Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy.
Biological interpretation of miRNA dysregulation
Cholesterol
DLK1-DIO3
Duchenne muscular dystrophy
Glucocorticoid
Host gene
Lipid metabolism
SREBP-1
SREBP-2
Simvastatin
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:
06 2021
06 2021
Historique:
revised:
22
03
2021
received:
25
02
2021
accepted:
29
03
2021
pubmed:
27
5
2021
medline:
26
11
2021
entrez:
26
5
2021
Statut:
ppublish
Résumé
Duchenne muscular dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca We sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4-8, 8-12, and 12-20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis. We identified 96 dysregulated miRNAs (adjusted P-value <0.1), of which 74 were up-regulated and 22 were down-regulated in DMD. We confirmed the dysregulation in DMD of Dystro-miRs, Cardio-miRs, and a large number of the DLK1-DIO3 miRNAs. We also identified numerous dysregulated miRNAs yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP-1 and SREBP-2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol-reducing agent, normalized these perturbations and partially restored the dystrophic parameters. This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.
Sections du résumé
BACKGROUND
Duchenne muscular dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca
METHODS
We sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4-8, 8-12, and 12-20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis.
RESULTS
We identified 96 dysregulated miRNAs (adjusted P-value <0.1), of which 74 were up-regulated and 22 were down-regulated in DMD. We confirmed the dysregulation in DMD of Dystro-miRs, Cardio-miRs, and a large number of the DLK1-DIO3 miRNAs. We also identified numerous dysregulated miRNAs yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP-1 and SREBP-2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol-reducing agent, normalized these perturbations and partially restored the dystrophic parameters.
CONCLUSIONS
This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.
Identifiants
pubmed: 34037326
doi: 10.1002/jcsm.12708
pmc: PMC8200436
doi:
Substances chimiques
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
677-693Informations de copyright
© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.
Références
Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12864-9
pubmed: 26417069
Sci Rep. 2018 Sep 11;8(1):13624
pubmed: 30206270
Genes Dev. 2007 Apr 1;21(7):770-83
pubmed: 17403779
Cell. 1997 May 2;89(3):331-40
pubmed: 9150132
Nat Commun. 2018 Nov 19;9(1):4849
pubmed: 30451841
PLoS One. 2018 Mar 12;13(3):e0194225
pubmed: 29529088
Nucleic Acids Res. 2015 Jul 1;43(W1):W460-6
pubmed: 25977294
PLoS One. 2013;8(2):e55281
pubmed: 23418438
Sci Rep. 2020 Jun 4;10(1):9139
pubmed: 32499563
Ther Adv Neurol Disord. 2017 Aug;10(8):293-296
pubmed: 28781610
Nucleic Acids Res. 2014 Jan;42(Database issue):D68-73
pubmed: 24275495
J Nutr Sci. 2017 Nov 23;6:e57
pubmed: 29209496
PLoS One. 2014 Mar 13;9(3):e91514
pubmed: 24626262
Cell Death Differ. 2013 Sep;20(9):1194-208
pubmed: 23764775
Skelet Muscle. 2017 Sep 12;7(1):19
pubmed: 28899419
Cell Rep. 2015 Sep 8;12(10):1678-90
pubmed: 26321630
Mol Biol Cell. 2009 Jan;20(1):146-52
pubmed: 18946078
Cell Stem Cell. 2019 Mar 7;24(3):419-432.e6
pubmed: 30713094
Int J Endocrinol. 2015;2015:867273
pubmed: 26089900
FASEB J. 2009 Oct;23(10):3335-46
pubmed: 19528256
Curr Treat Options Neurol. 2014 May;16(5):287
pubmed: 24619767
Hum Mol Genet. 2015 Sep 1;24(17):4916-32
pubmed: 26060189
Am J Pathol. 2013 Feb;182(2):485-504
pubmed: 23332367
Glycobiology. 2019 Feb 1;29(2):110-123
pubmed: 29924302
J Cell Sci. 2013 Jun 15;126(Pt 12):2678-91
pubmed: 23606743
Magn Reson Imaging. 2017 May;38:163-173
pubmed: 28069416
RNA. 2005 Mar;11(3):241-7
pubmed: 15701730
J Clin Lipidol. 2020 Jul - Aug;14(4):459-469.e0
pubmed: 32593511
J Cachexia Sarcopenia Muscle. 2021 Jun;12(3):677-693
pubmed: 34037326
Mol Ther. 2017 May 3;25(5):1125-1131
pubmed: 28416280
EMBO Mol Med. 2011 May;3(5):258-65
pubmed: 21425469
PLoS One. 2018 Oct 10;13(10):e0205514
pubmed: 30304034
Sci Rep. 2016 Jun 21;6:28097
pubmed: 27323895
Mol Ther Nucleic Acids. 2012 Aug 14;1:e39
pubmed: 23344181
Nat Rev Endocrinol. 2017 Dec;13(12):710-730
pubmed: 28849786
Am J Pathol. 2014 Nov;184(11):2885-98
pubmed: 25194663
Database (Oxford). 2014 Oct 06;2014:
pubmed: 25288656
J Clin Neurosci. 2018 Mar;49:1-6
pubmed: 29254734
J Cell Biol. 2001 Mar 19;152(6):1207-18
pubmed: 11257121
Med Hypotheses. 2015 Dec;85(6):1021-33
pubmed: 26365249
J Cell Biol. 1993 Aug;122(4):809-23
pubmed: 8349731
Annu Rev Genomics Hum Genet. 2015;16:281-308
pubmed: 26048046
Semin Cell Dev Biol. 2018 Mar;75:3-12
pubmed: 28811264
Mol Biosyst. 2016 Feb;12(2):477-9
pubmed: 26661513
PLoS One. 2013 Nov 25;8(11):e80263
pubmed: 24282529
BMC Genomics. 2010 Oct 01;11:533
pubmed: 20920310
PLoS One. 2012;7(11):e49346
pubmed: 23209572
Mol Ther Nucleic Acids. 2014 Jul 22;3:e177
pubmed: 25050825
Nat Commun. 2017 May 25;8:15201
pubmed: 28541289
Biochim Biophys Acta. 2015 Jul;1852(7):1451-64
pubmed: 25892183
PLoS One. 2013 Aug 09;8(8):e70987
pubmed: 23951060
Cell. 2002 Aug 23;110(4):489-500
pubmed: 12202038
PLoS One. 2015 Feb 17;10(2):e0118229
pubmed: 25689854
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4218-23
pubmed: 20142475