Genetic deletion of microRNA biogenesis in muscle cells reveals a hierarchical non-clustered network that controls focal adhesion signaling during muscle regeneration.
Animals
Cell Differentiation
/ genetics
Cell Line
Focal Adhesions
/ genetics
Gene Deletion
Gene Regulatory Networks
/ genetics
Humans
Mice
Mice, Inbred C57BL
MicroRNAs
/ biosynthesis
Muscle Development
/ genetics
Muscle Fibers, Skeletal
/ metabolism
Muscle, Skeletal
/ metabolism
Myoblasts
/ cytology
Regeneration
/ genetics
Signal Transduction
/ genetics
Focal adhesion signalling
Glycogen synthesis
Primary human muscle cells
Skeletal muscle regeneration
microRNA network
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
27
09
2019
revised:
19
02
2020
accepted:
20
02
2020
pubmed:
3
4
2020
medline:
3
7
2021
entrez:
3
4
2020
Statut:
ppublish
Résumé
Decreased muscle mass is a major contributor to age-related morbidity, and strategies to improve muscle regeneration during ageing are urgently needed. Our aim was to identify the subset of relevant microRNAs (miRNAs) that partake in critical aspects of muscle cell differentiation, irrespective of computational predictions, genomic clustering or differential expression of the miRNAs. miRNA biogenesis was deleted in primary myoblasts using a tamoxifen-inducible CreLox system and combined with an add-back miRNA library screen. RNA-seq experiments, cellular signalling events, and glycogen synthesis, along with miRNA inhibitors, were performed in human primary myoblasts. Muscle regeneration in young and aged mice was assessed using the cardiotoxin (CTX) model. We identified a hierarchical non-clustered miRNA network consisting of highly (miR-29a), moderately (let-7) and mildly active (miR-125b, miR-199a, miR-221) miRNAs that cooperate by directly targeting members of the focal adhesion complex. Through RNA-seq experiments comparing single versus combinatorial inhibition of the miRNAs, we uncovered a fundamental feature of this network, that miRNA activity inversely correlates to miRNA cooperativity. During myoblast differentiation, combinatorial inhibition of the five miRNAs increased activation of focal adhesion kinase (FAK), AKT, and p38 mitogen-activated protein kinase (MAPK), and improved myotube formation and insulin-dependent glycogen synthesis. Moreover, antagonizing the miRNA network in vivo following CTX-induced muscle regeneration enhanced muscle mass and myofiber formation in young and aged mice. Our results provide novel insights into the dynamics of miRNA cooperativity and identify a miRNA network as therapeutic target for impaired focal adhesion signalling and muscle regeneration during ageing.
Identifiants
pubmed: 32240622
pii: S2212-8778(20)30040-5
doi: 10.1016/j.molmet.2020.02.010
pmc: PMC7139120
pii:
doi:
Substances chimiques
MicroRNAs
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100967Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.
Références
Chem Biol. 2014 Oct 23;21(10):1265-1270
pubmed: 25242288
Nat Med. 2014 Mar;20(3):265-71
pubmed: 24531379
Mol Cell Biol. 2000 Jun;20(11):3951-64
pubmed: 10805738
RNA. 2005 Mar;11(3):241-7
pubmed: 15701730
Best Pract Res Clin Endocrinol Metab. 2016 Oct;30(5):551-561
pubmed: 27923450
J Cachexia Sarcopenia Muscle. 2010 Sep;1(1):1-5
pubmed: 21475699
Dev Cell. 2009 Nov;17(5):662-73
pubmed: 19922871
Proc Natl Acad Sci U S A. 1983 Feb;80(4):1008-12
pubmed: 6405378
J Biol Chem. 1996 Oct 18;271(42):26329-34
pubmed: 8824286
Nucleic Acids Res. 2007;35(7):2333-42
pubmed: 17389647
Nucleic Acids Res. 2014 Jul;42(12):7539-52
pubmed: 24875477
Elife. 2020 Jan 24;9:
pubmed: 31976858
Nature. 2012 Feb 23;482(7386):524-8
pubmed: 22358842
