Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's ataxia.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
19 06 2023
19 06 2023
Historique:
received:
10
01
2023
revised:
11
03
2023
accepted:
24
03
2023
medline:
22
6
2023
pubmed:
8
4
2023
entrez:
7
4
2023
Statut:
ppublish
Résumé
In Friedreich's ataxia (FRDA), the most affected tissues are not accessible to sampling and available transcriptomic findings originate from blood-derived cells and animal models. Herein, we aimed at dissecting for the first time the pathophysiology of FRDA by means of RNA-sequencing in an affected tissue sampled in vivo. Skeletal muscle biopsies were collected from seven FRDA patients before and after treatment with recombinant human Erythropoietin (rhuEPO) within a clinical trial. Total RNA extraction, 3'-mRNA library preparation and sequencing were performed according to standard procedures. We tested for differential gene expression with DESeq2 and performed gene set enrichment analysis with respect to control subjects. FRDA transcriptomes showed 1873 genes differentially expressed from controls. Two main signatures emerged: (1) a global downregulation of the mitochondrial transcriptome as well as of ribosome/translational machinery and (2) an upregulation of genes related to transcription and chromatin regulation, especially of repressor terms. Downregulation of the mitochondrial transcriptome was more profound than previously shown in other cellular systems. Furthermore, we observed in FRDA patients a marked upregulation of leptin, the master regulator of energy homeostasis. RhuEPO treatment further enhanced leptin expression. Our findings reflect a double hit in the pathophysiology of FRDA: a transcriptional/translational issue and a profound mitochondrial failure downstream. Leptin upregulation in the skeletal muscle in FRDA may represent a compensatory mechanism of mitochondrial dysfunction, which is amenable to pharmacological boosting. Skeletal muscle transcriptomics is a valuable biomarker to monitor therapeutic interventions in FRDA.
Identifiants
pubmed: 37027192
pii: 7110888
doi: 10.1093/hmg/ddad051
pmc: PMC10281753
doi:
Substances chimiques
Leptin
0
Erythropoietin
11096-26-7
RNA
63231-63-0
Iron-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2241-2250Informations de copyright
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Mov Disord. 2011 Aug 15;26(10):1935-8
pubmed: 21692115
Science. 1996 Mar 8;271(5254):1423-7
pubmed: 8596916
Ann Neurol. 2011 Nov;70(5):790-804
pubmed: 22162061
F1000Res. 2015 Dec 30;4:1521
pubmed: 26925227
Neurotherapeutics. 2019 Oct;16(4):1032-1049
pubmed: 31317428
Hum Mol Genet. 2003 Dec 15;12(24):3331-42
pubmed: 14570713
Nat Genet. 1997 Oct;17(2):215-7
pubmed: 9326946
Mitochondrion. 2015 Nov;25:1-5
pubmed: 26321457
PLoS One. 2013 Jul 29;8(7):e69229
pubmed: 23922695
J Neurochem. 2013 Aug;126 Suppl 1:53-64
pubmed: 23859341
Sci Rep. 2021 Nov 4;11(1):21705
pubmed: 34737331
Science. 2015 Jan 23;347(6220):1260419
pubmed: 25613900
Neuronal Signal. 2021 May 17;5(2):NS20200093
pubmed: 34046211
Innovation (Camb). 2021 Jul 01;2(3):100141
pubmed: 34557778
Skelet Muscle. 2022 Jul 2;12(1):16
pubmed: 35780170
Ann Neurol. 2001 May;49(5):590-6
pubmed: 11357949
Diabetes. 2013 Oct;62(10):3488-99
pubmed: 23863811
Nature. 2003 Apr 24;422(6934):909-13
pubmed: 12712207
Genome Biol. 2014;15(12):550
pubmed: 25516281
Bioinformatics. 2011 Jun 15;27(12):1739-40
pubmed: 21546393
Nat Methods. 2016 Jul;13(7):577-80
pubmed: 27240256
Pharmacol Res. 2022 Apr;178:106028
pubmed: 34896541
Nat Biotechnol. 2020 Mar;38(3):276-278
pubmed: 32055031
J Biol Chem. 2019 Feb 8;294(6):1846-1859
pubmed: 30552117
Hum Mol Genet. 2009 Jul 1;18(13):2452-61
pubmed: 19376812
J Neuropathol Exp Neurol. 2012 Aug;71(8):708-15
pubmed: 22805773
PLoS Genet. 2010 Jan 15;6(1):e1000812
pubmed: 20090835
J Neurochem. 2013 Aug;126 Suppl 1:11-20
pubmed: 23859338
Angiogenesis. 2019 Feb;22(1):103-115
pubmed: 30121753
J Tissue Eng. 2016 Sep 27;7:2041731416671278
pubmed: 27738510
Hum Mol Genet. 2021 Feb 4;29(23):3818-3829
pubmed: 33432325
Neurobiol Dis. 2006 May;22(2):302-11
pubmed: 16442805
Cell. 2019 May 30;177(6):1536-1552.e23
pubmed: 31150623
J Biol Chem. 2002 Sep 13;277(37):34601-9
pubmed: 12084725
Dis Model Mech. 2017 Nov 1;10(11):1353-1369
pubmed: 29125828
Cell Death Dis. 2020 Jan 23;11(1):51
pubmed: 31974344
Ann Neurol. 2021 Feb;89(2):212-225
pubmed: 33068037
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Hum Mol Genet. 2007 Apr 15;16(8):929-41
pubmed: 17331979
J Neurochem. 2013 Aug;126 Suppl 1:80-7
pubmed: 23859343
Nat Methods. 2017 Apr;14(4):417-419
pubmed: 28263959
J Neuropathol Exp Neurol. 2017 Feb 1;76(2):101-108
pubmed: 28082326
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11492-5
pubmed: 10500204
J Neurochem. 2020 Sep;155(2):191-206
pubmed: 32157699
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12321-6
pubmed: 12221295
Nucleic Acids Res. 2017 Jun 20;45(11):e103
pubmed: 28369524
Biochem J. 2010 Nov 15;432(1):165-72
pubmed: 20819074
J Neurochem. 2013 Aug;126 Suppl 1:103-17
pubmed: 23859346