A simple and rapid immunoassay predicts dysferlinopathies in peripheral blood film

Dysferlin is encoded by the DYSF gene on chromosome 2p13 as a protein of approximately 237 kDa. Dysferlin is widely expressed, but it predominates at the sarcolemma of striated muscle [1] where it is involved in membrane repair [2,3], regeneration [4] and differentiation [5]. Mutations in DYSF cause the autosomal recessive muscular disorders limb girdle muscular dystrophy R2 (LGMDR2 dysferlin-related, formerly LGMD2B, OMIM 253601), Miyoshi Myopathy (OMIM 254130), distal myopathy with anterior tibial onset (OMIM 606768) and congenital muscular dystrophy [1,6 –8].
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research

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Gene editing could be a powerful tool to repair disease-causing mutations in patient-derived primary cells, but precise gene correction remains inefficient. In our study, we aimed to repair mutations in the Calpain 3 (CAPN3) gene, which causes limb girdle muscular dystrophy 2A (LGMD2A) upon loss. CAPN3 is a cysteine-protease predominantly expressed in skeletal muscle tissue. We have human primary muscle stem cells available from 35 patients covering 37 different CAPN3 mutations. 30% of patients carry CAPN3c.550delA in one or both of their alleles causing frame shift.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Dysferlinopathy, also known as limb-girdle muscular dystrophy type 2B (LGMD2B), is caused by mutations in DYSF. It is one of the most frequent of> 40 untreatable muscular dystrophies leading to progressive muscle degeneration and wheel-chair-dependency. We generated hiPSC from two patients carrying a founder frameshift mutation (c.1624delG) in DYSF exon 44 that results in a complete absence of dysferlin protein and developed various gene editing approaches to repair this mutation using CRISPR/Cas9.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Membrane repair is essential to cell survival. In skeletal muscle, injury often associates with plasma membrane disruption. Additionally, muscular dystrophy is linked to mutations in genes that produce fragile membranes or reduce membrane repair. Methods to enhance repair and reduce susceptibility to injury could benefit muscle in both acute and chronic injury settings. Annexins are a family of membrane-associated Ca2+-binding proteins implicated in repair, and annexin A6 was previously identified as a genetic modifier of muscle injury and disease. Annexin A6 forms the repair cap over the site of membrane disruption. To el...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
s A Abstract Mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5), is a member of the dual-specificity family of protein tyrosine phosphatases, which negatively regulates p38 MAPK and the c-Jun NH2 kinase (JNK). MKP-5-deficient mice exhibit improved muscle repair and reduced fibrosis in an animal model of muscular dystrophy. Here, we asked whether the effects of MKP-5 on muscle fibrosis extends to other tissues. Using a bleomycin-induced model of pulmonary fibrosis, we found that MKP-5-deficient mice were protected from the development of lung fibrosis and expressed reduced levels of hydroxyproline and fi...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research
Publication date: Available online 25 July 2019Source: Stem Cell ReportsAuthor(s): Takahiko Sato, Koki Higashioka, Hidetoshi Sakurai, Takuya Yamamoto, Naoki Goshima, Morio Ueno, Chie SotozonoSummaryThe use of adult skeletal muscle stem cells (MuSCs) for cell therapy has been attempted for decades, but still encounters considerable difficulties. MuSCs derived from human induced pluripotent stem cells (hiPSCs) are promising candidates for stem cell therapy to treat Duchenne muscular dystrophy (DMD). Here we report that four transcription factors, HEYL, KLF4, MYOD, and PAX3, selected by comprehensive screening of different Mu...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research
Viravuth (“Voot”) Yin, associate professor of regenerative biology and medicine at MDI Biological Laboratory and chief scientific officer at Novo Biosciences, Inc., in Bar Harbor, Maine. Credit: MDI Biological Laboratory. In 1980, a week after his 6th birthday, Viravuth (“Voot”) Yin immigrated with his mother, grandfather, and three siblings from Cambodia to the United States. Everything they owned fit into a single, 18-inch carry-on bag. They had to build new lives from almost nothing. So, it’s perhaps fitting that Yin studies regeneration, the fascinating ability of some animals, such ...
Source: Biomedical Beat Blog - National Institute of General Medical Sciences - Category: Research Authors: Tags: Being a Scientist Cool Creatures Regeneration Research Organisms RNA Source Type: blogs
This article introduces a new mathematical model, the FRiND model, to further elucidate these known immunological actions. We will perform stability and sensitivity analyses on this model. The models time course results will be verified by biological studies in the literature. This model could be the foundation for further understanding of immunological muscle repair. PMID: 31302876 [PubMed - as supplied by publisher]
Source: Bulletin of Mathematical Biology - Category: Bioinformatics Authors: Tags: Bull Math Biol Source Type: research
AbstractRotator cuff tears are common musculoskeletal injuries that can cause significant pain and disability. While the clinical results of rotator cuff repair can be good, failure of tendon healing remains a significant problem. Molecular mechanisms underlying structural failure following surgical repair remain unclear. Histologically, enhanced inflammation, disorganization of the collagen fibers, calcification, apoptosis and tissue necrosis affect the normal healing process. Mesenchymal stem cells (MSCs) have the ability to provide improved healing following rotator cuff repair via the release of mediators from secreted...
Source: Journal of Bone and Mineral Metabolism - Category: Orthopaedics Source Type: research
Conclusion and Perspectives The IL-6/JAK/STAT signaling cascade plays a dominant role in skeletal muscle pathophysiology. IL-6 autocrine, paracrine, and endocrine functions assign to its downstream effectors pivotal importance in skeletal muscle-wasting-associated diseases and other multiple system diseases where muscle acts in communication with other organs. Targeting the components of the JAK/STAT pathway recently emerged as a strategic approach for the treatment of inflammatory diseases and human cancer. This review highlights the opposite outcomes on muscle biology caused by the amount of local and systemic release ...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
In this study, we report the age-associated differences between fetal MSC (fMSC) populations and MSCs isolated from elderly donors with respect to their transcriptomes. We successfully reprogrammed fMSCs (55 days post conception) and adult MSC (aMSC; 60-74 years) to iPSCs and, subsequently, generated the corresponding iMSCs. In addition, iMSCs were also derived from ESCs. The iMSCs were similar although not identical to primary MSCs. We unraveled a putative rejuvenation and aging gene expression signature. We show that iMSCs irrespective of donor age and cell type re-acquired a similar secretome to that of th...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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