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Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies.

ABSTRACT: Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics, and it is important to identify markers of disease activity to inform clinical trial design. For drugs that inhibit DUX4 expression, measuring DUX4 or DUX4-target gene expression might be an interim measure of drug activity; however, only a subset of FHSD muscle biopsies shows evidence of DUX4 expression. Our prior study showed that MRI T2-STIR-positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a 1-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was little change in MRI characteristics over the 1-year period and, similar to the initial evaluation, MRI T2-STIR-postive muscles had a higher expression of DUX4-regulated genes, as well as genes associated with inflammation, extracellular matrix and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the 1-year period; however, there was some variability for each individual muscle biopsied. The pooled data from both the initial and 1-year follow-up evaluations identified several FSHD subgroups based on gene expression, as well as a set of genes-composed of DUX4-target genes, inflammatory and immune genes and cell cycle control genes-that distinguished all of the FSHD samples from the controls. These candidate markers of disease activity need to be replicated in independent datasets and, if validated, may provide useful measures of disease progression and response to therapy.

SUBMITTER: Wong CJ

PROVIDER: S-EPMC7158378 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies

Project description:Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics and it is important to identify markers of disease activity and progression to inform clinical trial design. For drugs that inhibit the expression of DUX4, measuring DUX4 or DUX4 target gene expression might be an interim outcome measure of drug activity, however, only a subset of muscle biopsies in FSHD show evidence of DUX4 expression. Our prior study showed that MRI T2-STIR positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a one-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was very little change in the muscle MRI characteristics over the one-year period and, similar to the initial evaluation MRI T2-STIR-postive muscles had a higher expression of DUX4 regulated genes, as well as genes associated with inflammation, extracellular matrix, and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the one-year period, however, there was some variability for each individual muscle biopsied. We pooled the data from both the initial and one-year follow-up evaluations and identified several subgroups based on gene expression, as well as a set of genes that distinguished all of the FSHD samples from the controls that include DUX4-regulated genes, inflammatory immune genes, and cell cycle control genes. These candidate markers of disease activity need to be validated on independent datasets, but will hopefully be useful in studies of disease progression and response to therapy.

2020-02-25 | GSE140261 | GEO

Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies

Project description:Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies

| PRJNA589062 | ENA

miRNA expression in control and FSHD fetal human muscle biopsies.

Project description:BACKGROUND:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder and is one of the most common forms of muscular dystrophy. We have recently shown that some hallmarks of FSHD are already expressed in fetal FSHD biopsies, thus opening a new field of investigation for mechanisms leading to FSHD. As microRNAs (miRNAs) play an important role in myogenesis and muscle disorders, in this study we compared miRNAs expression levels during normal and FSHD muscle development. METHODS:Muscle biopsies were obtained from quadriceps of both healthy control and FSHD1 fetuses with ages ranging from 14 to 33 weeks of development. miRNA expression profiles were analyzed using TaqMan Human MicroRNA Arrays. RESULTS:During human skeletal muscle development, in control muscle biopsies we observed changes for 4 miRNAs potentially involved in secondary muscle fiber formation and 5 miRNAs potentially involved in fiber maturation. When we compared the miRNA profiles obtained from control and FSHD biopsies, we did not observe any differences in the muscle specific miRNAs. However, we identified 8 miRNAs exclusively expressed in FSHD1 samples (miR-330, miR-331-5p, miR-34a, miR-380-3p, miR-516b, miR-582-5p, miR-517* and miR-625) which could represent new biomarkers for this disease. Their putative targets are mainly involved in muscle development and morphogenesis. Interestingly, these FSHD1 specific miRNAs do not target the genes previously described to be involved in FSHD. CONCLUSIONS:This work provides new candidate mechanisms potentially involved in the onset of FSHD pathology. Whether these FSHD specific miRNAs cause deregulations during fetal development, or protect against the appearance of the FSHD phenotype until the second decade of life still needs to be investigated.

| S-EPMC4333765 | biostudies-literature

MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD.

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle magnetic resonance imaging (MRI) changes is crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology and expression of DUX4 target genes. Results show that the presence of elevated MRI short tau inversion recovery signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression.

| S-EPMC6337697 | biostudies-literature

DUX4 expressing immortalized FSHD lymphoblastoid cells express genes elevated in FSHD muscle biopsies, correlating with the early stages of inflammation.

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disorder linked to ectopic expression of DUX4. However, DUX4 is notoriously difficult to detect in FSHD muscle cells, while DUX4 target gene expression is an inconsistent biomarker for FSHD skeletal muscle biopsies, displaying efficacy only on pathologically inflamed samples. Immune gene misregulation occurs in FSHD muscle, with DUX4 target genes enriched for those associated with inflammatory processes. However, there lacks an assessment of the FSHD immune cell transcriptome, and its contribution to gene expression in FSHD muscle biopsies. Here, we show that EBV-immortalized FSHD lymphoblastoid cell lines express DUX4 and both early and late DUX4 target genes. Moreover, a biomarker of 237 up-regulated genes derived from FSHD lymphoblastoid cell lines is elevated in FSHD muscle biopsies compared to controls. The FSHD Lymphoblast score is unaltered between FSHD myoblasts/myotubes and their controls however, implying a non-myogenic cell source in muscle biopsies. Indeed, the FSHD Lymphoblast score correlates with the early stages of muscle inflammation identified by histological analysis on muscle biopsies, while our two late DUX4 target gene expression biomarkers associate with macroscopic inflammation detectable via MRI. Thus, FSHD lymphoblastoid cell lines express DUX4 and early and late DUX4 target genes, therefore, muscle-infiltrated immune cells may contribute the molecular landscape of FSHD muscle biopsies.

| S-EPMC7424723 | biostudies-literature

Correlation Between Quantitative MRI and Muscle Histopathology in Muscle Biopsies from Healthy Controls and Patients with IBM, FSHD and OPMD.

