Dysferlin Regulates Cell Adhesion in Human Monocytes

Morrée, Antoine de; Flix, Bàrbara; Bagaric, Ivana; Wang, Jun; Boogaard, Marlinde L. van den; Moursel, Laure Grand; Frants, Rune R.; Illa, Isabel; Gallardo, Eduard; Toes, René E. M.; Maarel, Silvère M. van der

doi:10.1074/jbc.m112.448589

Cited by 53 publications

(39 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The presence of inflammation has been observed in other muscular dystrophies such as Duchenne muscular dystrophy (DMD) [21] and facioscapulohumeral muscular dystrophy [11,21,22]. The absence of dysferlin has also been reported to enhance phagocytosis in murine monocytes [16], and macrophages from patients with dysferlinopathy show altered adhesion and motility [23]. These findings suggest that in dysferlinopathies, muscle inflammatory infiltrates could worsen and perpetuate the dystrophic process.…”

mentioning

confidence: 78%

Bone Marrow Transplantation in Dysferlin-Deficient Mice Results in a Mild Functional Improvement

Flix

Suárez‐Calvet²,

Díaz‐Manera³

et al. 2013

Stem Cells and Development

Self Cite

View full text Add to dashboard Cite

Dysferlinopathies are caused by mutations in the DYSF gene. Dysferlin is a protein mainly expressed in the skeletal muscle and monocytes. Cell therapy constitutes a promising tool for the treatment of muscular dystrophies. The aim of our study was to evaluate the effect of bone marrow transplantation (BMT) using the A/J Dysf prmd mouse model of dysferlinopathy. For that purpose, we studied dysferlin expression by western blot and/or immunohistochemistry in transplanted mice and controls. Computerized analyses of locomotion and electrophysiological techniques were also performed to test the functional improvement. We observed dysferlin expression in splenocytes, but not in the skeletal muscle of the transplanted mice. However, the locomotion test, electromyography studies, and muscle histology showed an improvement in all transplanted mice that was more significant in the animals transplanted with dysferlin + / + cells. In conclusion, although BMT restores dysferlin expression in monocytes, but not in skeletal muscle, muscle function was partially recovered. We propose that the slight improvement observed in the functional studies could be related with factors, such as the hepatocyte growth factor, released after BMT that prevented muscle degeneration.

show abstract

mentioning

confidence: 78%

Bone Marrow Transplantation in Dysferlin-Deficient Mice Results in a Mild Functional Improvement

Flix

Suárez‐Calvet²,

Díaz‐Manera³

et al. 2013

Stem Cells and Development

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, freshly isolated monocytes of dysferlinopathy patients show deregulated expression of fibronectin and fibronectin-binding integrins which is recapitulated by transient knockdown of dysferlin in the human monocytic cell line, THP1. Dysferlin regulates cellular interactions by forming a complex with integrins at the cell membrane (de Morree et al, 2013). In humans, the dysferlin transcript is highly expressed in skeletal muscle, heart, placenta, and more weakly in liver, lung, kidney and pancreas (Bashir et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Dysferlin is essential for endocytosis in the sea star oocyte

Oulhen

Onorato

Ramos

et al. 2014

Developmental Biology

View full text Add to dashboard Cite

Dysferlin is a calcium-binding transmembrane protein involved in membrane fusion and membrane repair. In humans, mutations in the dysferlin gene are associated with muscular dystrophy. In this study, we isolated plasma membrane-enriched fractions from full-grown immature oocytes of the sea star, and identified dysferlin by mass spectrometry analysis. The full-length dysferlin sequence is highly conserved between human and the sea star. We learned that in the sea star Patiria miniata, dysferlin RNA and protein are expressed from oogenesis to gastrulation. Interestingly, the protein is highly enriched in the plasma membrane of oocytes. Injection of a morpholino against dysferlin leads to a decrease of endocytosis in oocytes, and to a developmental arrest during gastrulation. These results suggest that dysferlin is critical for normal endocytosis during oogenesis and for embryogenesis in the sea star and that this animal may be a useful model for studying the relationship of dysferlin structure as it relates to its function.

