Progressive cardiomyopathy with intercalated disc disorganization in a rat model of Becker dystrophy.
Becker Muscular Dystrophy
Connexins
Dilated Cardiomyopathy
Heart Failure
Tmem65
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
02 Oct 2024
02 Oct 2024
Historique:
received:
28
11
2023
accepted:
22
08
2024
revised:
09
08
2024
medline:
3
10
2024
pubmed:
3
10
2024
entrez:
2
10
2024
Statut:
aheadofprint
Résumé
Becker muscular dystrophy (BMD) is an X-linked disorder due to in-frame mutations in the DMD gene, leading to a less abundant and truncated dystrophin. BMD is less common and severe than Duchenne muscular dystrophy (DMD) as well as less investigated. To accelerate the search for innovative treatments, we developed a rat model of BMD by deleting the exons 45-47 of the Dmd gene. Here, we report a functional and histopathological evaluation of these rats during their first year of life, compared to DMD and control littermates. BMD rats exhibit moderate damage to locomotor and diaphragmatic muscles but suffer from a progressive cardiomyopathy. Single nuclei RNA-seq analysis of cardiac samples revealed shared transcriptomic abnormalities in BMD and DMD rats and highlighted an altered end-addressing of TMEM65 and Connexin-43 at the intercalated disc, along with electrocardiographic abnormalities. Our study documents the natural history of a translational preclinical model of BMD and reports a cellular mechanism for the cardiac dysfunction in BMD and DMD offering opportunities to further investigate the organization role of dystrophin in intercellular communication.
Identifiants
pubmed: 39358550
doi: 10.1038/s44319-024-00249-9
pii: 10.1038/s44319-024-00249-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : AFM Telethon
ID : 19507
Organisme : AFM Telethon
ID : 22946
Organisme : Fondation pour la Recherche Médicale (FRM)
ID : EQU20200301021
Organisme : Fondation pour la Recherche Médicale (FRM)
ID : SPF20170938733
Organisme : Agence Nationale de la Recherche (ANR)
ID : ANR-21-CE13-0006
Organisme : Agence Nationale de la Recherche (ANR)
ID : ANR-10-LABX-73
Informations de copyright
© 2024. The Author(s).
Références
Beggs AH, Hoffman EP, Snyder JR, Arahata K, Specht L, Shapiro F, Angelini C, Sugita H, Kunkel LM (1991) Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 49:54–67
pubmed: 2063877
pmcid: 1683222
Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ, Davis JL, Douglas PS, Faxon DP, Gillam LD, Kimball TR et al (2003) ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). J Am Soc Echocardiogr 16:1091–1110
pubmed: 14566308
Concordet JP, Haeussler M (2018) CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucleic Acids Res 46:W242–W245
pubmed: 29762716
pmcid: 6030908
doi: 10.1093/nar/gky354
Connuck DM, Sleeper LA, Colan SD, Cox GF, Towbin JA, Lowe AM, Wilkinson JD, Orav EJ, Cuniberti L, Salbert BA et al (2008) Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry. Am Heart J 155:998–1005
pubmed: 18513510
pmcid: 2729548
doi: 10.1016/j.ahj.2008.01.018
D’Angelo MG, Romei M, Lo Mauro A, Marchi E, Gandossini S, Bonato S, Comi GP, Magri F, Turconi AC, Pedotti A et al (2011) Respiratory pattern in an adult population of dystrophic patients. J Neurol Sci 306:54–61
pubmed: 21529845
doi: 10.1016/j.jns.2011.03.045
Del Rio-Pertuz G, Morataya C, Parmar K, Dubay S, Argueta-Sosa E (2022) Dilated cardiomyopathy as the initial presentation of Becker muscular dystrophy: a systematic review of published cases. Orphanet J Rare Dis 17:1–10
