Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
26 06 2021
26 06 2021
Historique:
received:
24
03
2021
revised:
26
04
2021
accepted:
29
04
2021
pubmed:
6
5
2021
medline:
8
4
2022
entrez:
5
5
2021
Statut:
ppublish
Résumé
ΔR4-R23/ΔCT micro-dystrophin (μDys) is a miniaturized version of dystrophin currently evaluated in a Duchenne muscular dystrophy (DMD) gene therapy trial to treat skeletal and cardiac muscle disease. In pre-clinical studies, μDys efficiently rescues cardiac histopathology, but only partially normalizes cardiac function. To gain insights into factors that may impact the cardiac therapeutic efficacy of μDys, we compared by mass spectrometry the composition of purified dystrophin and μDys protein complexes in the mouse heart. We report that compared to dystrophin, μDys has altered associations with α1- and β2-syntrophins, as well as cavins, a group of caveolae-associated signaling proteins. In particular, we found that membrane localization of cavin-1 and cavin-4 in cardiomyocytes requires dystrophin and is profoundly disrupted in the heart of mdx5cv mice, a model of DMD. Following cardiac stress/damage, membrane-associated cavin-4 recruits the signaling molecule ERK to caveolae, which activates key cardio-protective responses. Evaluation of ERK signaling revealed a profound inhibition, below physiological baseline, in the mdx5cv mouse heart. Expression of μDys in mdx5cv mice prevented the development of cardiac histopathology but did not rescue membrane localization of cavins nor did it normalize ERK signaling. Our study provides the first comparative analysis of purified protein complexes assembled in vivo by full-length dystrophin and a therapeutic micro-dystrophin construct. This has revealed disruptions in cavins and ERK signaling that may contribute to DMD cardiomyopathy. This new knowledge is important for ongoing efforts to prevent and treat heart disease in DMD patients.
Identifiants
pubmed: 33949649
pii: 6265025
doi: 10.1093/hmg/ddab133
pmc: PMC8255133
doi:
Substances chimiques
Dystrophin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1321-1336Subventions
Organisme : NHLBI NIH HHS
ID : R00 HL116769
Pays : United States
Organisme : NIBIB NIH HHS
ID : R21 EB026518
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS090634
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press.
Références
Circ Res. 2000 Sep 15;87(6):480-8
pubmed: 10988240
Circ Res. 2006 Aug 18;99(4):407-14
pubmed: 16857961
Anat Rec (Hoboken). 2014 Sep;297(9):1694-705
pubmed: 25125182
Ann Med. 2012 Sep;44(6):530-41
pubmed: 21651441
J Biol Chem. 2011 Feb 18;286(7):5404-13
pubmed: 21119217
Biochim Biophys Acta Mol Cell Res. 2019 Aug;1866(8):1249-1259
pubmed: 30951783
J Cell Biol. 1990 Dec;111(6 Pt 1):2427-36
pubmed: 2277065
Int J Mol Sci. 2019 Aug 22;20(17):
pubmed: 31443395
J Mol Cell Cardiol. 2012 Aug;53(2):217-22
pubmed: 22587991
Pharmacol Rev. 2013 Dec 24;66(1):308-33
pubmed: 24368739
Mol Ther Methods Clin Dev. 2017 Jul 27;6:216-230
pubmed: 28932757
J Biol Chem. 1995 Mar 10;270(10):4975-8
pubmed: 7890602
Mol Ther. 2007 Jun;15(6):1086-92
pubmed: 17440445
J Physiol. 2007 Feb 15;579(Pt 1):161-73
pubmed: 17138609
Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):149-60
pubmed: 19351512
JAMA Neurol. 2020 Sep 1;77(9):1122-1131
pubmed: 32539076
Neurology. 1994 Sep;44(9):1648-51
pubmed: 7936290
