Résumé :
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Communication n° 433. INTRODUCTION : Muscle regeneration is a highly regulated process. Upon damage, satellite cells of the periphery of muscle fibers undergo activation, proliferation, differentiation, and fusion to replace damaged tissue. Damaged fibers also have increased protein turnover and synthesis to complete muscle repair. OBJECTIVES : Because Insulin-like Growth Factor I (IGF-I) has been shown to enhance repair in aging and disease, genetic and pharmacologic approaches were employed to determine which members of the IGF-I signaling cascade were important for the repair process. METHODS : Mice for this study included wildtype, Akt1 null, Akt2 null, transgenic mice expressing constitutively active Glycogen Synthase Kinase 3 beta (GSKSer9Ala), and wildtype mice subjected to rapamicin treatment . The tibialis anterior muscles of young adult mice were injected with cardiotoxin to instigate the process of degeneration and regeneration. Muscles were dissected at 3, 5, 11, and 22 days post cardiotoxin injection and subjected either to histological analysis or immunoblotting for phosphorylated signaling intermediates. RESULTS : A robust and transient increase in P-Akt was observed in all muscle samples, including those lacking Akt1 or Akt2. Nuclear P-Akt accumulated starting at 5 days post cardiotoxin and persisted through 11 days. The lack of either Akt isoform did not inhibit the process of regeneration. Transgenic mice for constitutively active GSK3beta also displayed no significant impairment. However, inhibition of the downstream effector mTOR by rapamicin significantly impaired regeneration. CONCLUSIONS : This study shows that the Akt isoforms maintain functional overlap in driving the regeneration process. Further, it provides evidence that protein translation driven by the mTOR arm of the IGF-I pathway is critical for complete muscle repair. Finally, it suggests that the inhibition of GSK3beta by Akt phosphorylation is not critical for muscle regeneration to proceed properly.
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