期刊
JOURNAL OF CELL SCIENCE
卷 129, 期 8, 页码 1671-1684出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.175927
关键词
RNAseq; Circadian rhythms; Interactome pathway; Myopathies
类别
资金
- BIO-NMD European Union Seventh Framework Programme [241665]
- Fondazione Telethon [GGP08017, GUP11007]
- RD-Connect EU project [305444]
- National Institutes of Health [AR066082]
- Muscular Dystrophy Campaign Centre Grant at UCL
- MRC Neuromuscular Centre at UCL
- Biomedical Research Centre at Great Ormond Street Hospital
- Great Ormond Street Hospital Children's Charity
- Medical Research Council [MR/N027302/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10036] Funding Source: researchfish
Collagen VI myopathies are genetic disorders caused by mutations in collagen 6 A1, A2 and A3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, which is recapitulated by collagen-VI-null (Col6a1(-/-)) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies, we performed a deep RNA profiling in both Col6a1(-/-) mice and patients with collagen VI pathology. The interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1(-/-) (also known as Arntl) mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and of autophagy-related genes. The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that might modify muscle damage pathogenesis.
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