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.
Background: Full-length dysferlin exceeds adeno-associated virus encapsulation capacity, requiring the generation of mini-dysferlin molecules. Results: By studying the modular dispensability of the dysferlin C2 domains regarding plasmalemmal repair and localization, functional mini-dysferlin constructs were designed. Conclusion: Mini-dysferlin constructs retained a similar capacity for plasmalemmal localization and repair as full-length dysferlin. Significance: These mini-dysferlins can now be used to study their therapeutic effect in animal models of dysferlinopathy.
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