Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

Kaiser, M. S.; Milan, G.; Lin, S.; Oliveri, F.; Chojnowska, K.; Tintignac, L. A.; Mittal, N.; Zimmerli, C. E.; Glass, D. J.; Zavolan, M.; Ham, D. J.; Ruegg, M. A.

doi:10.1101/2021.11.16.468773

bioRxiv · 10.1101/2021.11.16.468773

Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

Kaiser, M. S.·Milan, G.·Lin, S.·Oliveri, F.·Chojnowska, K.·Tintignac, L. A.·Mittal, N.·Zimmerli, C. E.·Glass, D. J.·Zavolan, M.·Ham, D. J.·Ruegg, M. A.

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Abstract

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.

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Kaiser, M. S., Milan, G., Lin, S., Oliveri, F., Chojnowska, K., Tintignac, L. A., Mittal, N., Zimmerli, C. E., Glass, D. J., Zavolan, M., Ham, D. J., Ruegg, M. A.. 2021-11-19. Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis. https://doi.org/10.1101/2021.11.16.468773

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