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. 2023 Jun 19;32(13):2241-2250.
doi: 10.1093/hmg/ddad051.

Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's ataxia

Elisabetta Indelicato  1   2 , Alexander Kirchmair  3 , Matthias Amprosi  1   2 , Stephan Steixner  4 , Wolfgang Nachbauer  1   2 , Andreas Eigentler  1   2 , Nico Wahl  5 , Galina Apostolova  5 , Anne Krogsdam  3 , Rainer Schneider  6   7 , Julia Wanschitz  2 , Zlatko Trajanoski  3 , Sylvia Boesch  1   2
Affiliations

Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's ataxia

Elisabetta Indelicato et al. Hum Mol Genet. .

Abstract

Objective: 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.

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'-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.

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Figures

Figure 1
Figure 1
Transcriptomic analysis of skeletal muscle biopsies of FRDA patients before and after rhu-EPO treatment as compared to controls. (A) FRDA patients and controls are listed along their Patient_ID and demographic data. (B) PCA of the 500 most variable genes shows a separation of gene expression profiles according to disease status (blue controls, orange FRDA before rhuEPO treatment, red FRDA after rhuEPO treatment) along principal component 1 (PC1). (C) Boxplots of normalized expression values of FXN in control, FRDA and post-treatment FRDA samples. Patient ID is shown in red. Adjusted P-values from DESeq2 DE analysis. (D, E): Volcano plot of differentially expressed genes in FRDA samples compared to control samples (D) and of rhuEPO-treated FRDA patients compared to matched pre-treatment samples (E). Genes with an adjusted P-value lower than 0.05 were considered significant, genes upregulated in FRDA are shown in orange and downregulated genes are shown in blue.
Figure 2
Figure 2
Correlation between the GAA1 repeats and FXN expression in FRDA patients.
Figure 3
Figure 3
GSEA. Barplot of the 10 most significantly up- and downregulated gene sets in FRDA versus control samples.
Figure 4
Figure 4
GSEA. Barplot of the 10 most significantly up- and downregulated gene sets in rhuEPO-treated versus untreated FRDA samples.
Figure 5
Figure 5
Boxplots of log-transformed normalized expression values of LEP in control, FRDA and post-treatment FRDA samples. Patient ID is shown. Adjusted P-values from DESeq2 DE analysis.
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