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mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4

Castets, Perrine and Rion, Nathalie and Théodore, Marine and Falcetta, Denis and Lin, Shuo and Reischl, Markus and Wild, Franziska and Guérard, Laurent and Eickhorst, Christopher and Brockhoff, Marielle and Guridi, Maitea and Ibebunjo, Chikwendu and Cruz, Joseph and Sinnreich, Michael and Rudolf, Rüdiger and Glass, David J. and Rüegg, Markus A.. (2019) mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4. Nature communications, 10 (1). p. 3187.

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Official URL: https://edoc.unibas.ch/71537/

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Abstract

Loss of innervation of skeletal muscle is a determinant event in several muscle diseases. Although several effectors have been identified, the pathways controlling the integrated muscle response to denervation remain largely unknown. Here, we demonstrate that PKB/Akt and mTORC1 play important roles in regulating muscle homeostasis and maintaining neuromuscular endplates after nerve injury. To allow dynamic changes in autophagy, mTORC1 activation must be tightly balanced following denervation. Acutely activating or inhibiting mTORC1 impairs autophagy regulation and alters homeostasis in denervated muscle. Importantly, PKB/Akt inhibition, conferred by sustained mTORC1 activation, abrogates denervation-induced synaptic remodeling and causes neuromuscular endplate degeneration. We establish that PKB/Akt activation promotes the nuclear import of HDAC4 and is thereby required for epigenetic changes and synaptic gene up-regulation upon denervation. Hence, our study unveils yet-unknown functions of PKB/Akt-mTORC1 signaling in the muscle response to nerve injury, with important implications for neuromuscular integrity in various pathological conditions.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Schwede)
05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Research
ISSN:2041-1723
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:30 Jul 2019 15:00
Deposited On:30 Jul 2019 14:59

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