Muscle Development and Muscular Dystrophy in Chicken

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.

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Role of proteoglycans and glycosaminoglycans in Duchenne muscular dystrophy

Glycobiology ◽

10.1093/glycob/cwy058 ◽

2018 ◽

Vol 29 (2) ◽

pp. 110-123 ◽

Cited By ~ 8

Author(s):

Laurino Carmen ◽

Vadala’ Maria ◽

Julio Cesar Morales-Medina ◽

Annamaria Vallelunga ◽

Beniamino Palmieri ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mammalian Cells ◽

Muscle Development ◽

Glycoprotein Complex ◽

Experimental Therapies ◽

Dystrophin Protein

Abstract Duchenne muscular dystrophy (DMD) is an inherited fatal X-linked myogenic disorder with a prevalence of 1 in 3500 male live births. It affects voluntary muscles, and heart and breathing muscles. DMD is characterized by continuous degeneration and regeneration cycles resulting in extensive fibrosis and a progressive reduction in muscle mass. Since the identification of a reduction in dystrophin protein as the cause of this disorder, numerous innovative and experimental therapies, focusing on increasing the levels of dystrophin, have been proposed, but the clinical improvement has been unsatisfactory. Dystrophin forms the dystrophin-associated glycoprotein complex and its proteins have been studied as a promising novel therapeutic target to treat DMD. Among these proteins, cell surface glycosaminoglycans (GAGs) are found almost ubiquitously on the surface and in the extracellular matrix (ECM) of mammalian cells. These macromolecules interact with numerous ligands, including ECM constituents, adhesion molecules and growth factors that play a crucial role in muscle development and maintenance. In this article, we have reviewed in vitro, in vivo and clinical studies focused on the functional role of GAGs in the pathophysiology of DMD with the final aim of summarizing the state of the art of GAG dysregulation within the ECM in DMD and discussing future therapeutic perspectives.

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cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00555.2011 ◽

2012 ◽

Vol 303 (1) ◽

pp. E1-E17 ◽

Cited By ~ 75

Author(s):

Rebecca Berdeaux ◽

Randi Stewart

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Molecular Mechanisms ◽

Muscle Development ◽

Camp Signaling ◽

Metabolic Phenotype ◽

Muscle Adaptation ◽

Age Related ◽

Organ Systems

Among organ systems, skeletal muscle is perhaps the most structurally specialized. The remarkable subcellular architecture of this tissue allows it to empower movement with instructions from motor neurons. Despite this high degree of specialization, skeletal muscle also has intrinsic signaling mechanisms that allow adaptation to long-term changes in demand and regeneration after acute damage. The second messenger adenosine 3′,5′-monophosphate (cAMP) not only elicits acute changes within myofibers during exercise but also contributes to myofiber size and metabolic phenotype in the long term. Strikingly, sustained activation of cAMP signaling leads to pronounced hypertrophic responses in skeletal myofibers through largely elusive molecular mechanisms. These pathways can promote hypertrophy and combat atrophy in animal models of disorders including muscular dystrophy, age-related atrophy, denervation injury, disuse atrophy, cancer cachexia, and sepsis. cAMP also participates in muscle development and regeneration mediated by muscle precursor cells; thus, downstream signaling pathways may potentially be harnessed to promote muscle regeneration in patients with acute damage or muscular dystrophy. In this review, we summarize studies implicating cAMP signaling in skeletal muscle adaptation. We also highlight ligands that induce cAMP signaling and downstream effectors that are promising pharmacological targets.

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Actinin-Associated LIM Protein-Deficient Mice Maintain Normal Development and Structure of Skeletal Muscle

Molecular and Cellular Biology ◽

10.1128/mcb.21.5.1682-1687.2001 ◽

2001 ◽

Vol 21 (5) ◽

pp. 1682-1687 ◽

Cited By ~ 23

Author(s):

Kiwon Jo ◽

Bart Rutten ◽

Robert C. Bunn ◽

David S. Bredt

Keyword(s):

Muscular Dystrophy ◽

Muscle Development ◽

Pdz Domain ◽

Heterochromatic Region ◽

Large Family ◽

Facioscapulohumeral Muscular Dystrophy ◽

Lim Domain ◽

Lim Protein ◽

Lim Domains ◽

Lim Proteins

ABSTRACT The actinin-associated LIM protein, ALP, is the prototype of a large family of proteins containing an N-terminal PDZ domain and a C-terminal LIM domain. These PDZ-LIM proteins are components of the muscle cytoskeleton and occur along the Z lines owing to interaction of the PDZ domain with the spectrin-like repeats of α-actinin. Because PDZ and LIM domains are typically found in proteins that mediate cellular signaling, PDZ-LIM proteins are suspected to participate in muscle development. Interestingly the ALP gene occurs at 4q35 near the heterochromatic region mutated in facioscapulohumeral muscular dystrophy, indicating a possible role for ALP in this disease. Here, we describe the generation and analysis of mice lacking the ALP gene. Surprisingly, the ALP knockout mice show no gross histological abnormalities and maintain sarcolemmal integrity as determined by serum pyruvate kinase assays. The absence of a dystrophic phenotype in these mice suggests that down-regulation of ALP does not participate in facioscapulohumeral muscular dystrophy. These data suggest that ALP does not participate in muscle development or that an alternative PDZ-LIM protein can compensate for the lack of ALP.