Delalande O, Molza AE, Dos Santos Morais R, Cheron A, Pollet E, Raguenes-Nicol C, Tascon C, Giudice E, Guilbaud M, Nicolas A et al (2018) Dystrophin’s central domain forms a complex filament that becomes disorganized by in-frame deletions. J Biol Chem 293:6637–6646
pubmed: 29535188
pmcid: 5936807
doi: 10.1074/jbc.M117.809798
Dos Santos M, Backer S, Saintpierre B, Izac B, Andrieu M, Letourneur F, Relaix F, Sotiropoulos A, Maire P (2020) Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers. Nat Commun 11:5102
pubmed: 33037211
pmcid: 7547110
doi: 10.1038/s41467-020-18789-8
Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A (2021) Duchenne muscular dystrophy. Nat Rev Dis Prim 7:13
pubmed: 33602943
doi: 10.1038/s41572-021-00248-3
Finsterer J, Stollberger C (2008) Cardiac involvement in Becker muscular dystrophy. Can J Cardiol 24:786–792
pubmed: 18841259
pmcid: 2643160
doi: 10.1016/S0828-282X(08)70686-X
Fiorillo AA, Heier CR, Novak JS, Tully CB, Brown KJ, Uaesoontrachoon K, Vila MC, Ngheim PP, Bello L, Kornegay JN et al (2015) TNF-alpha-induced microRNAs control dystrophin expression in becker muscular dystrophy. Cell Rep. 12:1678–1690
pubmed: 26321630
pmcid: 4757433
doi: 10.1016/j.celrep.2015.07.066
Florczyk-Soluch U, Polak K, Dulak J (2021) The multifaceted view of heart problem in Duchenne muscular dystrophy. Cell Mol Life Sci 78:5447–5468
pubmed: 34091693
pmcid: 8257522
doi: 10.1007/s00018-021-03862-2
Gaina G, Popa Gruianu A (2021) Muscular dystrophy: experimental animal models and therapeutic approaches (Review). Exp Ther Med 21:610
pubmed: 33936267
pmcid: 8082581
doi: 10.3892/etm.2021.10042
Ghasemi A, Jeddi S, Kashfi K (2021) The laboratory rat: age and body weight matter. EXCLI J 20:1431–1445
pubmed: 34737685
pmcid: 8564917
Gonzalez JP, Ramachandran J, Himelman E, Badr MA, Kang C, Nouet J, Fefelova N, Xie LH, Shirokova N, Contreras JE et al (2018) Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice. Neuromuscul Disord 28:361–372
pubmed: 29477453
doi: 10.1016/j.nmd.2018.01.012
Gonzalez JP, Ramachandran J, Xie LH, Contreras JE, Fraidenraich D (2015) Selective Connexin43 inhibition prevents isoproterenol-induced arrhythmias and lethality in muscular dystrophy mice. Sci Rep. 5:13490
pubmed: 26311238
doi: 10.1038/srep13490
Guilbaud M, Gentil C, Peccate C, Gargaun E, Holtzmann I, Gruszczynski C, Falcone S, Mamchaoui K, Ben Yaou R, Leturcq F et al (2018) miR-708-5p and miR-34c-5p are involved in nNOS regulation in dystrophic context. Skelet Muscle 8:15
pubmed: 29703249
pmcid: 5924477
doi: 10.1186/s13395-018-0161-2
Hagdorn QAJ, Bossers GPL, Koop AC, Piek A, Eijgenraam TR, van der Feen DE, Sillje HHW, de Boer RA, Berger RMF (2019) A novel method optimizing the normalization of cardiac parameters in small animal models: the importance of dimensional indexing. Am J Physiol Heart Circ Physiol 316:H1552–H1557
pubmed: 30978120
doi: 10.1152/ajpheart.00182.2019
Heier CR, McCormack NM, Tully CB, Novak JS, Newell-Stamper BL, Russell AJ, Fiorillo AA (2023) The X-linked Becker muscular dystrophy (bmx) mouse models Becker muscular dystrophy via deletion of murine dystrophin exons 45-47. J Cachexia Sarcopenia Muscle 14:940–954
pubmed: 36628607
pmcid: 10067474
doi: 10.1002/jcsm.13171
Heslop L, Morgan JE, Partridge TA (2000) Evidence for a myogenic stem cell that is exhausted in dystrophic muscle. J Cell Sci 113:2299–2308.
