Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies

1997 ◽  
Vol 110 (22) ◽  
pp. 2873-2881 ◽  
Author(s):  
B.L. Hodges ◽  
Y.K. Hayashi ◽  
I. Nonaka ◽  
W. Wang ◽  
K. Arahata ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Gene Transcription ◽  
Muscle Development ◽  
Structural Integrity ◽  
Laminin Receptor ◽  
Muscular Dystrophies ◽  
Mdx Mice ◽  
Altered Expression ◽  
Alternatively Spliced ◽  
Alpha7beta1 Integrin

The alpha7beta1 integrin is the primary laminin receptor on skeletal myoblasts and adult myofibers. It has distinct functions during muscle development and contributes to muscle structural integrity. We have studied this integrin in cases where expression of dystrophin or laminin are compromised. Immunofluorescence demonstrates an increase in alpha7beta1 in patients with Duchenne muscular dystrophy and in mdx mice that lack dystrophin. Analysis of RNA from mdx mice and from patients with Duchenne and Becker muscular dystrophies indicates that the increase in the alpha7beta1 integrin is regulated at the level of alpha7 gene transcription. In contrast, the levels of alpha7beta1 integrin are severely diminished in patients with laminin alpha2 chain congenital dystrophy muscular dystrophy and in dy/dy mice that also do not make the alpha2 laminin chain. Analysis of RNA from the hindlimbs of dy/dy mice demonstrated that in the absence of laminin alpha7 gene transcription is inhibited and limited to specific alternatively spliced isoforms. We suggest that the increased expression of alpha7beta1 integrin in the absence of dystrophin compensates for the reduced dystrophin-mediated linkage of fibers with the basal lamina and modulates the development of pathology associated with these diseases. The decrease in alpha7beta1 integrin and its transcripts in the absence of laminin likely contributes to the severe myopathy that results from laminin alpha2 chain deficiency and suggests that laminin-2 regulates expression of the alpha7 integrin gene. The role of the alpha7beta1 integrin in muscle integrity also suggests that compromised expression of this receptor may underlie as yet undefined myopathies.

Gene expression profiling of diaphragm muscle in α2-laminin (merosin)-deficient dy/dy dystrophic mice

2006 ◽  
Vol 25 (1) ◽  
pp. 85-95 ◽  
Author(s):  
Erik van Lunteren ◽  
Michelle Moyer ◽  
Patrick Leahy
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Muscle Fiber ◽  
Muscle Development ◽  
Biological Process ◽  
Expression Profiles ◽  
Congenital Muscular Dystrophy ◽  
Diaphragm Muscle ◽  
Altered Expression ◽  
Process Groups

Deficiency of α2-laminin (merosin) underlies classical congenital muscular dystrophy in humans and dy/dy muscular dystrophy in mice and causes severe muscle dysfunction in both species. To gain greater insight into the biochemical and molecular events that link α2-laminin deficiency with muscle fiber necrosis, and the associated compensatory responses, gene expression profiles were characterized in diaphragm muscle from 8-wk-old dy/dy mice using oligonucleotide microarrays. Compared with age-matched normal muscle, dystrophic diaphragm was characterized by predominantly augmented gene expression, irrespective of the fold-change threshold. Among the 69 genes with at least plus or minus twofold significantly altered expression, 30 belonged to statistically overrepresented Gene Ontology (GO) biological process groups. These covered four specific themes: development including muscle development, cell motility with an emphasis on muscle contraction, defense/immune response, and cell adhesion. An additional 11 gene transcripts were assigned to more general overrepresented GO biological process groups (e.g., cellular process, organismal physiological process); the remaining 28 did not belong to any overrepresented groups. GO cellular constituent assignment resulted in the highest degree of overrepresentation in extracellular and muscle fiber locations, whereas GO molecular function assignment was most notable for various types of binding. RT-PCR was performed on 38 of 41 genes with at least plus or minus twofold significantly altered expression that were assigned to overrepresented GO biological process groups, with expression changes verified for 36 of 38 genes. These results indicate that several specific groups of genes have altered expression in response to genetic α2-laminin deficiency, with both similarities and differences compared with data reported for dystrophin-deficient muscular dystrophies.

scholarly journals Sarcospan reduces dystrophic pathology: stabilization of the utrophin–glycoprotein complex

2008 ◽  
Vol 183 (3) ◽  
pp. 419-427 ◽  
Author(s):  
Angela K. Peter ◽  
Jamie L. Marshall ◽  
Rachelle H. Crosbie
Keyword(s):  
Muscular Dystrophy ◽  
Dystrophin Gene ◽  
Muscular Dystrophies ◽  
Mdx Mice ◽  
Future Design ◽  
Glycoprotein Complex ◽  
Analogous Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Extrasynaptic Membrane ◽  
Dystrophin Glycoprotein

Mutations in the dystrophin gene cause Duchenne muscular dystrophy and result in the loss of dystrophin and the entire dystrophin–glycoprotein complex (DGC) from the sarcolemma. We show that sarcospan (SSPN), a unique tetraspanin-like component of the DGC, ameliorates muscular dystrophy in dystrophin-deficient mdx mice. SSPN stabilizes the sarcolemma by increasing levels of the utrophin–glycoprotein complex (UGC) at the extrasynaptic membrane to compensate for the loss of dystrophin. Utrophin is normally restricted to the neuromuscular junction, where it replaces dystrophin to form a functionally analogous complex. SSPN directly interacts with the UGC and functions to stabilize utrophin protein without increasing utrophin transcription. These findings reveal the importance of protein stability in the prevention of muscular dystrophy and may impact the future design of therapeutics for muscular dystrophies.

