{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:15:47Z","timestamp":1789470947232,"version":"build-2803163510"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T00:00:00Z","timestamp":1680825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"European Reference Network for Rare Neurological Diseases","award":["739510"],"award-info":[{"award-number":["739510"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Objective: In Friedreich\u2019s 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. Methods: 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\u2032-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. Results: 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. Interpretation: 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddad051","type":"journal-article","created":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T15:48:36Z","timestamp":1680882516000},"page":"2241-2250","source":"Crossref","is-referenced-by-count":9,"title":["Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich\u2019s ataxia"],"prefix":"10.1093","volume":"32","author":[{"given":"Elisabetta","family":"Indelicato","sequence":"first","affiliation":[{"name":"Center for Rare Movement Disorders Innsbruck, Medical University of Innsbruck , Innsbruck 6020 , Austria"},{"name":"Department of Neurology, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kirchmair","sequence":"additional","affiliation":[{"name":"Biocenter, Institute of Bioinformatics, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Amprosi","sequence":"additional","affiliation":[{"name":"Center for Rare Movement Disorders Innsbruck, Medical University of Innsbruck , Innsbruck 6020 , Austria"},{"name":"Department of Neurology, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Steixner","sequence":"additional","affiliation":[{"name":"Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Nachbauer","sequence":"additional","affiliation":[{"name":"Center for Rare Movement Disorders Innsbruck, Medical University of Innsbruck , Innsbruck 6020 , Austria"},{"name":"Department of Neurology, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Eigentler","sequence":"additional","affiliation":[{"name":"Center for Rare Movement Disorders Innsbruck, Medical University of Innsbruck , Innsbruck 6020 , Austria"},{"name":"Department of Neurology, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"Wahl","sequence":"additional","affiliation":[{"name":"Institute for Neuroscience, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Apostolova","sequence":"additional","affiliation":[{"name":"Institute for Neuroscience, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Krogsdam","sequence":"additional","affiliation":[{"name":"Biocenter, Institute of Bioinformatics, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Schneider","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Leopold Franzens University , Innsbruck 6020 , Austria"},{"name":"Center of Molecular Biosciences Innsbruck (CMBI) , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Wanschitz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zlatko","family":"Trajanoski","sequence":"additional","affiliation":[{"name":"Biocenter, Institute of Bioinformatics, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Boesch","sequence":"additional","affiliation":[{"name":"Center for Rare Movement Disorders Innsbruck, Medical University of Innsbruck , Innsbruck 6020 , Austria"},{"name":"Department of Neurology, Medical University of Innsbruck , Innsbruck 6020 , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,7]]},"reference":[{"key":"2023062021502944300_ref1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/jnc.12215","article-title":"Prevalence gradients of Friedreich's ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge","volume":"126","author":"Vankan","year":"2013","journal-title":"J. Neurochem."},{"key":"2023062021502944300_ref2","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1126\/science.271.5254.1423","article-title":"Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion","volume":"271","author":"Campuzano","year":"1996","journal-title":"Science"},{"key":"2023062021502944300_ref3","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/nature01596","article-title":"DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing","volume":"422","author":"Saveliev","year":"2003","journal-title":"Nature"},{"key":"2023062021502944300_ref4","doi-asserted-by":"crossref","first-page":"3818","DOI":"10.1093\/hmg\/ddaa267","article-title":"Methylated and unmethylated epialleles support variegated epigenetic silencing in Friedreich ataxia","volume":"29","author":"Rodden","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"2023062021502944300_ref5","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1007\/s13311-019-00764-x","article-title":"Molecular mechanisms and therapeutics for the GAA.TTC expansion disease Friedreich ataxia","volume":"16","author":"Gottesfeld","year":"2019","journal-title":"Neurotherapeutics"},{"key":"2023062021502944300_ref6","doi-asserted-by":"crossref","first-page":"12321","DOI":"10.1073\/pnas.192449599","article-title":"Inhibition of Fe-S cluster biosynthesis decreases mitochondrial iron export: evidence that Yfh1p affects Fe-S cluster synthesis","volume":"99","author":"Chen","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023062021502944300_ref7","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/ng1097-215","article-title":"Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia","volume":"17","author":"Rotig","year":"1997","journal-title":"Nat. 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Neurol."},{"key":"2023062021502944300_ref14","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1097\/NEN.0b013e31825fed76","article-title":"Skeletal muscle involvement in Friedreich ataxia and potential effects of recombinant human erythropoietin administration on muscle regeneration and neovascularization","volume":"71","author":"Nachbauer","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2023062021502944300_ref15","doi-asserted-by":"crossref","first-page":"e69229","DOI":"10.1371\/journal.pone.0069229","article-title":"Bioenergetics of the calf muscle in Friedreich ataxia patients measured by 31P-MRS before and after treatment with recombinant human erythropoietin","volume":"8","author":"Nachbauer","year":"2013","journal-title":"PLoS One"},{"key":"2023062021502944300_ref16","first-page":"101","article-title":"Friedreich ataxia: hypoplasia of spinal cord and dorsal root ganglia","volume":"76","author":"Koeppen","year":"2017","journal-title":"J. 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