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Collagen type VI regulates TGFβ bioavailability in skeletal muscle

ABSTRACT: Collagen VI-related disorders (COL6-RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes. ¬¬Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. Collagen VI absence or mislocalization in the skeletal muscle ECM underlies the non-cell autonomous dystrophic changes and dysfunction in skeletal muscle in COL6-RDs with an as of yet elusive direct mechanistic link between the ECM and myofiber dysfunction. Here, we derive a novel mouse model of COL6-RD, Col6a2-/- mice, and conduct a comprehensive natural history study in male and female animals aged to 60 weeks of age. Col6a2-/- mice have a normal lifespan but develop muscle weakness based on standardized behavioral tests (grip and hanging wire test), muscle atrophy with histologic hallmarks of muscular dystrophy, and reduced muscle force prodcution on physiologic parameters. We also report a robust dysregulation of TGFβ pathway early in the disease process and thus propose a new mechanism for pathogenesis of the disease that links the ECM regulation of TGFβ with downstream skeletal muscle abnormalities, paving the way for developing therapeutics that target this pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE228223 | GEO | 2023/12/04

REPOSITORIES: GEO

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Transcriptional profile in dermal fibroblasts from patients with collagen VI related muscular dystrophy

Project description:Objectives: The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies, but the pathogenesis, including the role of mutant collagen VI in the matrix is poorly understood. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD patients from controls. Methods: We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD patients (8 dominant negative and 5 null) and 6 controls. Sequence reads were analyzed using the TopHat/Cufflinks pipeline. Results: Differentially expressed transcripts between COL6-RD patient and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples

2017-12-04 | GSE103270 | GEO

Comparative Genomic Hybridization: genomic control vs. Ullrich Congenital Muscular Dystrophy and Bethlem myopathy

Project description:Molecular characterization of collagen-VI related myopathies currently relies on standard sequencing, which yields a detection rate approximating 75-79% in Ullrich congenital muscular dystrophy (UCMD) and 60-65% in Bethlem myopathy (BM) patients as PCR-based techniques tend to miss gross genomic rearrangements as well as copy number variations (CNVs) in both the coding sequence and intronic regions. We have designed a custom oligonucleotide CGH array in order to investigate the presence of CNVs in the coding and non-coding regions of COL6A1, A2, A3, A5 and A6 genes and a group of genes functionally related to collagen VI. A cohort of 12 patients with UCMD/BM negative at sequencing analysis and 2 subjects carrying a single COL6 mutation whose clinical phenotype was not explicable by inheritance were selected and the occurrence of allelic and genetic heterogeneity explored. A deletion within intron 1A of the COL6A2 gene, occurring in compound heterozygosity with a small deletion in exon 28, previously detected by routine sequencing, was identified in a BM patient. RNA studies showed monoallelic transcription of the COL6A2 gene, thus elucidating the functional effect of the intronic deletion. No pathogenic mutations were identified in the remaining analyzed patients, either within COL6A genes, or in genes functionally related to collagen VI. Our custom CGH array may represent a useful complementary diagnostic tool, especially in recessive forms of the disease, when only one mutant allele is detected by standard sequencing. The intronic deletion we identified represents the first example of a pure intronic mutation in COL6A genes. Comparative Genomic Hybridization experiment. Experimental Replicates: twice

2010-01-27 | E-GEOD-20025 | biostudies-arrayexpress

Transcriptome analysis of collagen VI-related muscular dystrophy muscle biopsies [RNA-Seq].