scholarly journals Profiling of Age-Related Changes in theTibialis AnteriorMuscle Proteome of the mdx Mouse Model of Dystrophinopathy

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Steven Carberry ◽  
Margit Zweyer ◽  
Dieter Swandulla ◽  
Kay Ohlendieck
Keyword(s):  
Muscular Dystrophy ◽  
Tibialis Anterior ◽  
Large Scale ◽  
Small Heat Shock Protein ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Global Changes ◽  
Altered Expression ◽  
Age Related

X-linked muscular dystrophy is a highly progressive disease of childhood and characterized by primary genetic abnormalities in the dystrophin gene. Senescent mdx specimens were used for a large-scale survey of potential age-related alterations in the dystrophic phenotype, because the established mdx animal model of dystrophinopathy exhibits progressive deterioration of muscle tissue with age. Since the mdxtibialis anteriormuscle is a frequently used model system in muscular dystrophy research, we employed this particular muscle to determine global changes in the dystrophic skeletal muscle proteome. The comparison of mdx mice aged 8 weeks versus 22 months by mass-spectrometry-based proteomics revealed altered expression levels in 8 distinct protein species. Increased levels were shown for carbonic anhydrase, aldolase, and electron transferring flavoprotein, while the expressions of pyruvate kinase, myosin, tropomyosin, and the small heat shock protein Hsp27 were found to be reduced in aged muscle. Immunoblotting confirmed age-dependent changes in the density of key muscle proteins in mdx muscle. Thus, segmental necrosis in mdxtibialis anteriormuscle appears to trigger age-related protein perturbations due to dystrophin deficiency. The identification of novel indicators of progressive muscular dystrophy might be useful for the establishment of a muscle subtype-specific biomarker signature of dystrophinopathy.

scholarly journals Advances in gene therapy for muscular dystrophies

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2030 ◽  
Author(s):  
Hayder Abdul-Razak ◽  
Alberto Malerba ◽  
George Dickson
Keyword(s):  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Gene Transcription ◽  
Therapeutic Strategies ◽  
Mrna Processing ◽  
Muscular Dystrophies ◽  
Gene Encoding ◽  
Recessive Lethal ◽  
Cellular Machinery

Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments.

Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

1987 ◽  
Vol 45 ◽  
pp. 726-727
Author(s):  
H. D. Geissinge ◽  
L.D. Rhodes
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Tibialis Anterior ◽  
Physiological Activity ◽  
Mdx Mice ◽  
Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

scholarly journals Age-Dependent Dysregulation of Muscle Vasculature and Blood Flow Recovery after Hindlimb Ischemia in the mdx Model of Duchenne Muscular Dystrophy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 481
Author(s):  
Paulina Podkalicka ◽  
Olga Mucha ◽  
Katarzyna Kaziród ◽  
Iwona Bronisz-Budzyńska ◽  
Sophie Ostrowska-Paton ◽  
...  
Keyword(s):  
Blood Flow ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Blood Vessels ◽  
Mdx Mice ◽  
Hindlimb Ischemia ◽  
Double Positive ◽  
Functional Studies ◽  
Age Dependent ◽  
Dystrophic Mice

Duchenne muscular dystrophy (DMD), caused by a lack of functional dystrophin, is characterized by progressive muscle degeneration. Interestingly, dystrophin is also expressed in endothelial cells (ECs), and insufficient angiogenesis has already been hypothesized to contribute to DMD pathology, however, its status in mdx mice, a model of DMD, is still not fully clear. Our study aimed to reveal angiogenesis-related alterations in skeletal muscles of mdx mice compared to wild-type (WT) counterparts. By investigating 6- and 12-week-old mice, we sought to verify if those changes are age-dependent. We utilized a broad spectrum of methods ranging from gene expression analysis, flow cytometry, and immunofluorescence imaging to determine the level of angiogenic markers and to assess muscle blood vessel abundance. Finally, we implemented the hindlimb ischemia (HLI) model, more biologically relevant in the context of functional studies evaluating angiogenesis/arteriogenesis processes. We demonstrated that both 6- and 12-week-old dystrophic mice exhibited dysregulation of several angiogenic factors, including decreased vascular endothelial growth factor A (VEGF) in different muscle types. Nonetheless, in younger, 6-week-old mdx animals, neither the abundance of CD31+α-SMA+ double-positive blood vessels nor basal blood flow and its restoration after HLI was affected. In 12-week-old mdx mice, although a higher number of CD31+α-SMA+ double-positive blood vessels and an increased percentage of skeletal muscle ECs were found, the abundance of pericytes was diminished, and blood flow was reduced. Moreover, impeded perfusion recovery after HLI associated with a blunted inflammatory and regenerative response was evident in 12-week-old dystrophic mice. Hence, our results reinforce the hypothesis of age-dependent angiogenic dysfunction in dystrophic mice. In conclusion, we suggest that older mdx mice constitute an appropriate model for preclinical studies evaluating the effectiveness of vascular-based therapies aimed at the restoration of functional angiogenesis to mitigate DMD severity.

scholarly journals Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies

2021 ◽  
Vol 22 (10) ◽  
pp. 5276
Author(s):  
Coralie Croissant ◽  
Romain Carmeille ◽  
Charlotte Brévart ◽  
Anthony Bouter
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Genetic Disorders ◽  
Muscle Cells ◽  
Cell Types ◽  
Clinical Severity ◽  
Skeletal Muscle Cells ◽  
Muscular Dystrophies ◽  
Membrane Repair ◽  
Human Skeletal Muscle Cells

Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.

Sign in / Sign up

Export Citation Format

Share Document