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Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4638255
Author(s)
Kaiser, Marco S.; Milan, Giulia; Lin, Shuo; Oliveri, Filippo; Chojnowska, Kathrin; Tintignac, Lionel A.; Mittal, Nitish; Zimmerli, Christian E.; Glass, David J.; Zavolan, Mihaela; Ham, Daniel J.; Rüegg, Markus A.
Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity.