Project description:Collagen VI-related muscular dystrophies (COL6RD) are a rare, inherited group of congenital muscular dystrophies. The phenotype spans from an early-onset, severe, and rapidly progressive clinical course in Ullrich congenital muscular dystrophy (UCMD), to a late-onset, mild and slowly progressive form in Bethlem muscular dystrophy (BM). COL6RD are caused by pathogenic variants in any of the three collagen type VI genes (COL6A1, COL6A2, COL6A3), which cause absence, reduction, mislocalization, or dysfunction of the collagen VI microfibrils in the skeletal muscle extracellular matrix (myomatrix), leading to yet incompletely understood downstream effects. Pathologic alterations in muscle biopsies of COL6RD varies, ranging from severely dystrophic changes, to mildly myopathic, represented by isolated myofiber atrophy. In this study, we aim to define the pathophysiologic events responsible for the histologic alterations of muscle and their progression in COL6RD. Aided by automated image analysis, we reviewed COL6RD patient muscle biopsies (n=22) and stratified them to three groups based on the degree of fibrosis and muscle fiber atrophy. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared it with controls (n=14). Different histologic groups were characterized by similar transcriptional signatures predominantly featuring the upregulation of myomatrix component genes and downregulation of skeletal muscle and mitochondrion-specific genes. Our results also identified the TGFβ1 pathway in strong correlation with the development of COL6RD pathology at the histologic level, beginning early in the disease process, preceding fibrosis, and increasing in direct correlation with increased histologic severity. Overall, our study identifies COL6RD as a primary disorder of the myomatrix and posits dysregulation of TGFβ1-dependent pathways as a potential factor in pathogenesis of the disease.

2022-03-22 | GSE103608 | GEO

Transcriptome analysis of collagen VI-related muscular dystrophy muscle biopsies [Microarray].

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Muscle from patients with mitochondrial myopathies and congenital muscular dystrophies versus normal human muscle

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2010-01-28 | GSE20025 | GEO

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Gene expression analysis of human adipose-derived stem cells.

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Gene expression analysis of human adipose-derived stem cells.

Project description:Transcriptional activity was identified in all categories of genes expressed by ADSC, including collagens, ECM and basement membrane constituents, adhesion molecules involved in cell-cell and cell-matrix interactions, and proteases involved in degradation of the ECM and their inhibitors. Importantly, it was observed that ADSC synthesize and secrete all three collagen VI chains, suggesting suitability of ADSC for collagen VI congenital muscular dytrophy treatment. We developed a procedure for isolation of human stem cells from adipose layer of neonatal foreskin skin. The adipose-derived stem cells (ADSC) were examined for expression of extracellular matrix (ECM) and related genes using gene expression array analysis.

2013-09-21 | E-GEOD-51030 | biostudies-arrayexpress

Collagen VI sustains cell stemness and chemotherapy resistance in glioblastoma.

Project description:Microenvironmental factors are known fundamentals regulators of the phenotype and aggressiveness of glioblastoma (GBM), the most lethal brain tumor, characterized by fast progression and marked resistance to treatments. In this context, the extracellular matrix (ECM) is known to heavily influence the behavior of cancer cells from several origins, contributing to stem cell niches, influencing tumor invasiveness and response to chemotherapy, mediating survival signaling cascades, and modulating inflammatory cell recruitment. Here we show that collagen VI (COL6), an ECM protein widely expressed in both normal and pathological tissues, has a distinctive distribution within the GBM mass, strongly correlating with the most aggressive and phenotypically immature cells. Our data demonstrate that COL6 sustains the stem-like properties of GBM cells and supports the maintenance of an aggressive transcriptional program promoting cancer cell proliferation and survival. In particular, we identified a specific subset of COL6-transcriptionally regulated genes, required for the response of cells to replicative stress and DNA damage, supporting the concept that COL6 is an essential stimulus for the activation of GBM cell response and resistance to chemotherapy, through the ATM/ATR axis. Altogether, these findings indicate that COL6 plays a pivotal role in GBM tumor biology, exerting a pleiotropic action across different GBM hallmarks, including phenotypic identity and gene transcription, as well as response to treatments, thus providing valuable information for the understanding of the complex microenvironmental cues underlying GBM malignancy. Collagen VI is over-expressed in the cancer stem cell niche in glioblastoma and protects them from differentiation stimuli and chemotherapy exposure.

2023-08-03 | GSE226700 | GEO

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