PT  - JOURNAL ARTICLE
AU  - Marco S. Kaiser
AU  - Giulia Milan
AU  - Shuo Lin
AU  - Filippo Oliveri
AU  - Kathrin Chojnowska
AU  - Lionel A. Tintignac
AU  - Nitish Mittal
AU  - Christian E. Zimmerli
AU  - David J. Glass
AU  - Mihaela Zavolan
AU  - Daniel J. Ham
AU  - Markus A. Rüegg
TI  - Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis
AID  - 10.1101/2021.11.16.468773
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.11.16.468773
4099  - http://biorxiv.org/content/early/2021/11/19/2021.11.16.468773.short
4100  - http://biorxiv.org/content/early/2021/11/19/2021.11.16.468773.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.