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MRI and gene signatures in facioscapulohumeral dystrophy muscle: implications for clinical trial design and mechanisms of disease progression

ABSTRACT: Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA, indicating that regional biopsies can accurately measure progression in the whole muscle and providing a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design. An unanticipated finding was the strong correlations of molecular signatures in the bilateral comparisons, including markers of B-cells and other immune cell populations, suggesting that a systemic immune cell infiltration of skeletal muscle might have a role in disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242912 | GEO | 2024/10/31

REPOSITORIES: GEO

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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

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

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 expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of yet unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration. RNA-seq for muscle cells and biopsies from control and FSHD individuals.

2014-07-03 | E-GEOD-56787 | biostudies-arrayexpress

Proteomics of muscle microdialysates identifies potential circulating biomarkers in Facioscapulohumeral muscular dystrophy

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is caused by a complex epigenetic mechanism finally leading to the misexpression of DUX4, a transcription factor normally silenced in skeletal muscle. Detecting DUX4 in skeletal muscle and quantifying disease progression in FSHD is extremely challenging, thus increasing the need for other surrogate biomarkers. We applied a shotgun proteomic approach with two different setups to analyze the protein repertoire of interstitial fluids obtained from 20 FSHD patients’ muscles in different disease stages classified by Magnetic Resonance Imaging (MRI) and controls. Serum samples from the same subjects were also analyzed. A total of 1156 proteins were identified in the microdialysates by Data Independent Acquisition, 130 of which only found in muscles in active disease stage. Proteomic profiles of interstitial fluids were able to distinguish FSHD patients from controls. Among the upregulated proteins in muscles with active disease, two innate immunity mediators (S100-A8 and A9) and Dermcidin were detected with both proteomic approaches and selectively present in the sera of FSHD patients. Structural muscle proteins were downregulated, consistent with signs of early damage, as well as proteins of the plasminogen pathway. This suggests, together with upstream inhibition in FSHD samples of myogenic factors, defective muscle regeneration and increased fibrosis already in early/active disease. Conclusions: our MRI targeted exploratory approach provided insights on pathophysiological pathways activated in early disease, confirming that inflammatory response has a prominent role, together with impaired muscle regeneration. We also identified three proteins as tissue and possibly circulating prognostic biomarkers in FSHD.

2021-09-09 | PXD021838 | Pride

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

2014-07-03 | GSE56787 | GEO

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

Project description:Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. Examine Dux4 full isoform binding sites in human fibroblast.

2012-01-03 | E-GEOD-33838 | biostudies-arrayexpress

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

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

| PRJNA475678 | ENA

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

Project description:Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. [Overexpression experiment] Quadruplicate total RNA samples were collected from control human primary myoblasts transduced with lentivirus carrying DUX4-fl, DUX4-s or GFP (MOI = 15) for 24 h and from untransduced myoblasts. [Defensin experiment] Quadruplicate samples were also collected from myoblasts and myotubes grown in media containing human beta-defensin 3 peptide or in control media.

2012-01-03 | E-GEOD-33799 | biostudies-arrayexpress

Gene expression analysis of FSHD muscle with different MRI pattern

Project description:Objective: to focus on the molecular mechanisms involved in the dystrophic process that leads to selective wasting of single muscles or muscle groups in Facioscapulohumeral muscular dystrophy (FSHD). By muscle MRI we observed that T2-short tau inversion recovery (T2-STIR) sequences identify two different patterns in which each muscle can be found before the irreversible dystrophic alteration, marked as T1-weighted sequence hyperintensity. We studied these conditions in order to obtain further information on the disease pathogenesis. Design: histopathology, gene expression profiling and real time PCR were performed on muscle biopsies. Subjects: muscles (n=8) with different MRI pattern (T1-weighted normal/T2-STIR normal and T1-weighted normal/T2-STIR hyperintense) from FSHD patients. Data were also compared with inflammatory myopathies (n=7), dysferlinopathies (n=4) and normal controls (n=7). Results: myopathic and inflammatory changes characterize T2-STIR hyperintense FSHD muscles, at variance with T2-STIR normal muscles. These two states can be easily distinguished from each other by their transcriptional profile. Comparison of T2-STIR hyperintense FSHD muscles with muscles of inflammatory myopathies shows peculiar changes, although many alterations are shared among these conditions. Conclusions: at the single muscle level, different stages of the disease correspond to the two MRI patterns. T2-STIR hyperintense FSHD muscles are more similar to inflammatory myopathies than to T2-STIR normal FSHD muscles or other muscular dystrophies, and share with them upregulation of genes involved in innate and adaptive immunity. Our data suggest that selective inflammation, together with perturbation in biological processes such as neoangiogenesis, lipid metabolism and adipokine production, may play a role in FSHD progression. 26 samples of human muscle muscle tissue were analysed using the Illumina beadchip technology.

2012-09-14 | E-GEOD-26852 | biostudies-arrayexpress

Porcine DUXC and human DUX4 activate similar embryonic programs cross species: implications for preclinical model of FSHD

Project description:DUX4 and its mouse ortholog Dux are normally expressed in the early embryo—the 4 cell or 2 cell cleavage stage embryo, respectively—and activate a portion of the first wave of zygotic gene expression. DUX4 is epigenetically suppressed in nearly all somatic tissue, whereas FSHD-causing mutations result in its aberrant expression in skeletal muscle, transcriptional activation of the early embryonic program, and subsequent muscle pathology. Although DUX4 and Dux both activate an early totipotent transcriptional program, divergence of their DNA binding domains limits the use of DUX4 expressed in mice as a pre-clinical model for FSHD. In this study, we identify the porcine DUXC mRNA expressed in early development and show that both pig DUXC and human DUX4 robustly activate a highly similar early embryonic program in pig muscle cells. These results support further investigation of pig preclinical models for FSHD.

2023-05-10 | GSE210772 | GEO

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