pubmed: 10825301
doi: 10.1242/jcs.113.12.2299
Hilton S, Christen M, Bilzer T, Jagannathan V, Leeb T, Giger U (2023) Dystrophin (DMD) missense variant in cats with Becker-type muscular dystrophy. Int J Mol Sci 24:3192
pubmed: 36834603
pmcid: 9964367
doi: 10.3390/ijms24043192
Ho R, Nguyen ML, Mather P (2016) Cardiomyopathy in Becker muscular dystrophy: overview. World J Cardiol 8:356–361
pubmed: 27354892
pmcid: 4919702
doi: 10.4330/wjc.v8.i6.356
Hoffman EP, Kunkel LM, Angelini C, Clarke A, Johnson M, Harris JB (1989) Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology 39:1011–1017
pubmed: 2668783
doi: 10.1212/WNL.39.8.1011
Ito Y, Yoshida M, Masuda H, Maeda D, Kudo-Asabe Y, Umakoshi M, Nanjo H, Goto A (2021) Disorganization of intercalated discs in dilated cardiomyopathy. Sci Rep 11:11852
pubmed: 34088908
pmcid: 8178322
doi: 10.1038/s41598-021-90502-1
Kaspar RW, Allen HD, Ray WC, Alvarez CE, Kissel JT, Pestronk A, Weiss RB, Flanigan KM, Mendell JR, Montanaro F (2009) Analysis of dystrophin deletion mutations predicts age of cardiomyopathy onset in becker muscular dystrophy. Circ Cardiovasc Genet 2:544–551
pubmed: 20031633
pmcid: 2826810
doi: 10.1161/CIRCGENETICS.109.867242
Kesari A, Pirra LN, Bremadesam L, McIntyre O, Gordon E, Dubrovsky AL, Viswanathan V, Hoffman EP (2008) Integrated DNA, cDNA, and protein studies in Becker muscular dystrophy show high exception to the reading frame rule. Hum Mutat 29:728–737
pubmed: 18348289
doi: 10.1002/humu.20722
Kmecova J, Klimas J (2010) Heart rate correction of the QT duration in rats. Eur J Pharmacol 641(2-3):187–192
Koenig AL, Shchukina I, Amrute J, Andhey PS, Zaitsev K, Lai L, Bajpai G, Bredemeyer A, Smith G, Jones C et al (2022) Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure. Nat Cardiovasc Res 1:263–280
pubmed: 35959412
pmcid: 9364913
doi: 10.1038/s44161-022-00028-6
Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, Meng G, Muller CR, Lindlof M, Kaariainen H et al (1989) The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 45:498–506
pubmed: 2491009
pmcid: 1683519
Lai Y, Thomas GD, Yue Y, Yang HT, Li D, Long C, Judge L, Bostick B, Chamberlain JS, Terjung RL et al (2009) Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J Clin Invest 119:624–635
pubmed: 19229108
pmcid: 2648692
doi: 10.1172/JCI36612
Le Dour C, Chatzifrangkeskou M, Macquart C, Magiera MM, Peccate C, Jouve C, Virtanen L, Helio T, Aalto-Setala K, Crasto S et al (2022) Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations. Nat Commun 13:7886
pubmed: 36550158
pmcid: 9780334
doi: 10.1038/s41467-022-35639-x
Lo Mauro A, Aliverti A (2016) Physiology of respiratory disturbances in muscular dystrophies. Breathe 12:318–327
pubmed: 28210319
pmcid: 5297947
doi: 10.1183/20734735.012716
Luz MA, Marques MJ, Santo Neto H (2002) Impaired regeneration of dystrophin-deficient muscle fibers is caused by exhaustion of myogenic cells. Braz J Med Biol Res 35:691–695
pubmed: 12045834
doi: 10.1590/S0100-879X2002000600009
Maeda M, Nakao S, Miyazato H, Setoguchi M, Arima S, Higuchi I, Osame M, Taira A, Nomoto K, Toda H et al (1995) Cardiac dystrophin abnormalities in Becker muscular dystrophy assessed by endomyocardial biopsy. Am Heart J 129:702–707
pubmed: 7900621
doi: 10.1016/0002-8703(95)90319-4
Maruyama T, Fujino T, Fukuoka Y, Tsukamoto K, Mawatari S (1995) Notched T wave as evidence of autonomic nervous lability in Duchenne progressive muscular dystrophy. Jpn Heart J 36:741–750
