Small-molecule-mediated chemical knock-down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure.
Animals
Cell Line
Chronic Disease
Diaphragm
/ drug effects
Echocardiography
Female
Heart Failure
/ complications
Humans
Mice
Mitochondria
/ drug effects
Muscle Contraction
/ drug effects
Muscle Proteins
/ antagonists & inhibitors
Proteomics
/ methods
Tripartite Motif Proteins
/ antagonists & inhibitors
Ubiquitin-Protein Ligases
/ antagonists & inhibitors
Cardiac cachexia
Chronic heart failure
Diaphragm
Mitochondrial metabolism
MuRF1
Muscle wasting
Journal
Journal of cachexia, sarcopenia and muscle
ISSN: 2190-6009
Titre abrégé: J Cachexia Sarcopenia Muscle
Pays: Germany
ID NLM: 101552883
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
29
11
2018
revised:
15
04
2019
accepted:
17
04
2019
pubmed:
30
5
2019
medline:
21
7
2020
entrez:
30
5
2019
Statut:
ppublish
Résumé
Chronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small-molecule inhibitor of MuRF1 in treating CHF-induced diaphragm myopathy and loss of contractile function. Myocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham-operated animals (sham) served as controls. One week post-left anterior descending coronary artery ligation animals were randomized into two groups-one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946-a recently described MuRF1-interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed. Chronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by ~20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P < 0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects on the diaphragm: contractile function was protected, while mitochondrial enzyme activity and up-regulation of the MuRF1 and MuRF2 was attenuated after infarct. Our murine CHF model presented with diaphragm fibre atrophy, impaired contractile function, and reduced mitochondrial enzyme activities. Compound ID#704946 rescued from this partially, possibly by targeting MuRF1/MuRF2. However, at this stage of our study, we refrain to claim specific mechanism(s) and targets of compound ID#704946, because the nature of changes after 12 weeks of feeding is likely to be complex and is not necessarily caused by direct mechanistic effects.
Sections du résumé
BACKGROUND
Chronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small-molecule inhibitor of MuRF1 in treating CHF-induced diaphragm myopathy and loss of contractile function.
METHODS
Myocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham-operated animals (sham) served as controls. One week post-left anterior descending coronary artery ligation animals were randomized into two groups-one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946-a recently described MuRF1-interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed.
RESULTS
Chronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by ~20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P < 0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects on the diaphragm: contractile function was protected, while mitochondrial enzyme activity and up-regulation of the MuRF1 and MuRF2 was attenuated after infarct.
CONCLUSIONS
Our murine CHF model presented with diaphragm fibre atrophy, impaired contractile function, and reduced mitochondrial enzyme activities. Compound ID#704946 rescued from this partially, possibly by targeting MuRF1/MuRF2. However, at this stage of our study, we refrain to claim specific mechanism(s) and targets of compound ID#704946, because the nature of changes after 12 weeks of feeding is likely to be complex and is not necessarily caused by direct mechanistic effects.
Identifiants
pubmed: 31140761
doi: 10.1002/jcsm.12448
pmc: PMC6818456
doi:
Substances chimiques
Muscle Proteins
0
TRIM55 protein, human
0
Tripartite Motif Proteins
0
TRIM63 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1102-1115Subventions
Organisme : Wilhelm Müller Foundation
Pays : International
Organisme : AFBS
Pays : International
Organisme : European Union Horizon 2020
ID : 645648
Pays : International
Organisme : Fondation Leducq
ID : 13CVD04
Pays : International
Informations de copyright
© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.
