PMID- 36233091
OWN - NLM
STAT- MEDLINE
DCOM- 20221017
LR  - 20221019
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 19
DP  - 2022 Oct 4
TI  - Neuronal Agrin Promotes Proliferation of Primary Human Myoblasts in an 
      Age-Dependent Manner.
LID - 10.3390/ijms231911784 [doi]
LID - 11784
AB  - Neuronal agrin, a heparan sulphate proteoglycan secreted by the alpha-motor neurons, 
      promotes the formation and maintenance of the neuromuscular junction by binding 
      to Lrp4 and activating muscle-specific kinase (MuSK). Neuronal agrin also 
      promotes myogenesis by enhancing differentiation and maturation of myotubes, but 
      its effect on proliferating human myoblasts, which are often considered to be 
      unresponsive to agrin, remains unclear. Using primary human myoblasts, we 
      determined that neuronal agrin induced transient dephosphorylation of ERK1/2, 
      while c-Abl, STAT3, and focal adhesion kinase were unresponsive. Gene silencing 
      of Lrp4 and MuSK markedly reduced the BrdU incorporation, suggesting the 
      functional importance of the Lrp4/MuSK complex for myoblast proliferation. Acute 
      and chronic treatments with neuronal agrin increased the proliferation of human 
      myoblasts in old donors, but they did not affect the proliferation of myoblasts 
      in young donors. The C-terminal fragment of agrin which lacks the Lrp4-binding 
      site and cannot activate MuSK had a similar age-dependent effect, indicating that 
      the age-dependent signalling pathways activated by neuronal agrin involve the 
      Lrp4/MuSK receptor complex as well as an Lrp4/MuSK-independent pathway which 
      remained unknown. Collectively, our results highlight an age-dependent role for 
      neuronal agrin in promoting the proliferation of human myoblasts.
FAU - Gros, Katarina
AU  - Gros K
AD  - Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 
      Ljubljana, Slovenia.
FAU - Matkovic, Urska
AU  - Matkovic U
AD  - Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 
      Ljubljana, Slovenia.
FAU - Parato, Giulia
AU  - Parato G
AD  - Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
AD  - The B.R.A.I.N. Centre for Neuroscience, University of Trieste, 34127 Trieste, 
      Italy.
FAU - Mis, Katarina
AU  - Mis K
AD  - Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 
      Ljubljana, Slovenia.
FAU - Luin, Elisa
AU  - Luin E
AD  - Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
AD  - The B.R.A.I.N. Centre for Neuroscience, University of Trieste, 34127 Trieste, 
      Italy.
FAU - Bernareggi, Annalisa
AU  - Bernareggi A
AUID- ORCID: 0000-0002-7007-8466
AD  - Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
AD  - The B.R.A.I.N. Centre for Neuroscience, University of Trieste, 34127 Trieste, 
      Italy.
FAU - Sciancalepore, Marina
AU  - Sciancalepore M
AUID- ORCID: 0000-0002-6872-9477
AD  - Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
AD  - The B.R.A.I.N. Centre for Neuroscience, University of Trieste, 34127 Trieste, 
      Italy.
FAU - Mars, Tomaz
AU  - Mars T
AD  - Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 
      Ljubljana, Slovenia.
FAU - Lorenzon, Paola
AU  - Lorenzon P
AUID- ORCID: 0000-0002-9526-6471
AD  - Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
AD  - The B.R.A.I.N. Centre for Neuroscience, University of Trieste, 34127 Trieste, 
      Italy.
FAU - Pirkmajer, Sergej
AU  - Pirkmajer S
AUID- ORCID: 0000-0003-1459-6936
AD  - Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 
      Ljubljana, Slovenia.
LA  - eng
GR  - P3-0043/Slovenian Research Agency/
GR  - J7-3153/Slovenian Research Agency/
GR  - MR (Katarina Gros)/Slovenian Research Agency/
GR  - BI-IT/11-13-009/Slovenian Research Agency/
GR  - Cofin 2010-2011/Ministry of Education, Universities and Research/
GR  - FRA2013/University of Trieste/
GR  - Fondazione Benefica Kathleen Foreman Casali/
PT  - Journal Article
DEP - 20221004
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Agrin)
RN  - 0 (Heparan Sulfate Proteoglycans)
RN  - 0 (LDL-Receptor Related Proteins)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
RN  - G34N38R2N1 (Bromodeoxyuridine)
SB  - IM
MH  - *Age Factors
MH  - *Agrin/genetics/metabolism
MH  - Bromodeoxyuridine
MH  - Cell Proliferation
MH  - Focal Adhesion Protein-Tyrosine Kinases
MH  - Heparan Sulfate Proteoglycans
MH  - Humans
MH  - *LDL-Receptor Related Proteins/metabolism
MH  - Motor Neurons/metabolism
MH  - Myoblasts/metabolism
MH  - Receptor Protein-Tyrosine Kinases/genetics/metabolism
PMC - PMC9570459
OTO - NOTNLM
OT  - Lrp4
OT  - MuSK
OT  - agrin
OT  - myoblast proliferation
OT  - skeletal muscle regeneration
COIS- The authors declare no conflict of interest.
EDAT- 2022/10/15 06:00
MHDA- 2022/10/18 06:00
PMCR- 2022/10/04
CRDT- 2022/10/14 02:12
PHST- 2022/08/11 00:00 [received]
PHST- 2022/09/06 00:00 [revised]
PHST- 2022/09/22 00:00 [accepted]
PHST- 2022/10/14 02:12 [entrez]
PHST- 2022/10/15 06:00 [pubmed]
PHST- 2022/10/18 06:00 [medline]
PHST- 2022/10/04 00:00 [pmc-release]
AID - ijms231911784 [pii]
AID - ijms-23-11784 [pii]
AID - 10.3390/ijms231911784 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Oct 4;23(19):11784. doi: 10.3390/ijms231911784.