Muscular dystrophies involving the dystrophin–glycoprotein complex: an overview of current mouse models

Durbeej, Madeleine; Campbell, Kevin P.

doi:10.1016/s0959-437x(02)00309-x

Cited by 402 publications

(337 citation statements)

References 131 publications

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“…Organization of each of these structures is essential for proper functioning of the sarcomere and their perturbation can lead to malfunctioning of cardiac tissue. Several studies have linked cytoskeletal proteins to cardiomyopathy such as the Z-disc proteins ALP and ZASP/cypher [49,50], the membrane-associated cytoskeletal proteins dystrophin [51] and sarcoglycans [52], and the intermediate filament component desmin [53].…”

Section: Discussionmentioning

confidence: 99%

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Peche

Holak

Burgute

et al. 2012

Cell. Mol. Life Sci.

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Cyclase-associated proteins are highly conserved proteins that have a role in the regulation of actin dynamics. Higher eukaryotes have two isoforms, CAP1 and CAP2. To study the in vivo function of CAP2, we generated mice in which the CAP2 gene was inactivated by a gene-trap approach. Mutant mice showed a decrease in body weight and had a decreased survival rate. Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times. Moreover, CAP2-deficient myofibrils exhibited reduced cooperativity of calciumregulated force development. At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis. We analyzed CAP2's role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain. Thus CAP2 is an essential component of the myocardial sarcomere and is essential for physiological functioning of the cardiac system, and a deficiency leads to DCM and various cardiac defects.

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Section: Discussionmentioning

confidence: 99%

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Peche

Holak

Burgute

et al. 2012

Cell. Mol. Life Sci.

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“…Those components include dystroglycans, sarcoglycans, sarcospan and dystrobrevin. 16,17 However, restoration of nNOS has not been previously detected after microdystrophin expression in dystrophindeficient mouse muscle 18 and the reasons remain elusive. In our previous studies, we did not make the effort to detect the restoration of nNOS.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 These proteins interact with each other and serve as a mechanical link and possibly signaling partners to protect the myofibers. At 3 months, after AAV1-cMinidys vector injection into neonatal (10 day of age) mdx mice, immunoflurescent staining was performed on the cryo-thin-sections of the gastrocnemius muscles from the normal C57/B10 mice, the untreated mdx littermates and the AAV-treated mdx mice, at same age.…”

Section: Cloning and Construction Of The Aav1-cminidys Vectormentioning

confidence: 99%

A canine minidystrophin is functional and therapeutic in mdx mice

Wang

Qiao

et al. 2008

Gene Ther

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Duchenne muscular dystrophy (DMD) is the most common and lethal genetic muscle disorder lacking a curative treatment. We wish to use the dystrophin-deficient golden retriever muscular dystrophy (GRMD) dog, a canine model of DMD, to investigate adeno-associated virus (AAV) vectormediated minidystrophin gene therapy. The dog model is useful in evaluating vector dose requirement and immunological consequences owing to its large size and outbred nature. In this study, we have cloned and constructed a canine minidystrophin gene vector. Owing to limited availability of the GRMD dogs, here we first examined the functions and therapeutic effects of the canine minidystrophin in the mdx mouse model. We observed efficient minigene expression without cellular immune responses in mdx mice after AAV1-cMinidys vector intramuscular injection. We also observed restoration of the missing dystrophin-associated protein complex (DPC) onto the sarcolemma, including sarcoglycans and dystrobrevin, and a partial restoration of a-syntrophin and neural nitric oxide synthase (nNOS). In addition, minidystrophin treatment ameliorated dystrophic pathology, such as fibrosis and myofiber central nucleation (CN). CN remained minimal (o2%) after AAV injection in the neonatal mdx mice and was reduced from more than 75% to about 25% after AAV injection in adult mdx mice. Finally, in vivo cell membrane leakage test with Evans blue dye showed that the canine minidystrophin could effectively protect the myofiber plasma membrane integrity. Our results, thus, demonstrated the functionality and therapeutic potential of the canine minidystrophin and paved its way for further testing in the GRMD dog model.

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“…The mdx mouse is an established and widely employed animal model of x-linked muscular dystrophy with a point mutation in the dystrophin gene [25]. Mildly affected EOM and severely dystrophic diaphragm muscle from male 9-week-old mdx mice and normal tissues from age-matched C57 mice were obtained from the Bioresource Unit of NUI Maynooth [7].…”

Section: Dystrophic Muscle Samplesmentioning

confidence: 99%

“…The mdx mouse represents an established animal model of DMD, which exhibits severe muscle degeneration in the diaphragm, segmental necrosis in leg muscles, and a mild phenotype in EOM [25]. Proteomic profiling of Dp427-deficient leg and diaphragm muscles has revealed drastic changes in the expression levels of adenylate kinase, the luminal Ca 2+ -binding protein calsequestrin (CSQ), the cytosolic Ca 2+ -binding protein regucalcin, and the cardiovascular heat shock protein (cvHsp), as well as a large number of metabolic and contractile muscle proteins, as recently reviewed by Lewis et al [2].…”

Section: Introductionmentioning

confidence: 99%

Proteomic profiling of naturally protected extraocular muscles from the dystrophin-deficient mdx mouse

Lewis

Ohlendieck

2010

Biochemical and Biophysical Research Communications

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a b s t r a c tDuchenne muscular dystrophy is the most frequent neuromuscular disorder of childhood. Although this xlinked muscle disease is extremely progressive, not all subtypes of skeletal muscles are affected in the same way. While extremities and trunk muscles are drastically weakened, extraocular muscles are usually spared in Duchenne patients. In order to determine the global protein expression pattern in these naturally protected muscles we have performed a comparative proteomic study of the established mdx mouse model of x-linked muscular dystrophy. Fluorescence difference in-gel electrophoretic analysis of 9-week-old dystrophin-deficient versus age-matched normal extraocular muscle, using a pH 4-7 gel range, identified out of 1088 recognized protein spots a moderate expression change in only seven protein species. Desmin, apolipoprotein A-I binding protein and perilipin-3 were found to be increased and gelsolin, gephyrin, transaldolase, and acyl-CoA dehydrogenase were shown to be decreased in mdx extraocular muscles. Immunoblotting revealed a drastic up-regulation of utrophin, comparable levels of b-dystroglycan and key Ca 2+ -regulatory elements, and an elevated concentration of small stress proteins in mdx extraocular muscles. This suggests that despite the lack of dystrophin only a limited number of cellular systems are perturbed in mdx extraocular muscles, probably due to the substitution of dystrophin by its autosomal homolog. Utrophin appears to prevent the loss of dystrophin-associated proteins and Ca 2+ -handling elements in extraocular muscle tissue. Interestingly, the adaptive mechanisms that cause the sparing of extraocular fibers seem to be closely linked to an enhanced cellular stress response.

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Muscular dystrophies involving the dystrophin–glycoprotein complex: an overview of current mouse models

Cited by 402 publications

References 131 publications

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

A canine minidystrophin is functional and therapeutic in mdx mice

Proteomic profiling of naturally protected extraocular muscles from the dystrophin-deficient mdx mouse

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