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

Rion, Nathalie
Théodore, Marine
Falcetta, Denis
Lin, Shuo
Reischl, Markus
Wild, Franziska
Guérard, Laurent
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Published in Nature Communications. 2019, vol. 10, no. 1, p. 3187
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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Research group Muscle et jonction neuromusculaire (1007)
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CASTETS, Perrine et al. mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4. In: Nature Communications, 2019, vol. 10, n° 1, p. 3187. doi: 10.1038/s41467-019-11227-4

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Deposited on : 2019-10-23

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