ERK1/2 inhibition promotes robust myotube growth via CaMKII activation resulting in myoblast-to-myotube fusion.
Actins
/ metabolism
Animals
Calcium
/ metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2
/ metabolism
Cell Differentiation
/ drug effects
Cell Fusion
Cell Proliferation
/ drug effects
Enzyme Activation
/ drug effects
Extracellular Signal-Regulated MAP Kinases
/ antagonists & inhibitors
Mice, Inbred C57BL
Models, Biological
Muscle Fibers, Skeletal
/ cytology
Muscle Proteins
/ metabolism
Myoblasts
/ cytology
Protein Binding
Protein Kinase Inhibitors
/ pharmacology
Receptors, Retinoic Acid
/ metabolism
Signal Transduction
rac1 GTP-Binding Protein
/ metabolism
CaMKII
ERK1/2
calcium
cultivated meat
muscle regeneration
myoblast fusion
myogenesis
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
20 12 2021
20 12 2021
Historique:
received:
08
12
2020
revised:
28
07
2021
accepted:
21
11
2021
entrez:
21
12
2021
pubmed:
22
12
2021
medline:
13
1
2022
Statut:
ppublish
Résumé
Myoblast fusion is essential for muscle development and regeneration. Yet, it remains poorly understood how mononucleated myoblasts fuse with preexisting fibers. We demonstrate that ERK1/2 inhibition (ERKi) induces robust differentiation and fusion of primary mouse myoblasts through a linear pathway involving RXR, ryanodine receptors, and calcium-dependent activation of CaMKII in nascent myotubes. CaMKII activation results in myotube growth via fusion with mononucleated myoblasts at a fusogenic synapse. Mechanistically, CaMKII interacts with and regulates MYMK and Rac1, and CaMKIIδ/γ knockout mice exhibit smaller regenerated myofibers following injury. In addition, the expression of a dominant negative CaMKII inhibits the formation of large multinucleated myotubes. Finally, we demonstrate the evolutionary conservation of the pathway in chicken myoblasts. We conclude that ERK1/2 represses a signaling cascade leading to CaMKII-mediated fusion of myoblasts to myotubes, providing an attractive target for the cultivated meat industry and regenerative medicine.
Identifiants
pubmed: 34932950
pii: S1534-5807(21)00946-1
doi: 10.1016/j.devcel.2021.11.022
pmc: PMC8693863
pii:
doi:
Substances chimiques
Actins
0
Muscle Proteins
0
Protein Kinase Inhibitors
0
Receptors, Retinoic Acid
0
Calcium-Calmodulin-Dependent Protein Kinase Type 2
EC 2.7.11.17
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
rac1 GTP-Binding Protein
EC 3.6.5.2
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3349-3363.e6Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests T.E, E.T., and O.A. hold a patent related to the scientific findings presented in this manuscript and are the founders of ProFuse Technology. T.E. is the CTO and E.T. and O.A. are the scientific advisors of ProFuse Technology.
Références
Development. 2014 Jul;141(13):2611-20
pubmed: 24924195
Front Cell Dev Biol. 2016 Aug 30;4:91
pubmed: 27626031
J Biol Chem. 1997 Aug 8;272(32):19808-13
pubmed: 9242641
Dev Cell. 2009 Jun;16(6):822-32
pubmed: 19531353
Skelet Muscle. 2019 Jan 8;9(1):2
pubmed: 30621783
PLoS One. 2012;7(9):e44358
pubmed: 22970203
Dev Cell. 2018 Sep 24;46(6):767-780.e7
pubmed: 30197239
J Cell Biol. 2003 Mar 17;160(6):919-28
pubmed: 12629052
Dev Biol. 1977 Jul 15;58(2):328-38
pubmed: 885292
J Cell Sci. 2019 Sep 16;132(18):
pubmed: 31527149
Sci Transl Med. 2018 Jul 4;10(448):
pubmed: 29973406
Dev Biol. 1978 Oct;66(2):294-307
pubmed: 100355
Nat Commun. 2021 Feb 2;12(1):750
pubmed: 33531466
Compr Rev Food Sci Food Saf. 2021 Jan;20(1):429-457
pubmed: 33443788
Physiol Rev. 2013 Jul;93(3):993-1017
pubmed: 23899560
Genomics Proteomics Bioinformatics. 2020 Feb;18(1):72-80
pubmed: 32200042
Endocrinology. 2004 Nov;145(11):4991-6
pubmed: 15489316
EMBO Rep. 2001 Sep;2(9):829-34
pubmed: 11520859
Int J Mol Sci. 2020 Feb 04;21(3):
pubmed: 32033037
Oncogene. 1998 Jul 2;16(26):3369-78
pubmed: 9692544
