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Nat Commun. 2019 Jul 18;10(1):3187. doi: 10.1038/s41467-019-11227-4.

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

Author information

1
Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland. perrine.castets@unibas.ch.
2
Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland.
3
Neuromuscular Center, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland.
4
Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, 76344, Eggenstein-Leopoldshafen, Germany.
5
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344, Eggenstein-Leopoldshafen, Germany.
6
Institute of Molecular and Cell Biology, University of Applied Sciences Mannheim, Mannheim, Germany.
7
Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany.
8
Imaging Core Facility, Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland.
9
Novartis Institutes for Biomedical Research, Cambridge, USA.
10
Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland. markus-a.ruegg@unibas.ch.

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.

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