Project description:BackgroundMuscle MRI is increasingly used as a diagnostic and research tool in muscle disorders. However, the correlation between MRI abnormalities and histopathological severity is largely unknown.ObjectiveTo investigate correlations between muscle MRI abnormalities and histopathological severity in healthy controls and patients with muscle disease.MethodsWe performed quantitative MRI and histopathological analysis in 35 patients with inclusion body myositis, facioscapulohumeral muscular dystrophy or oculopharyngeal muscular dystrophy and 12 healthy controls. Participants contributed needle biopsies of the vastus lateralis and/or tibialis anterior, yielding 77 muscle biopsies with matched T1, T2 and TIRM MRI imaging. Muscle biopsies were evaluated with a semi-quantitative histopathology severity grading scale (range 0-12) and an inflammation severity grading scale (range 0-3).ResultsIn muscle disease, histopathology sum scores ranged from 0 to 11 and correlated significantly with fat percentage as measured on MRI (Spearman's rho = 0.594, p < 0.001). Muscle edema on muscle MRI was associated with increased amounts of inflammation (p < 0.001). Mild abnormalities occured in 95% of control biopsies and were more pronounced in tibialis anterior (median sum score of 1±1 in vastus lateralis and 2±1 in tibialis anterior (p = 0.048)).ConclusionIn muscle disease, fatty infiltration on MRI correlates moderately with muscle histopathology. Histopathological abnormalities can occur prior to the onset of fatty infiltration. In middle-aged controls, almost all biopsies showed some histopathological abnormalities. The findings from this study may facilitate the choice for appropriate imaging sequences as outcome measures in therapeutic trials.

| S-EPMC7739972 | biostudies-literature

MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in somatic cells. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle MRI changes are crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology, and expression of DUX4 target genes. Results show that the presence of elevated MRI STIR signal has substantial predictive value in identifying muscles with active disease and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles, and higher levels of DUX4 target expression was associated with more advanced muscle pathology. These results support the use of MRI to identify FSHD muscles with active disease as measured by histopathology and DUX4 target gene expression and might be useful for the design of studies of disease progression and response to intervention.

2018-09-04 | GSE115650 | GEO

Altered expression of cyclin A 1 in muscle of patients with facioscapulohumeral muscle dystrophy (FSHD-1).

Project description:ObjectivesCyclin A1 regulates cell cycle activity and proliferation in somatic and germ-line cells. Its expression increases in G1/S phase and reaches a maximum in G2 and M phases. Altered cyclin A1 expression might contribute to clinical symptoms in facioscapulohumeral muscular dystrophy (FSHD).MethodsMuscle biopsies were taken from the Vastus lateralis muscle for cDNA microarray, RT-PCR, immunohistochemistry and Western blot analyses to assess RNA and protein expression of cyclin A1 in human muscle cell lines and muscle tissue. Muscle fibers diameter was calculated on cryosections to test for hypertrophy.ResultscDNA microarray data showed specifically elevated cyclin A1 levels in FSHD vs. other muscular disorders such as caveolinopathy, dysferlinopathy, four and a half LIM domains protein 1 deficiency and healthy controls. Data could be confirmed with RT-PCR and Western blot analysis showing up-regulated cyclin A1 levels also at protein level. We found also clear signs of hypertrophy within the Vastus lateralis muscle in FSHD-1 patients.ConclusionsIn most somatic human cell lines, cyclin A1 levels are low. Overexpression of cyclin A1 in FSHD indicates cell cycle dysregulation in FSHD and might contribute to clinical symptoms of this disease.

| S-EPMC3760810 | biostudies-literature

DUX4-expressing immortalised FSHD lymphoblastoid cells express genes elevated in FSHD muscle biopsies, correlating with the early stages of inflammation

Project description:RNAseq of FSHD and control LCLs and primary myoblasts with corresponding in vitro differentiated myotubes

2020-06-30 | GSE153523 | GEO

DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle.

Project description:Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 macrosatellite array and recent studies have shown that this results in the expression of low levels of the DUX4 mRNA in skeletal muscle. Several other mechanisms have been suggested for FSHD pathophysiology and it remains unknown whether DUX4 expression can account for most of the molecular changes seen in FSHD. Since DUX4 is a transcription factor, we used RNA-seq to measure gene expression in muscle cells transduced with DUX4, and in muscle cells and biopsies from control and FSHD individuals. We show that DUX4 target gene expression is the major molecular signature in FSHD muscle together with a gene expression signature consistent with an immune cell infiltration. In addition, one unaffected individual without a known FSHD-causing mutation showed the expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of an unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that the expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration.

| S-EPMC4168822 | biostudies-literature

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