Mol Cell Biol. 2008 May;28(10):3424-36
pubmed: 18332105
Int J Mol Sci. 2019 May 01;20(9):
pubmed: 31052420
Circulation. 1996 Dec 15;94(12):3168-75
pubmed: 8989125
J Biol Chem. 2011 Apr 15;286(15):12820-4
pubmed: 21343302
J Cell Sci. 2017 Sep 1;130(17):2781-2788
pubmed: 28808089
Mol Cell Biol. 2001 Nov;21(21):7460-9
pubmed: 11585926
J Cell Biol. 1997 Jul 14;138(1):81-93
pubmed: 9214383
Nat Rev Dis Primers. 2021 Feb 18;7(1):13
pubmed: 33602943
Hum Mol Genet. 2000 Apr 12;9(7):1033-40
pubmed: 10767327
J Clin Invest. 2007 Jul;117(7):1805-13
pubmed: 17607357
Am J Pathol. 2013 Feb;182(2):485-504
pubmed: 23332367
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12413-8
pubmed: 9356463
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12331-6
pubmed: 21746915
Int Rev Cytol. 2008;265:191-225
pubmed: 18275889
Eur Neurol. 1999;42(3):145-9
pubmed: 10529540
Ann N Y Acad Sci. 2010 Feb;1188:96-102
pubmed: 20201891
EMBO J. 2000 Dec 1;19(23):6341-50
pubmed: 11101507
Cochrane Database Syst Rev. 2018 Oct 16;10:CD009068
pubmed: 30326162
Mol Ther. 2011 Oct;19(10):1826-32
pubmed: 21811246
Cell. 2008 Jan 11;132(1):113-24
pubmed: 18191225
J Clin Invest. 2009 Mar;119(3):624-35
pubmed: 19229108
Hum Mol Genet. 2018 Jun 15;27(12):2090-2100
pubmed: 29618008
Circulation. 2004 Apr 27;109(16):1938-41
pubmed: 15096454
Neuromuscul Disord. 2010 Apr;20(4):251-4
pubmed: 20153965
J Neurol Neurosurg Psychiatry. 2014 Jan;85(1):92-8
pubmed: 23667215
Neuropathol Appl Neurobiol. 2010 Jun;36(4):265-74
pubmed: 20002311
PLoS One. 2012;7(8):e43515
pubmed: 22937058
Neuromuscul Disord. 2018 Sep;28(9):711-716
pubmed: 30064893
Elife. 2013 Sep 17;2:e00926
pubmed: 24052812
Brain. 1994 Feb;117 ( Pt 1):1-14
pubmed: 8149204
J Clin Invest. 2003 Jun;111(11):1783-91
pubmed: 12782680
Mol Ther. 2018 Oct 3;26(10):2337-2356
pubmed: 30093306
PLoS One. 2016 Sep 09;11(9):e0162513
pubmed: 27612189
Proc Natl Acad Sci U S A. 2014 Mar 11;111(10):3811-6
pubmed: 24567387
J Neurol. 1993 Feb;240(2):105-12
pubmed: 8437017
Front Cardiovasc Med. 2019 Mar 06;6:20
pubmed: 30895179
J Cell Biol. 1995 Feb;128(3):363-71
pubmed: 7844150
Gene Ther. 2011 Sep;18(9):910-9
pubmed: 21451578
Nat Commun. 2013;4:1831
pubmed: 23652019
J Mol Biol. 2017 Jan 6;429(1):128-141
pubmed: 27884606
J Mol Cell Cardiol. 2017 Nov;112:123-130
pubmed: 28822805
Circ Cardiovasc Genet. 2009 Dec;2(6):544-51
pubmed: 20031633
PLoS One. 2017 Dec 7;12(12):e0188471
pubmed: 29216197
Skelet Muscle. 2015 Apr 28;5:13
pubmed: 25954502
Circ Res. 2011 Jan 21;108(2):176-83
pubmed: 21127295
J Cell Biol. 2009 Jun 29;185(7):1259-73
pubmed: 19546242
Biochem Biophys Res Commun. 2002 May 17;293(4):1265-72
pubmed: 12054513
Biochem J. 2004 Oct 15;383(Pt 2):237-48
pubmed: 15242332
Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14074-9
pubmed: 17709754
Hum Gene Ther. 2008 Aug;19(8):851-6
pubmed: 18666839
J Cell Biol. 1995 Feb;128(3):373-81
pubmed: 7844151
Ann N Y Acad Sci. 2018 Jan;1412(1):62-72
pubmed: 29068540
Circ Res. 2004 Apr 30;94(8):1023-31
pubmed: 15117830
Mol Cell Proteomics. 2005 Sep;4(9):1265-72
pubmed: 15958392
Hum Mol Genet. 2018 Sep 1;27(17):2978-2985
pubmed: 29790927
Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5723-8
pubmed: 24706788
Pediatr Res. 1992 Jul;32(1):128-31
pubmed: 1635838
J Cell Biol. 2009 Aug 10;186(3):363-9
pubmed: 19651889
Nat Rev Mol Cell Biol. 2013 Feb;14(2):98-112
pubmed: 23340574