Researchers have found that RNA sequencing in skeletal muscle samples highlights the transcriptional/translational issues and profound mitochondrial failure downstream.

These issues and downstream failures manifest as pathophysiological processes involved in the development of Friedreich ataxia (FA), according to a study published in Human Molecular Genetics.

The researchers collected skeletal muscle biopsies from 7 patients with FA before and after treatment with recombinant human erythropoietin within a clinical trial and performed standard total RNA extraction, 3’-mRNA library preparation, and sequencing.

The researchers then performed differential gene expression with DESeq2 and gene set enrichment analysis and compared the results with healthy controls.

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According to the study results, the FA transcriptomes showed 1873 genes differentially expressed than in controls. The researchers especially highlighted a global downregulation of the mitochondrial transcriptome and ribosome/translational machinery as well as an upregulation of genes related to transcription and chromatin regulation, especially of repressor terms.

Furthermore, the downregulation of the mitochondrial transcriptome was more pronounced than in other cellular systems. The patients with FA also had a marked upregulation of leptin, a substance highly involved in homeostasis regulation.

“The recognition of FA as a mitochondrial disorder dates back to early studies revealing a deficiency of mitochondrial proteins involved in the biosynthesis of iron-sulfur clusters in affected tissues,” Indelicato and colleagues wrote. “From a pathophysiological point of view, mitochondrial damage is believed to be a downstream effect consequent to frataxin deficiency and iron-sulfur clusters synthesis failure.”

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“RNA-sequencing data offer insight in a very early stage of the pathophysiological cascade and concomitant evaluation of proteomic and metabolomic data is required to delineate the final picture of a disease model at a cellular level,” they concluded.

FA transcriptomic analysis is usually performed on blood-derived cells and animal models instead of the most affected tissues. This study takes a different approach by dissecting for the first time the pathophysiology of FA on muscle tissue sampled in vivo.


Indelicato E, Kirchmair A, Amprosi M, et al. Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich’s ataxia. Hum Mol Genet. Published online April 7, 2023. doi:10.1093/hmg/ddad051