PMID- 37961580
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231201
DP  - 2023 Oct 29
TI  - The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle 
      excitability.
LID - 2023.10.24.563837 [pii]
LID - 10.1101/2023.10.24.563837 [doi]
AB  - The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle 
      contraction. Broadly considered, the function of the NMJ is to transduce a nerve 
      action potential into a muscle fiber action potential (MFAP). Efficient 
      information transfer requires both cholinergic signaling, responsible for the 
      generation of endplate potentials (EPPs), and excitation, the activation of 
      postsynaptic voltage-gated sodium channels (Nav1.4) to trigger MFAPs. In contrast 
      to the cholinergic apparatus, the signaling pathways that organize Nav1.4 and 
      muscle fiber excitability are poorly characterized. Muscle-specific kinase 
      (MuSK), in addition to its Ig1 domain-dependent role as an agrin-LRP4 receptor, 
      is also a BMP co-receptor that binds BMPs via its Ig3 domain and shapes 
      BMP-induced signaling and transcriptional output. Here we probed the function of 
      the MuSK-BMP pathway at the NMJ using mice lacking the MuSK Ig3 domain 
      ('DeltaIg3-MuSK'). Synapses formed normally in DeltaIg3-MuSK animals, but the 
      postsynaptic apparatus was fragmented from the first weeks of life. Anatomical 
      denervation was not observed at any age examined. Moreover, spontaneous and 
      nerve-evoked acetylcholine release, AChR density, and endplate currents were 
      comparable to WT. However, trains of nerve-evoked MFAPs in DeltaIg3-MuSK muscle were 
      abnormal as revealed by increased jitter and blocking in single fiber 
      electromyography. Further, nerve-evoked compound muscle action potentials 
      (CMAPs), as well as twitch and tetanic muscle torque force production, were also 
      diminished. Finally, Nav1.4 levels were reduced at DeltaIg3-MuSK synapses but not at 
      the extrajunctional sarcolemma, indicating that the observed excitability defects 
      are the result of impaired localization of this voltage-gated ion channel at the 
      NMJ. We propose that MuSK plays two distinct roles at the NMJ: as an agrin-LRP4 
      receptor necessary for establishing and maintaining cholinergic signaling, and as 
      a BMP co-receptor required for maintaining proper Nav1.4 density, nerve-evoked 
      muscle excitability and force production. The MuSK-BMP pathway thus emerges as a 
      target for modulating excitability and functional innervation, which are 
      defective in conditions such as congenital myasthenic syndromes and aging.
FAU - Fish, L A
AU  - Fish LA
AUID- ORCID: 0000-0001-6437-777X
AD  - Neuroscience Graduate Program, Brown University, Providence, RI 02912.
AD  - Carney Institute for Brain Science, Brown University, Providence, RI 02912.
FAU - Ewing, M D
AU  - Ewing MD
AUID- ORCID: 0000-0002-7580-3276
AD  - Department of Neuroscience, Brown University, Providence, RI 02912.
FAU - Jaime, D
AU  - Jaime D
AUID- ORCID: 0000-0002-8903-9168
AD  - Department of Molecular Biology, Cell Biology, and Biochemistry, Brown 
      University, Providence, RI 02912.
FAU - Rich, K A
AU  - Rich KA
AUID- ORCID: 0000-0002-0027-0313
AD  - Neuroscience Graduate Program, Ohio State University, Columbus, OH 43210.
FAU - Xi, C
AU  - Xi C
AD  - Biotechnology Graduate Program, Brown University, Brown University, Providence, 
      RI 02912.
FAU - Wang, X
AU  - Wang X
AD  - Department of Neuroscience Cell Biology and Physiology, Wright State University, 
      Dayton, OH 45435.
FAU - Feder, R E
AU  - Feder RE
AD  - Department of Neuroscience, Brown University, Providence, RI 02912.
FAU - Wharton, K A
AU  - Wharton KA
AUID- ORCID: 0000-0001-9625-4336
AD  - Department of Molecular Biology, Cell Biology, and Biochemistry, Brown 
      University, Providence, RI 02912.
FAU - Rich, M M
AU  - Rich MM
AD  - Department of Neuroscience Cell Biology and Physiology, Wright State University, 
      Dayton, OH 45435.
FAU - Arnold, W D
AU  - Arnold WD
AD  - NextGen Precision Health Institute, University of Missouri, Columbia, MO 62511.
FAU - Fallon, J R
AU  - Fallon JR
AUID- ORCID: 0000-0001-6673-4451
AD  - Carney Institute for Brain Science, Brown University, Providence, RI 02912.
AD  - Department of Neuroscience, Brown University, Providence, RI 02912.
LA  - eng
GR  - R41 AG073144/AG/NIA NIH HHS/United States
GR  - T32 MH020068/MH/NIMH NIH HHS/United States
GR  - R01 AR074985/AR/NIAMS NIH HHS/United States
GR  - T32 AG041688/AG/NIA NIH HHS/United States
GR  - U01 NS064295/NS/NINDS NIH HHS/United States
GR  - S10 OD025181/OD/NIH HHS/United States
GR  - R01 GM068118/GM/NIGMS NIH HHS/United States
GR  - R21 AG073743/AG/NIA NIH HHS/United States
GR  - R25 GM083270/GM/NIGMS NIH HHS/United States
GR  - R21 NS112743/NS/NINDS NIH HHS/United States
GR  - F99 AG079815/AG/NIA NIH HHS/United States
PT  - Preprint
DEP - 20231029
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10634800
COIS- Conflict of interest: LAF, DJ and JRF are co-inventors on patents to Brown 
      University regarding the MuSK-BMP pathway. JRF is a co-founder of Bolden 
      Therapeutics, to which these patents are licensed.
EDAT- 2023/11/14 06:42
MHDA- 2023/11/14 06:43
PMCR- 2023/11/09
CRDT- 2023/11/14 04:00
PHST- 2023/11/14 06:42 [pubmed]
PHST- 2023/11/14 06:43 [medline]
PHST- 2023/11/14 04:00 [entrez]
PHST- 2023/11/09 00:00 [pmc-release]
AID - 2023.10.24.563837 [pii]
AID - 10.1101/2023.10.24.563837 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Oct 29:2023.10.24.563837. doi: 
      10.1101/2023.10.24.563837.