The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle excitability.

Area of Science:

• Neuroscience
• Molecular Biology
• Muscle Physiology

Background:

• The neuromuscular junction (NMJ) is crucial for muscle contraction, relying on cholinergic signaling and muscle fiber excitability.
• While the cholinergic system is well-understood, the pathways governing muscle fiber excitability and Nav1.4 channel organization are less clear.
• Muscle-specific kinase (MuSK) acts as an agrin-LRP4 receptor and a BMP co-receptor, influencing signaling.

Approach:

• Investigated the role of the MuSK-BMP pathway at the NMJ using mice lacking the MuSK Ig3 domain (ΔIg3-MuSK).
• Assessed synapse formation, postsynaptic apparatus integrity, and neuromuscular transmission.
• Analyzed muscle fiber action potentials, compound muscle action potentials, muscle force, and Nav1.4 localization.

Key Points:

• ΔIg3-MuSK mice exhibited fragmented postsynaptic apparatus but normal synapse formation and cholinergic signaling.
• Muscle fiber excitability was impaired in ΔIg3-MuSK mice, showing increased jitter and blocking in single fiber electromyography.
• Reduced Nav1.4 channel levels at the NMJ, but not extrajunctionally, were observed in ΔIg3-MuSK mice.
• Muscle force production was diminished in ΔIg3-MuSK mice.

Conclusions:

• MuSK has dual roles: maintaining cholinergic signaling via agrin-LRP4 and ensuring Nav1.4 localization and excitability via BMP signaling.
• The MuSK-BMP pathway is essential for Nav1.4 density, nerve-evoked muscle excitability, and force production.
• This pathway is a potential therapeutic target for neuromuscular conditions like congenital myasthenic syndromes and aging.