Dataset Information

Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's ataxia.

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.

SUBMITTER: Indelicato E

PROVIDER: S-EPMC10281753 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's ataxia.

Indelicato Elisabetta E Kirchmair Alexander A Amprosi Matthias M Steixner Stephan S Nachbauer Wolfgang W Eigentler Andreas A Wahl Nico N Apostolova Galina G Krogsdam Anne A Schneider Rainer R Wanschitz Julia J Trajanoski Zlatko Z Boesch Sylvia S

Human molecular genetics 20230601 13

<h4>Objective</h4>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.<h4>Methods</h4>Skeletal muscle biopsies were collected from seven FRDA patients before and after treatment with recombinant human Erythropoietin (rhuEPO) with ...[more]

PMID: 37027192

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Project description:Abstract Background: Friedreich’s Ataxia (FA) is a neurodegenerative disease caused by disruptions in the gene encoding frataxin, a protein involved in formation of the iron-sulfur clusters needed for mitochondrial oxidative phosphorylation (OXPHOS). FA confers an increased risk for diabetes mellitus, but the mechanisms underlying this propensity are not well understood. Design: Cross-sectional study (clinicaltrials.gov: NCT02920671) Methods: Participants were non-diabetic individuals with FA (ages 18y-<65y) and healthy controls with a similar distribution of age, sex, BMI, and ancestry. OXPHOS capacity of calf muscle was assessed using a non-invasive, exercise-based MRI technique, creatine chemical exchange saturation transfer (CrCEST); results for lateral gastrocnemius (LG), the most consistently exercised muscle, are shown. After an overnight fast, a stable isotope tracer-enhanced oral glucose tolerance test was done. Body composition was assessed using dual energy x-ray absorptiometry. Linear regression analyses of the entire sample tested the association between outcomes and covariates (results are shown as standardized coefficient β). Results: This interim analysis has n=34 participants (11 FA, 23 control). Participants with FA were 61% male, median age 27y (IQI, 23-39), median BMI 26.9 kg/m2 (IQI, 24.1-29.4), and median visceral fat mass 0.50 kg (IQI, 0.35-0.70). Controls were 61% male, median age 29y (IQI, 26-38), median BMI 24.6 kg/m2 (IQI, 21.7-28.5), and median visceral fat mass 0.45 kg (IQI, 0.27-0.64). Fasting glucose was higher in FA (91 vs. 82 mg/dL, p=0.006). Lactate was similar at baseline and increased after oral glucose in both, but remained higher after 180min in FA (at 210min, 1.13 vs. 0.88 mmol/L, p=0.01). Post-exercise CrCEST recovery time constant (τCr) was increased 2.2-fold in FA (p=0.02), consistent with decreased OXPHOS capacity. In univariate analyses, whole body insulin sensitivity (WBISI) was decreased in FA (β -1.14, p=0.003), decreased with longer τCr, (β -0.48, p=0.01), and decreased with higher visceral fat (β -0.55, p=0.004). In multivariate analyses, these associations were attenuated when FA diagnosis (β -0.85, p=0.06) and τCr (β -0.25, p=0.25) were included in the same model, but were persistent when FA diagnosis (β -0.93, p=0.008) and visceral fat (β -0.43, p=0.01) were included in the same model. In univariate analyses, lactate area under the curve (AUC) was nominally increased in FA (β 0.67, p=0.11), and significantly positively associated with longer τCr (β 0.51, p=0.008). Conclusions: Individuals with a genetic mitochondrial disorder conferring increased diabetes risk have decreased whole body insulin sensitivity that may be mediated by decreased skeletal muscle OXPHOS capacity. Studies in rare disorders may provide insights into the role of skeletal muscle metabolism in the pathogenesis of Type 2 diabetes. Funding: NIH/NIDDK Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Dataset Information

Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's ataxia.

Objective

Methods

Results

Interpretation

Publications

Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's ataxia.

Similar Datasets

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