells, elimination from the cell layer was not detected. These data suggested that the high level of IRS-1 in myoblasts induces elimination from the cell layer due to abnormal sustainment of IGF-I receptor activation.
Highlights
Myogenic differentiation is a tightly regulated complex process in which mononucleated myoblasts proliferate, express myogenic marker proteins (MyoD, myogenin, myosin heavy chain (MyHC), etc.), and fuse to form multinucleated myotubes
We found that cells expressing high Insulin receptor substrate (IRS)-1 levels are eliminated from the normal cell layer and undergo apoptosis upon culturing with normal cells due to sustained insulin-like growth factor (IGF) signal activation
Protein Levels of IRS-1 and Cleaved Caspase 3 Were Dramatically Changed During Myogenic Differentiation of L6 Myoblasts
Summary
Myogenic differentiation is a tightly regulated complex process in which mononucleated myoblasts proliferate, express myogenic marker proteins (MyoD, myogenin, myosin heavy chain (MyHC), etc.), and fuse to form multinucleated myotubes. Matured myotubes convert into myofibers, which are capable of muscle contraction These multiple processes of myogenic differentiation seem to depend on numerous pathways [1, 2]. IGFs are revealed to possess various bioactivities, including the induction of cell proliferation, Significance of Higher IRS-1 Level differentiation, and survival of target tissues. Phosphotyrosine residues in IRSs are recognized by several signaling molecules with an SH2 domain, resulting in activation of the phosphatidyl inositol 3-kinase-Akt pathway and Ras-mitogen activated protein kinase pathway Activation of these pathways is shown to be required for the expression of various IGF bioactivities. IGF has an essential role in myogenic differentiation It is unclear whether the activation of downstream IGF signaling pathways is constantly required for myogenesis. We found that cells expressing high IRS-1 levels are eliminated from the normal cell layer and undergo apoptosis upon culturing with normal cells due to sustained IGF signal activation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
