Dysferlin and the plasma membrane repair in muscular dystrophy

Bansal, Dimple; Campbell, Kevin P.

doi:10.1016/j.tcb.2004.03.001

Cited by 288 publications

(264 citation statements)

References 56 publications

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“…Notably, mutated calpain-3 in patients with LGMD type 2A (LGMD2A) was the first enzyme, rather than structural protein, to be associated with muscular dystrophy (4). Mutations in dysferlin, a muscle membrane protein that plays a role in membrane repair, cause the LGMD type 2B (LGMD2B) and Miyoshi myopathy (MM) (5). Facioscapulohumeral muscular dystrophy (FSHD), a progressive muscle disease affecting mainly the muscles of the face and upper arms caused by deletions of a 3.3-kb repeat region located on 4q35.2 (6), is an additional common type of muscular dystrophy.…”

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confidence: 99%

Distinctive patterns of microRNA expression in primary muscular disorders

Eisenberg

Eran

Nishino

et al. 2007

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

460

518

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The primary muscle disorders are a diverse group of diseases caused by various defective structural proteins, abnormal signaling molecules, enzymes and proteins involved in posttranslational modifications, and other mechanisms. Although there is increasing clarification of the primary aberrant cellular processes responsible for these conditions, the decisive factors involved in the secondary pathogenic cascades are still mainly obscure. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs regulated during the degenerative process of muscle to gain insight into the specific regulation of genes that are disrupted in pathological muscle conditions. We describe 185 miRNAs that are up- or down-regulated in 10 major muscular disorders in humans [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis, dermatomyositis, and inclusion body myositis]. Although five miRNAs were found to be consistently regulated in almost all samples analyzed, pointing to possible involvement of a common regulatory mechanism, others were dysregulated only in one disease and not at all in the other disorders. Functional correlation between the predicted targets of these miRNAs and mRNA expression demonstrated tight posttranscriptional regulation at the mRNA level in DMD and Miyoshi myopathy. Together with direct mRNA–miRNA predicted interactions demonstrated in DMD, some of which are involved in known secondary response functions and others that are involved in muscle regeneration, these findings suggest an important role of miRNAs in specific physiological pathways underlying the disease pathology.

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mentioning

confidence: 99%

Distinctive patterns of microRNA expression in primary muscular disorders

Eisenberg

Eran

Nishino

et al. 2007

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

460

518

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“…Thus, these model systems may not fully represent the role of dysferlin in mature myofibers. Studies performed in mature muscle have relied on electron microscopy of dysferlinopathic muscle and on laser wounding to study dysferlin and its function as a sarcolemmal repair protein (2,3,(36)(37)(38). However, the ability of laser wounding to predict the outcome of interventional treatments for dysferlinopathies has been recently questioned (39).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

“…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.…”

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confidence: 99%

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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.

116

176

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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...

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“…In skeletal muscle, disruptions of the membrane are more frequent due to the repeated lengthening and shortening of muscle cells during contraction (11). Defects in the dysferlin gene result in limb-girdle muscular dystrophy type 2B (LGMD2B) and its allelic disease Miyoshi myopathy (12) through alter-ations in repair-vesicle fusion with the phospholipid membrane, resulting in necrosis of muscle fibers in both humans (13) and mice (14).…”

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confidence: 99%

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis

Sher

Aoyama

Huebsch

et al. 2006

Journal of Biological Chemistry

110

102

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Muscular dystrophies include a diverse group of genetically heterogeneous disorders that together affect 1 in 2000 births worldwide. The diseases are characterized by progressive muscle weakness and wasting that lead to severe disability and often premature death. Rostrocaudal muscular dystrophy (rmd) is a new recessive mouse mutation that causes a rapidly progressive muscular dystrophy and a neonatal forelimb bone deformity. The rmd mutation is a 1.6-kb intragenic deletion within the choline kinase beta (Chkb) gene, resulting in a complete loss of CHKB protein and enzymatic activity. CHKB is one of two mammalian choline kinase (CHK) enzymes (␣ and ␤) that catalyze the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid phosphatidylcholine. While mutant rmd mice show a dramatic decrease of CHK activity in all tissues, the dystrophy is only evident in skeletal muscle tissues in an unusual rostral-to-caudal gradient. Minor membrane disruption similar to dysferlinopathies suggest that membrane fusion defects may underlie this dystrophy, because severe membrane disruptions are not evident as determined by creatine kinase levels, Evans Blue infiltration, and unaltered levels of proteins in the dystrophin-glycoprotein complex. The rmd mutant mouse offers the first demonstration of a defect in a phospholipid biosynthetic enzyme causing muscular dystrophy, representing a unique model for understanding mechanisms of muscle degeneration.Muscular dystrophies are a variable class of more than 20 human disorders characterized by progressive muscle wasting and weakness resulting from myofiber degeneration and regeneration. Histologically, variation in myofiber size with centrally localized nuclei, fibrosis, and fatty infiltration are common features (1, 2). Despite their common pathologies, the genetic causes, severity, age of onset, and inheritance patterns vary widely among the dystrophies. The Muscular Dystrophy Association currently lists over 40 neuromuscular diseases as targets for its research programs and categorizes them by phenotypic characteristics such as age of onset, affected muscle groups, and inheritance pattern (Muscular Dystrophy Association, www.mdausa.org). In the last 10 years, the genetic mapping and identification of novel skeletal muscle genes, including cytoskeletal, cytosolic, nuclear membrane, sarcolemmal and extracellular matrix proteins, has dramatically changed this phenotype-based classification and provided clues as to the molecular basis of these disorders (3). What was once considered a single disease entity such as limb-girdle muscular dystrophy (LGMD) 4 has now been subdivided into seven different molecularly defined autosomal dominant (LGMD1A-1G) and ten autosomal recessive (LGMD2A-2J) diseases. Not surprisingly, many of these genes have converged to define pathways critical for the normal functioning and maintenance of skeletal muscles. The fact that many muscular dystrophy cases exist in which mutations to known dystrophy-causing genes have...

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Dysferlin and the plasma membrane repair in muscular dystrophy

Cited by 288 publications

References 56 publications

Distinctive patterns of microRNA expression in primary muscular disorders

Distinctive patterns of microRNA expression in primary muscular disorders

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

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis

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Dysferlin and the plasma membrane repair in muscular dystrophy

Cited by 288 publications

References 56 publications

Distinctive patterns of microRNA expression in primary muscular disorders

Distinctive patterns of microRNA expression in primary muscular disorders

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

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis

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