Figure 8.

Schematic illustration showing EE and ICA promote myotube hypertrophy via IGF-1 signal pathway. Through triggering IGF-1R autophosphorylation, EE/ ICA activates key components of the IGF-1 signal cascades. As a consequence, the expression of MyHC and AR was up-regulated by the AKT/mTOR axis. In addition, two protein degradation signals, i.e. FoxO and MSTN/Smad are likely simultaneously inhibited by AKT to prevent from nuclear accumulation. Intranuclear FoxO induces atrogenes MAFbx and MuRF1 transcription, extranuclearly translocation of the phosphorylated FoxO induced by IGF-1 deactivates atrogene expression. Although EE and ICA may also reduce FoxO nuclear localization and MAFbx and MuRF1 transcription by activating AKT, the simultaneously activated AMPK/Thr172 reversely enhances FoxO function to result in a neutralizing effect on gene transcription. In contrast, heavier AKT phosphorylation induced by IGF-1 may induce AMPK/Ser485/491 phosphorylation instead, which may reduce the AMPK activity. The MSTN/Smad is another pathway to modulate protein degradation. The restricted function of Smad induced by AKT activation leads to a decrease of MSTN production. EE also suppresses the expression of MRF4 which is highly expressed in mature myotube as a growth repressor. To summarize, EE/ICA induces positive net protein balance by increasing MyHC isoforms and simultaneously suppressing atrogenes expression, which eventually leads to C2C12 myotube hypertrophy.