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

Perrine Castets (), Nathalie Rion, Marine Théodore, Denis Falcetta, Shuo Lin, Markus Reischl, Franziska Wild, Laurent Guérard, Christopher Eickhorst, Marielle Brockhoff, Maitea Guridi, Chikwendu Ibebunjo, Joseph Cruz, Michael Sinnreich, Rüdiger Rudolf, David J. Glass and Markus A. Rüegg ()
Additional contact information
Perrine Castets: Biozentrum, University of Basel
Nathalie Rion: Biozentrum, University of Basel
Marine Théodore: Biozentrum, University of Basel
Denis Falcetta: Biozentrum, University of Basel
Shuo Lin: Biozentrum, University of Basel
Markus Reischl: Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology
Franziska Wild: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology
Laurent Guérard: University of Basel
Christopher Eickhorst: Biozentrum, University of Basel
Marielle Brockhoff: University Hospital Basel
Maitea Guridi: Biozentrum, University of Basel
Chikwendu Ibebunjo: Novartis Institutes for Biomedical Research
Joseph Cruz: Novartis Institutes for Biomedical Research
Michael Sinnreich: University Hospital Basel
Rüdiger Rudolf: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology
David J. Glass: Novartis Institutes for Biomedical Research
Markus A. Rüegg: Biozentrum, University of Basel

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11227-4

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