Références
Nat Methods. 2007 Mar;4(3):207-14
pubmed: 17327847
PLoS One. 2018 Jan 19;13(1):e0191318
pubmed: 29351340
J Cachexia Sarcopenia Muscle. 2019 Oct;10(5):1102-1115
pubmed: 31140761
J Physiol. 2011 Oct 1;589(Pt 19):4759-76
pubmed: 21807613
Nat Protoc. 2009;4(4):484-94
pubmed: 19300442
Am J Respir Crit Care Med. 1999 Aug;160(2):529-34
pubmed: 10430724
Nat Rev Drug Discov. 2015 Jan;14(1):58-74
pubmed: 25549588
Int J Cardiol. 2019 May 1;282:68-75
pubmed: 30765281
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Circ Heart Fail. 2016 Sep;9(9):
pubmed: 27609832
Am J Physiol Cell Physiol. 2003 Oct;285(4):C806-12
pubmed: 12773310
FASEB J. 2017 Jan;31(1):60-71
pubmed: 27650398
Eur Heart J. 2013 Feb;34(7):512-9
pubmed: 23178647
Muscle Nerve. 2011 May;43(5):708-16
pubmed: 21462205
J Appl Physiol (1985). 2015 Jan 1;118(1):11-9
pubmed: 25359720
Am J Respir Crit Care Med. 2013 Jul 15;188(2):213-9
pubmed: 23641946
Am J Respir Crit Care Med. 2017 Dec 15;196(12):1544-1558
pubmed: 28787181
J Biol Chem. 1976 Apr 10;251(7):2155-60
pubmed: 818082
Curr Heart Fail Rep. 2009 Jun;6(2):95-101
pubmed: 19486593
Genome Biol. 2014;15(12):550
pubmed: 25516281
FASEB J. 2004 Jan;18(1):39-51
pubmed: 14718385
J Mol Biol. 2008 Dec 5;384(1):48-59
pubmed: 18804115
Dis Model Mech. 2013 Jan;6(1):25-39
pubmed: 23268536
Nature. 2013 May 23;497(7450):451-7
pubmed: 23698443
BMC Musculoskelet Disord. 2011 Aug 15;12:185
pubmed: 21843349
PLoS One. 2018 Aug 1;13(8):e0200429
pubmed: 30067847
Am J Respir Crit Care Med. 2011 Feb 15;183(4):483-90
pubmed: 20833824
Physiol Rep. 2017 Aug;5(16):
pubmed: 28839114
J Mol Biol. 2005 Jul 22;350(4):713-22
pubmed: 15967462
J Cachexia Sarcopenia Muscle. 2017 Dec;8(6):1081-1083
pubmed: 29098794
Metabolism. 2013 Oct;62(10):1495-502
pubmed: 23866982
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Anesthesiology. 2014 Jul;121(1):115-26
pubmed: 24681580
IUBMB Life. 2012 Nov;64(11):901-10
pubmed: 23024034
Curr Opin Clin Nutr Metab Care. 2003 May;6(3):271-5
pubmed: 12690258
J Mol Biol. 2008 Jun 13;379(4):666-77
pubmed: 18468620
J Clin Oncol. 2013 Apr 20;31(12):1539-47
pubmed: 23530101
PLoS One. 2014 Jul 17;9(7):e102947
pubmed: 25032690
PLoS One. 2013 Apr 22;8(4):e62702
pubmed: 23614054
J Cachexia Sarcopenia Muscle. 2017 Dec;8(6):939-953
pubmed: 28887874
Int J Biochem Cell Biol. 2013 Oct;45(10):2121-9
pubmed: 23665154
Essays Biochem. 2005;41:173-86
pubmed: 16250905
Cell Biochem Biophys. 2011 Jun;60(1-2):113-8
pubmed: 21448668
Circ Res. 2007 Mar 2;100(4):456-9
pubmed: 17272810
Mol Cell Biochem. 1999 Nov;201(1-2):33-40
pubmed: 10630620
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Intensive Care Med. 2012 Apr;38(4):702-9
pubmed: 22327561
FASEB J. 2007 May;21(7):1383-92
pubmed: 17215480
J Mol Cell Cardiol. 2013 Feb;55:64-72
pubmed: 22902321
Circulation. 2012 Jun 5;125(22):2716-27
pubmed: 22565934
Science. 2001 Nov 23;294(5547):1704-8
pubmed: 11679633
J Cell Biol. 2009 Jun 15;185(6):1083-95
pubmed: 19506036
J Cachexia Sarcopenia Muscle. 2018 Feb;9(1):129-145
pubmed: 29271608
Am J Respir Crit Care Med. 2015 May 15;191(10):1126-38
pubmed: 25760684
Cell Metab. 2007 Nov;6(5):376-85
pubmed: 17983583
Eur J Heart Fail. 2015 Mar;17(3):263-72
pubmed: 25655080
J Cachexia Sarcopenia Muscle. 2015 Dec;6(4):381-90
pubmed: 26674018
J Cancer Res Clin Oncol. 2013 Jul;139(7):1105-15
pubmed: 23535871
J Physiol. 2014 Sep 1;592(17):3767-82
pubmed: 24951621
J Mol Histol. 2010 Feb;41(1):81-7
pubmed: 20349269
Am J Clin Nutr. 2007 Nov;86(5):1339-46
pubmed: 17991644
Biochim Biophys Acta. 1979 Aug 30;574(2):258-67
pubmed: 486511
J Gerontol A Biol Sci Med Sci. 2000 Mar;55(3):M168-73
pubmed: 10795731
Ann Clin Lab Sci. 1985 Jan-Feb;15(1):13-31
pubmed: 3882046
J Cachexia Sarcopenia Muscle. 2015 Sep;6(3):197-207
pubmed: 26401465
Med Sci Sports Exerc. 2016 Nov;48(11):2118-2124
pubmed: 27327028
J Nutr. 1999 Jan;129(1S Suppl):227S-237S
pubmed: 9915905
Am Rev Respir Dis. 1992 Aug;146(2):467-72
pubmed: 1489142
Am J Physiol Lung Cell Mol Physiol. 2009 Jun;296(6):L994-L1001
pubmed: 19376888
J Appl Physiol (1985). 2016 Apr 1;120(7):733-42
pubmed: 26846552