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Development of muscle pathology in canine X-linked muscular dystrophy. II. Quantitative characterization of histopathological progression during postnatal skeletal muscle development

Acta Neuropathologica ◽

10.1007/s004010000308 ◽

2001 ◽

Vol 101 (5) ◽

pp. 469-478 ◽

Cited By ~ 23

Author(s):

Francesca Cozzi ◽

Massimiliano Cerletti ◽

Gaia C. Luvoni ◽

Rocco Lombardo ◽

Paola G. Brambilla ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Muscle Development ◽

Muscle Pathology ◽

Skeletal Muscle Development ◽

Quantitative Characterization

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Myostatin: a modulator of skeletal-muscle stem cells

Biochemical Society Transactions ◽

10.1042/bst0331513 ◽

2005 ◽

Vol 33 (6) ◽

pp. 1513-1517 ◽

Cited By ~ 26

Author(s):

F.S. Walsh ◽

A.J. Celeste

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Muscle Development ◽

Transforming Growth Factor ◽

Neutralizing Antibody ◽

Transforming Growth Factor Β ◽

Negative Regulator ◽

Mdx Mouse ◽

Specific Expression ◽

Myostatin Gene

Myostatin, or GDF-8 (growth and differentiation factor-8), was first identified through sequence identity with members of the BMP (bone morphogenetic protein)/TGF-β (transforming growth factor-β) superfamily. The skeletal-muscle-specific expression pattern of myostatin suggested a role in muscle development. Mice with a targeted deletion of the myostatin gene exhibit a hypermuscular phenotype. In addition, inactivating mutations in the myostatin gene have been identified in ‘double muscled’ cattle breeds, such as the Belgian Blue and Piedmontese, as well as in a hypermuscular child. These findings define myostatin as a negative regulator of skeletal-muscle development. Myostatin binds with high affinity to the receptor serine threonine kinase ActRIIB (activin type IIB receptor), which initiates signalling through a smad2/3-dependent pathway. In an effort to validate myostatin as a therapeutic target in a post-embryonic setting, a neutralizing antibody was developed by screening for inhibition of myostatin binding to ActRIIB. Administration of this antimyostatin antibody to adult mice resulted in a significant increase in both muscle mass and functional strength. Importantly, similar results were obtained in a murine model of muscular dystrophy, the mdx mouse. Unlike the myostatin-deficient animals, which exhibit both muscle hypertrophy and hyperplasia, the antibody-treated mice demonstrate increased musculature through a hypertrophic mechanism. These results validate myostatin inhibition as a therapeutic approach to muscle wasting diseases such as muscular dystrophy, sarcopenic frailty of the elderly and amylotrophic lateral sclerosis.

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

Physiological Genomics ◽

10.1152/physiolgenomics.00226.2005 ◽

2006 ◽

Vol 25 (1) ◽

pp. 85-95 ◽

Cited By ~ 18

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.

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Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment

10.1101/720920 ◽

2019 ◽

Cited By ~ 1

Author(s):

Virginie Mournetas ◽

Emmanuelle Massouridès ◽

Jean-Baptiste Dupont ◽

Etienne Kornobis ◽

Hélène Polvèche ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Pluripotent Stem Cells ◽

Muscle Development ◽

Mitochondrial Gene ◽

Therapeutic Interventions ◽

Disease Biomarkers ◽

Induced Pluripotent

ABSTRACTDuchenne muscular dystrophy (DMD) causes severe disability of children and death of young men, with an incidence of approximately 1/5,000 male births. Symptoms appear in early childhood, with a diagnosis made around 4 years old, a time where the amount of muscle damage is already significant, preventing early therapeutic interventions that could be more efficient at halting disease progression. In the meantime, the precise moment at which disease phenotypes arise – even asymptomatically – is still unknown. Thus, there is a critical need to better define DMD onset as well as its first manifestations, which could help identify early disease biomarkers and novel therapeutic targets.In this study, we have used human induced pluripotent stem cells (hiPSCs) from DMD patients to model skeletal myogenesis, and compared their differentiation dynamics to that of healthy control cells by a comprehensive multi-omic analysis. Transcriptome and miRnome comparisons combined with protein analyses at 7 time points demonstrated that hiPSC differentiation 1) mimics described DMD phenotypes at the differentiation endpoint; and 2) homogeneously and robustly recapitulates key developmental steps - mesoderm, somite, skeletal muscle - which offers the possibility to explore dystrophin functions and find earlier disease biomarkers.Starting at the somite stage, mitochondrial gene dysregulations escalate during differentiation. We also describe fibrosis as an intrinsic feature of skeletal muscle cells that starts early during myogenesis. In sum, our data strongly argue for an early developmental manifestation of DMD whose onset is triggered before the entry into the skeletal muscle compartment, data leading to a necessary reconsideration of dystrophin functions during muscle development.

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