pubmed: 8627980
doi: 10.1536/ihj.36.741
Mavrogeni S, Markousis-Mavrogenis G, Papavasiliou A, Kolovou G (2015) Cardiac involvement in Duchenne and Becker muscular dystrophy. World J Cardiol 7:410–414
pubmed: 26225202
pmcid: 4513493
doi: 10.4330/wjc.v7.i7.410
McCormack NM, Nguyen NY, Tully CB, Oliver T, Fiorillo AA, Heier CR (2023) Vamorolone improves Becker muscular dystrophy and increases dystrophin protein in BMX model mice. iScience 26:107161
pubmed: 37534133
pmcid: 10391915
doi: 10.1016/j.isci.2023.107161
Mirouse V (2023) Evolution and developmental functions of the dystrophin-associated protein complex: beyond the idea of a muscle-specific cell adhesion complex. Front Cell Dev Biol 11:1182524
pubmed: 37384252
pmcid: 10293626
doi: 10.3389/fcell.2023.1182524
Monaco AP, Bertelson CJ, Liechti-Gallati S, Moser H, Kunkel LM (1988) An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 2:90–95
pubmed: 3384440
doi: 10.1016/0888-7543(88)90113-9
Nakamura A, Matsumura T, Ogata K, Mori-Yoshimura M, Takeshita E, Kimura K, Kawashima T, Tomo Y, Arahata H, Miyazaki D et al (2023) Natural history of Becker muscular dystrophy: a multicenter study of 225 patients. Ann Clin Transl Neurol 10:2360–2372
pubmed: 37882106
pmcid: 10723226
doi: 10.1002/acn3.51925
Nicolas A, Raguenes-Nicol C, Ben Yaou R, Ameziane-Le Hir S, Cheron A, Vie V, Claustres M, Leturcq F, Delalande O, Hubert JF et al (2015) Becker muscular dystrophy severity is linked to the structure of dystrophin. Hum Mol Genet 24:1267–1279
pubmed: 25348330
doi: 10.1093/hmg/ddu537
Nigro G, Comi LI, Politano L, Bain RJ (1990) The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol 26:271–277
pubmed: 2312196
doi: 10.1016/0167-5273(90)90082-G
Nigro G, Comi LI, Politano L, Limongelli FM, Nigro V, De Rimini ML, Giugliano MA, Petretta VR, Passamano L, Restucci B et al (1995) Evaluation of the cardiomyopathy in Becker muscular dystrophy. Muscle Nerve 18:283–291
pubmed: 7870105
doi: 10.1002/mus.880180304
Piccolo G, Azan G, Tonin P, Arbustini E, Gavazzi A, Banfi P, Mora M, Morandi L, Tedeschi S (1994) Dilated cardiomyopathy requiring cardiac transplantation as initial manifestation of Xp21 Becker type muscular dystrophy. Neuromuscul Disord 4:143–146
pubmed: 8012195
doi: 10.1016/0960-8966(94)90006-X
Prior TW, Bridgeman SJ (2005) Experience and strategy for the molecular testing of Duchenne muscular dystrophy. J Mol Diagn 7:317–326
pubmed: 16049303
pmcid: 1867542
doi: 10.1016/S1525-1578(10)60560-0
Sharma P, Abbasi C, Lazic S, Teng ACT, Wang D, Dubois N, Ignatchenko V, Wong V, Liu J, Araki T et al (2015) Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function. Nat Commun 6:8391
pubmed: 26403541
doi: 10.1038/ncomms9391
Shih JA, Folch A, Wong BL (2020) Duchenne muscular dystrophy: the heart of the matter. Curr Heart Fail Rep 17:57–66
pubmed: 32270339
doi: 10.1007/s11897-020-00456-0
Silva MC, Meira ZM, Gurgel Giannetti J, da Silva MM, Campos AF, Barbosa Mde M, Starling Filho GM, Ferreira Rde A, Zatz M, Rochitte CE (2007) Myocardial delayed enhancement by magnetic resonance imaging in patients with muscular dystrophy. J Am Coll Cardiol 49:1874–1879
pubmed: 17481447
doi: 10.1016/j.jacc.2006.10.078
Steare SE, Dubowitz V, Benatar A (1992) Subclinical cardiomyopathy in Becker muscular dystrophy. Br Heart J 68:304–308
pubmed: 1389764