show abstract

“…Dysferlin is a 230-kDa protein composed of seven C2 domains with homology to synaptotagmin (2, 3) and a single transmembrane domain near its C terminus (4, 5). The complexity of dysferlin's potential role in muscle is highlighted by the number of its purported functions, including membrane repair (2, 3), vesicle fusion (4), microtubule regulation (5, 6), cell adhesion (7,8), and intercellular signaling (9). Understanding the contributions of dysferlin to the maintenance of normal skeletal muscle function is critical for the development of appropriate therapies for patients diagnosed with LGMD2B and MM.…”

mentioning

confidence: 99%

Dysferlin stabilizes stress-induced Ca ²⁺ signaling in the transverse tubule membrane

Kerr

Ziman

Mueller

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

114

176

View full text Add to dashboard Cite

Dysferlinopathies, most commonly limb girdle muscular dystrophy 2B and Miyoshi myopathy, are degenerative myopathies caused by mutations in the DYSF gene encoding the protein dysferlin. Studies of dysferlin have focused on its role in the repair of the sarcolemma of skeletal muscle, but dysferlin's association with calcium (Ca 2+ ) signaling proteins in the transverse (t-) tubules suggests additional roles. Here, we reveal that dysferlin is enriched in the t-tubule membrane of mature skeletal muscle fibers. Following experimental membrane stress in vitro, dysferlin-deficient muscle fibers undergo extensive functional and structural disruption of the t-tubules that is ameliorated by reducing external [Ca 2+ ] or blocking L-type Ca 2+ channels with diltiazem. Furthermore, we demonstrate that diltiazem treatment of dysferlin-deficient mice significantly reduces eccentric contraction-induced t-tubule damage, inflammation, and necrosis, which resulted in a concomitant increase in postinjury functional recovery. Our discovery of dysferlin as a t-tubule protein that stabilizes stress-induced Ca 2+ signaling offers a therapeutic avenue for limb girdle muscular dystrophy 2B and Miyoshi myopathy patients.excitation-contraction coupling | dihydropyridine receptor | triad junction | muscle injury D ysferlinopathies are degenerative myopathies secondary to mutations in the gene encoding the protein dysferlin. These myopathies, most commonly limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), are independent of motor neuron activation (1), indicating that they are myogenic in origin. Dysferlin is a 230-kDa protein composed of seven C2 domains with homology to synaptotagmin (2, 3) and a single transmembrane domain near its C terminus (4, 5). The complexity of dysferlin's potential role in muscle is highlighted by the number of its purported functions, including membrane repair (2, 3), vesicle fusion (4), microtubule regulation (5, 6), cell adhesion (7,8), and intercellular signaling (9). Understanding the contributions of dysferlin to the maintenance of normal skeletal muscle function is critical for the development of appropriate therapies for patients diagnosed with LGMD2B and MM.Recently, we demonstrated the localization of dysferlin at the A-I junction in mature muscle fibers (10). These results agree with earlier reports associating dysferlin with the dihydropyridine receptor (DHPR, L-type Ca 2+ channel), Ahnak, caveolin 3, and several other proteins involved in Ca 2+ -based signaling and the function of transverse (t-) tubules (11)(12)(13)(14). Consistent with this localization and the potential for a functional role in this specialized compartment, dysferlin-deficient murine muscle demonstrates altered transverse tubule (t-tubule) structure (15) as well as increased oxidative stress (16, 17), inflammation, and necrosis (18-20) after injury.Here we demonstrate that dysferlin is enriched in the t-tubule membrane, where it contributes to the maintenance of the t-tubule and Ca 2+ homeostasis. We show...

show abstract

Dysferlin Regulates Cell Adhesion in Human Monocytes

Cited by 53 publications

References 42 publications

Bone Marrow Transplantation in Dysferlin-Deficient Mice Results in a Mild Functional Improvement

Bone Marrow Transplantation in Dysferlin-Deficient Mice Results in a Mild Functional Improvement

Dysferlin is essential for endocytosis in the sea star oocyte

Dysferlin stabilizes stress-induced Ca ²⁺ signaling in the transverse tubule membrane

Contact Info

Product

Resources

About

Dysferlin Regulates Cell Adhesion in Human Monocytes

Cited by 53 publications

References 42 publications

Bone Marrow Transplantation in Dysferlin-Deficient Mice Results in a Mild Functional Improvement

Bone Marrow Transplantation in Dysferlin-Deficient Mice Results in a Mild Functional Improvement

Dysferlin is essential for endocytosis in the sea star oocyte

Dysferlin stabilizes stress-induced Ca 2+ signaling in the transverse tubule membrane

Contact Info

Product

Resources

About

Dysferlin stabilizes stress-induced Ca ²⁺ signaling in the transverse tubule membrane