Circulation. 2014 Oct 7;130(15):1262-73
pubmed: 25124496
EMBO J. 1997 Dec 1;16(23):6956-63
pubmed: 9384575
Mol Cell Biol. 1996 Jan;16(1):29-36
pubmed: 8524307
J Cell Biol. 1972 May;53(2):348-64
pubmed: 4554365
J Cell Physiol. 2001 Jan;186(1):104-15
pubmed: 11147804
Cell Mol Life Sci. 2019 Jul;76(13):2559-2570
pubmed: 30976839
Sci Signal. 2013 Apr 23;6(272):re2
pubmed: 23612709
Science. 2005 Apr 15;308(5720):369-73
pubmed: 15831748
Development. 2012 Feb;139(4):641-56
pubmed: 22274696
Development. 2017 Jun 15;144(12):2104-2122
pubmed: 28634270
J Biol Chem. 2011 Jul 29;286(30):26806-12
pubmed: 21653693
Exp Cell Res. 1969 Nov;58(1):163-7
pubmed: 5404063
Mol Endocrinol. 1997 Dec;11(13):2038-47
pubmed: 9415407
Semin Cell Dev Biol. 2017 Dec;72:10-18
pubmed: 29127045
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2116-21
pubmed: 26858401
Dev Dyn. 2017 May;246(5):359-367
pubmed: 28249356
Skelet Muscle. 2011 Sep 08;1:29
pubmed: 21902831
Biochem J. 1996 May 15;316 ( Pt 1):19-23
pubmed: 8645204
Cell. 2003 May 16;113(4):483-94
pubmed: 12757709
Dev Cell. 2016 Aug 8;38(3):291-304
pubmed: 27505416
Cell Calcium. 1996 May;19(5):365-74
pubmed: 8793176
Semin Cell Dev Biol. 2020 Aug;104:81-92
pubmed: 32063453
Mol Biol Cell. 2007 Dec;18(12):5024-33
pubmed: 17942605
J Biol Chem. 2008 Feb 22;283(8):4943-56
pubmed: 18003614
Curr Top Membr. 2011;68:235-58
pubmed: 21771502
Cell Death Differ. 2018 Sep;25(9):1581-1597
pubmed: 29449644
Development. 2001 Dec;128(24):5061-73
pubmed: 11748142
Annu Rev Genet. 2019 Dec 3;53:67-91
pubmed: 31283358
Mol Cell Biol. 2000 Jun;20(11):3951-64
pubmed: 10805738
Commun Biol. 2020 Jun 18;3(1):315
pubmed: 32555436
FASEB J. 2015 May;29(5):2137-49
pubmed: 25678623
Oncogene. 1998 Jan 15;16(2):273-82
pubmed: 9464546
Nat Protoc. 2007;2(5):1236-47
pubmed: 17546019
Dev Biol. 2010 May 1;341(1):66-83
pubmed: 19932206
Nature. 2013 Jul 18;499(7458):301-5
pubmed: 23868259
Development. 2017 Dec 15;144(24):4481-4495
pubmed: 29254991
Development. 2011 Sep;138(17):3625-37
pubmed: 21828091
Science. 2011 Apr 29;332(6029):589-92
pubmed: 21436398
Nat Methods. 2021 Jan;18(1):100-106
pubmed: 33318659
Genes Dev. 2014 Aug 1;28(15):1641-6
pubmed: 25085416
Nat Commun. 2017 Jun 01;8:15665
pubmed: 28569755
BMC Physiol. 2014 Dec 17;14:7
pubmed: 25515219
Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):8935-40
pubmed: 19443691
Dev Cell. 2015 Mar 9;32(5):561-73
pubmed: 25684354
Nat Commun. 2021 Feb 2;12(1):749
pubmed: 33531476
Science. 1997 Nov 14;278(5341):1288-91
pubmed: 9360925
Am J Physiol Endocrinol Metab. 2012 Aug 1;303(3):E322-31
pubmed: 22496345
Differentiation. 2009 Nov;78(4):195-204
pubmed: 19560855
Genes Dev. 1997 Aug 15;11(16):2040-51
pubmed: 9284044
Dev Cell. 2011 Feb 15;20(2):192-205
pubmed: 21316587
J Cell Sci. 2003 Apr 15;116(Pt 8):1589-97
pubmed: 12640042
J Physiol. 2007 Sep 1;583(Pt 2):785-95
pubmed: 17627985
Mol Cell Biol. 2003 Sep;23(17):6037-48
pubmed: 12917328
Dev Dyn. 2009 Jun;238(6):1513-25
pubmed: 19418445
J Biol Chem. 2008 Aug 22;283(34):23224-34
pubmed: 18552402
Dev Biol. 2007 Sep 1;309(1):113-25
pubmed: 17662708
Cancer Discov. 2013 Jul;3(7):719-21
pubmed: 23847348
Cancer Res. 2001 Oct 15;61(20):7675-82
pubmed: 11606411
Cancer Res. 2006 Feb 1;66(3):1320-6
pubmed: 16452185
Exp Cell Res. 1999 Jul 10;250(1):10-21
pubmed: 10388517
Cancer Discov. 2013 Jul;3(7):742-50
pubmed: 23614898
Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):870-4
pubmed: 7846069
Semin Cell Dev Biol. 2016 Dec;60:112-120
pubmed: 27423913
Mol Endocrinol. 1998 Dec;12(12):1870-8
pubmed: 9849961
Nat Methods. 2008 Jul;5(7):605-7
pubmed: 18536722
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Cell. 2000 May 12;101(4):365-76
pubmed: 10830164
Science. 2013 Apr 19;340(6130):359-63
pubmed: 23470732
Methods Mol Biol. 2017;1560:179-188
pubmed: 28155153
Redox Biol. 2018 Apr;14:59-71
pubmed: 28869833
Biomed Res Int. 2014;2014:943806
pubmed: 25054156