pmcid: 1025076
doi: 10.1136/hrt.68.9.304
Suselbeck T, Haghi D, Neff W, Borggrefe M, Papavassiliu T (2005) Midwall myocardial fibrosis in Becker-Kiener muscular dystrophy. Z Kardiol 94:465–468
pubmed: 15997348
doi: 10.1007/s00392-005-0249-7
Taglietti V, Kefi K, Bronisz-Budzynska I, Mirciloglu B, Rodrigues M, Cardone N, Coulpier F, Periou B, Gentil C, Goddard M et al (2022) Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis. Acta Neuropathol Commun 10:60
pubmed: 35468843
pmcid: 9036715
doi: 10.1186/s40478-022-01355-2
Taglietti V, Kefi K, Rivera L, Bergiers O, Cardone N, Coulpier F, Gioftsidi S, Drayton-Libotte B, Hou C, Authier FJ et al (2023) Thyroid-stimulating hormone receptor signaling restores skeletal muscle stem cell regeneration in rats with muscular dystrophy. Sci Transl Med 15:eadd5275
pubmed: 36857434
doi: 10.1126/scitranslmed.add5275
Takeshima Y, Yagi M, Okizuka Y, Awano H, Zhang Z, Yamauchi Y, Nishio H, Matsuo M (2010) Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. J Hum Genet 55:379–388
pubmed: 20485447
doi: 10.1038/jhg.2010.49
Teng ACT, Gu L, Di Paola M, Lakin R, Williams ZJ, Au A, Chen W, Callaghan NI, Zadeh FH, Zhou YQ et al (2022) Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts. Nat Commun 13:6166
pubmed: 36257954
pmcid: 9579145
doi: 10.1038/s41467-022-33303-y
Teramoto N, Sugihara H, Yamanouchi K, Nakamura K, Kimura K, Okano T, Shiga T, Shirakawa T, Matsuo M, Nagata T et al (2020) Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy. Dis Model Mech 13:dmm044701
pubmed: 32859695
pmcid: 7541341
doi: 10.1242/dmm.044701
van den Bergen JC, Wokke BH, Janson AA, van Duinen SG, Hulsker MA, Ginjaar HB, van Deutekom JC, Aartsma-Rus A, Kan HE, Verschuuren JJ (2014) Dystrophin levels and clinical severity in Becker muscular dystrophy patients. J Neurol Neurosurg Psychiatry 85:747–753
pubmed: 24292997
doi: 10.1136/jnnp-2013-306350
Vengalil S, Preethish-Kumar V, Polavarapu K, Mahadevappa M, Sekar D, Purushottam M, Thomas PT, Nashi S, Nalini A (2017) Duchenne muscular dystrophy and Becker muscular dystrophy confirmed by multiplex ligation-dependent probe amplification: genotype-phenotype correlation in a large cohort. J Clin Neurol 13:91–97
pubmed: 28079318
doi: 10.3988/jcn.2017.13.1.91
Wang L, Yu P, Zhou B, Song J, Li Z, Zhang M, Guo G, Wang Y, Chen X, Han L et al (2020) Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function. Nat Cell Biol 22:108–119
pubmed: 31915373
doi: 10.1038/s41556-019-0446-7
Wells D, Rizwan R, Jefferies JL, Bryant 3rd R, Ryan TD, Lorts A, Chin C, Zafar F, Morales DL (2020) Heart transplantation in muscular dystrophy patients: is it a viable option? Circ Heart Fail 13:e005447
pubmed: 32216460
doi: 10.1161/CIRCHEARTFAILURE.118.005447
Wittlieb-Weber CA, Knecht KR, Villa CR, Cunningham C, Conway J, Bock MJ, Gambetta KE, Lal AK, Schumacher KR, Law SP et al (2020) Risk factors for cardiac and non-cardiac causes of death in males with Duchenne muscular dystrophy. Pediatr Cardiol 41:764–771
pubmed: 32016582
pmcid: 7328368
doi: 10.1007/s00246-020-02309-y
Yilmaz A, Gdynia HJ, Baccouche H, Mahrholdt H, Meinhardt G, Basso C, Thiene G, Sperfeld AD, Ludolph AC, Sechtem U (2008) Cardiac involvement in patients with Becker muscular dystrophy: new diagnostic and pathophysiological insights by a CMR approach. J Cardiovasc Magn Reson 10:50
pubmed: 18983659
pmcid: 2585564
doi: 10.1186/1532-429X-10-50