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

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.

H2A.Z is dispensable for both basal and activated transcription in post-mitotic mouse muscles

“…These cells represent less than 20% of the muscle tissue but they are sufficiently represented to generate detectable expression of inactivated genes in muscle extracts. This is true for H2A.Z dKO muscles and for all muscle specific inactivation of ubiquitously expressed genes [38][39][40][41][42] . By allowing to visualize individual nuclei, immunofluorescence was therefore the best way to evaluate the efficiency of H2A.Z knock-down in muscle fibers.…”

Regenerating motor neurons prime muscle stem cells for myogenesis by enhancing protein synthesis and mitochondrial bioenergetics

“…In support of this notion, a recent study revealed that denervation-induced alterations in Ca 2+ signaling in muscle signals HDAC4 to shuttle between the nucleus and cytoplasm. HDAC4 has been shown to promote MuSC proliferation (Marroncelli et al, 2018) and co-localize with sub-synaptic myonuclei after denervation (Castets et al, 2019). Whether similar Ca 2+ -mediated mechanisms of myogenesis modulate MuSCs after denervation is unclear, but the calmodulin (CaM)-dependent kinase (CaMK), which prevents the formation of HDAC-myocyte enhancer factor 2 (HDAC-MEF2) complexes, releases MEF2 from HDAC4 and HDAC5 and promotes myogenic transcriptional activity in response to Ca 2+ activity.…”

Obestatin signaling controls Schwann cells and axonal transport to counteract neuromuscular synaptic loss in skeletal muscle

“…Importantly, we unveil a determinant function of obestatin signaling in neuromuscular integrity that allow to regulate muscle homeostasis via speci c activation of the Akt-mTORC1 axis. Although mTORC1 becomes activated in control muscle, constant activation of mTORC1 triggers feedback inhibition of Akt [80]. This fact determines a key difference between groups that establishes the activity of the ubiquitin/proteasome system by regulation of E3 ubiquitin-ligases under the control of HDAC4/myogenin and FoxO transcription factors [80][81][82][83][84].…”

“…Although mTORC1 becomes activated in control muscle, constant activation of mTORC1 triggers feedback inhibition of Akt [80]. This fact determines a key difference between groups that establishes the activity of the ubiquitin/proteasome system by regulation of E3 ubiquitin-ligases under the control of HDAC4/myogenin and FoxO transcription factors [80][81][82][83][84]. Interestingly, the activation of S6 alone, or lack of mTOR signaling to 4E-BP1 only, is not su cient to increase muscle mass in control muscle.…”