PLoS One. 2009 Oct 27;4(10):e7607
pubmed: 19859555
Nature. 2009 Jul 30;460(7255):627-31
pubmed: 19554048
J Muscle Res Cell Motil. 2015 Oct;36(4-5):305-15
pubmed: 26142360
Physiol Rep. 2015 Aug;3(8):
pubmed: 26290530
Nature. 2012 Oct 18;490(7420):355-60
pubmed: 23023126
Diabetes. 2008 Feb;57(2):432-9
pubmed: 18057090
Endocrinology. 2006 Jul;147(7):3333-43
pubmed: 16574795
Mol Cell. 2007 Jul 6;27(1):91-105
pubmed: 17612493
Cell Death Differ. 2013 Sep;20(9):1194-208
pubmed: 23764775
Cell Signal. 2011 Jul;23(7):1162-9
pubmed: 21397010
PLoS One. 2013 Aug 21;8(8):e71927
pubmed: 23991007
Nature. 2005 Dec 1;438(7068):685-9
pubmed: 16258535
Cell Prolif. 2002 Jun;35(3):131-42
pubmed: 12027949
Cell Metab. 2006 Jul;4(1):9-12
pubmed: 16814728
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17016-21
pubmed: 17942673
N Engl J Med. 2002 Mar 14;346(11):793-801
pubmed: 11893790
Am J Epidemiol. 1998 Apr 15;147(8):755-63
pubmed: 9554417
Nucleic Acids Res. 2005 May 12;33(8):2697-706
pubmed: 15891114
Int J Oncol. 2012 Sep;41(3):1005-12
pubmed: 22766763
Obesity (Silver Spring). 2016 May;24(5):1097-105
pubmed: 27030318
Cell. 2011 Sep 30;147(1):81-94
pubmed: 21962509
Development. 2016 Nov 15;143(22):4137-4148
pubmed: 27707793
BMC Cell Biol. 2008 Sep 04;9:48
pubmed: 18771597
Mol Cell. 2014 Nov 6;56(3):347-59
pubmed: 25449132
Biochem Biophys Res Commun. 2006 Oct 13;349(1):59-68
pubmed: 16934749
Genome Res. 2015 Nov;25(11):1680-91
pubmed: 26232411
Crit Rev Biochem Mol Biol. 2013 Jan-Feb;48(1):51-68
pubmed: 23163351
Science. 2015 Apr 3;348(6230):128-32
pubmed: 25838385
J Physiol. 2008 Aug 15;586(16):3825-37
pubmed: 18587052
Dev Biol. 2006 May 1;293(1):38-52
pubmed: 16533505
Am J Physiol. 1999 Jul;277(1):C152-62
pubmed: 10409118
Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4255-60
pubmed: 23440203
Mol Cell. 2007 Oct 26;28(2):200-13
pubmed: 17964260
J Clin Invest. 2011 Aug;121(8):3258-68
pubmed: 21737882
Nucleic Acids Res. 2015 Sep 3;43(15):7173-88
pubmed: 26170234
EMBO J. 2009 Sep 2;28(17):2568-82
pubmed: 19661918
Diabetes. 2000 Jun;49(6):992-8
pubmed: 10866052
Cancer Res. 2016 Jul 1;76(13):3666-70
pubmed: 27325641
Cell. 2009 Jan 23;136(2):215-33
pubmed: 19167326
Nat Rev Genet. 2011 Feb;12(2):99-110
pubmed: 21245828
Nat Med. 2015 Jun;21(6):619-27
pubmed: 25985365
Genesis. 2010 Jul;48(7):424-36
pubmed: 20641127
Am J Physiol Regul Integr Comp Physiol. 2005 Sep;289(3):R862-70
pubmed: 15890789
Int Orthop. 2011 Feb;35(2):165-71
pubmed: 21125270
Dev Biol. 2007 Nov 15;311(2):359-68
pubmed: 17936265
Pflugers Arch. 2015 Jun;467(6):1343-56
pubmed: 25070178
Nat Med. 2016 Aug;22(8):897-905
pubmed: 27376579
Stem Cells. 2016 Mar;34(3):768-80
pubmed: 26731484
Diabetologia. 2007 May;50(5):1058-69
pubmed: 17333113
J Cell Biol. 2011 Jan 10;192(1):69-81
pubmed: 21200031
EMBO Mol Med. 2009 Nov;1(8-9):381-91
pubmed: 20049743
Diabetologia. 2018 Feb;61(2):424-432
pubmed: 29022062
Exp Gerontol. 2018 Jun;106:28-38
pubmed: 29466693
Ann Surg. 1993 Sep;218(3):380-90; discussion 390-3
pubmed: 8373279
Mol Biol Cell. 2009 Jul;20(14):3422-35
pubmed: 19458188
J Cachexia Sarcopenia Muscle. 2016 Dec;7(5):604-614
pubmed: 27239416
N Engl J Med. 2014 Dec 4;371(23):2237-8
pubmed: 25470706
Nature. 2008 Sep 4;455(7209):64-71
pubmed: 18668037
Nat Genet. 2015 Jul;47(7):766-75
pubmed: 26029871
EMBO J. 2004 Jan 28;23(2):365-75
pubmed: 14739931
Acta Biochim Biophys Sin (Shanghai). 2015 May;47(5):355-61
pubmed: 25918183
Cell Rep. 2015 Sep 29;12(12):1960-7
pubmed: 26365191
J Nutr. 1997 May;127(5 Suppl):990S-991S
pubmed: 9164280
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21075-80
pubmed: 22160727
Compr Physiol. 2016 Jun 13;6(3):1279-94
pubmed: 27347893