scholarly journals Emery–Dreifuss muscular dystrophy–linked genes and centronuclear myopathy–linked genes regulate myonuclear movement by distinct mechanisms

2017 ◽  
Vol 28 (17) ◽  
pp. 2303-2317 ◽  
Author(s):  
Mary Ann Collins ◽  
Torrey R. Mandigo ◽  
Jaclyn M. Camuglia ◽  
Gabriella A. Vazquez ◽  
Alyssa J. Anderson ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Cells ◽  
Common Mechanism ◽  
Centronuclear Myopathy ◽  
Muscle Disorders ◽  
Nuclear Position ◽  
Initial Separation ◽  
Common Phenotype ◽  
Expression Of Genes ◽  
The Many

Muscle cells are a syncytium in which the many nuclei are positioned to maximize the distance between adjacent nuclei. Although mispositioned nuclei are correlated with many muscle disorders, it is not known whether this common phenotype is the result of a common mechanism. To answer this question, we disrupted the expression of genes linked to Emery–Dreifuss muscular dystrophy (EDMD) and centronuclear myopathy (CNM) in Drosophila and evaluated the position of the nuclei. We found that the genes linked to EDMD and CNM were each necessary to properly position nuclei. However, the specific phenotypes were different. EDMD-linked genes were necessary for the initial separation of nuclei into distinct clusters, suggesting that these factors relieve interactions between nuclei. CNM-linked genes were necessary to maintain the nuclei within clusters as they moved toward the muscle ends, suggesting that these factors were necessary to maintain interactions between nuclei. Together these data suggest that nuclear position is disrupted by distinct mechanisms in EDMD and CNM.

scholarly journals Nucleus-dependent sarcomere assembly is mediated by the LINC complex

2016 ◽  
Vol 27 (15) ◽  
pp. 2351-2359 ◽  
Author(s):  
Alexander L. Auld ◽  
Eric S. Folker
Keyword(s):  
Muscle Cells ◽  
Linc Complex ◽  
Nuclear Positioning ◽  
Nuclear Position ◽  
Early Stages ◽  
Cytoplasmic Face ◽  
Sarcomere Proteins ◽  
The Many ◽  
Sarcomere Assembly ◽  
The Relationship

Two defining characteristics of muscle cells are the many precisely positioned nuclei and the linearly arranged sarcomeres, yet the relationship between these two features is not known. We show that nuclear positioning precedes sarcomere formation. Furthermore, ZASP-GFP, a Z-line protein, colocalizes with F-actin in puncta at the cytoplasmic face of nuclei before sarcomere assembly. In embryos with mispositioned nuclei, ZASP-GFP is still recruited to the nuclei before its incorporation into sarcomeres. Furthermore, the first sarcomeres appear in positions close to the nuclei, regardless of nuclear position. These data suggest that the interaction between sarcomere proteins and nuclei is not dependent on properly positioned nuclei. Mechanistically, ZASP-GFP localization to the cytoplasmic face of the nucleus did require the linker of nucleoskeleton and cytoskeleton (LINC) complex. Muscle-specific depletion of klarsicht (nesprin) or klariod (SUN) blocked the recruitment of ZASP-GFP to the nucleus during the early stages of sarcomere assembly. As a result, sarcomeres were poorly formed and the general myofibril network was less stable, incomplete, and/or torn. These data suggest that the nucleus, through the LINC complex, is crucial for the proper assembly and stability of the sarcomere network.

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.

scholarly journals Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

2021 ◽  
Vol 22 (8) ◽  
pp. 4256
Author(s):  
Lorenzo Maggi ◽  
Manolis Mavroidis ◽  
Stelios Psarras ◽  
Yassemi Capetanaki ◽  
Giovanna Lattanzi
Keyword(s):  
Muscular Dystrophy ◽  
Cardiac Muscle ◽  
Intermediate Filament ◽  
Striated Muscle ◽  
Congenital Muscular Dystrophy ◽  
Left Ventricular ◽  
Intermediate Filament Proteins ◽  
Muscle Disorders ◽  
Genes Encoding ◽  
Molecular Aspects

Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery–Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

scholarly journals MiRNAs and Muscle Regeneration: Therapeutic Targets in Duchenne Muscular Dystrophy

2021 ◽  
Vol 22 (8) ◽  
pp. 4236
Author(s):  
Amelia Eva Aránega ◽  
Estefanía Lozano-Velasco ◽  
Lara Rodriguez-Outeiriño ◽  
Felicitas Ramírez de Acuña ◽  
Diego Franco ◽  
...  
Keyword(s):  
Stem Cell ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Regeneration ◽  
Transcriptional Control ◽  
Neuromuscular Disorders ◽  
Critical Role ◽  
Gene Replacement ◽  
Control Of Gene Expression ◽  
Muscle Disorders

microRNAs (miRNAs) are small non-coding RNAs required for the post-transcriptional control of gene expression. MicroRNAs play a critical role in modulating muscle regeneration and stem cell behavior. Muscle regeneration is affected in muscular dystrophies, and a critical point for the development of effective strategies for treating muscle disorders is optimizing approaches to target muscle stem cells in order to increase the ability to regenerate lost tissue. Within this framework, miRNAs are emerging as implicated in muscle stem cell response in neuromuscular disorders and new methodologies to regulate the expression of key microRNAs are coming up. In this review, we summarize recent advances highlighting the potential of miRNAs to be used in conjunction with gene replacement therapies, in order to improve muscle regeneration in the context of Duchenne Muscular Dystrophy (DMD).

scholarly journals In vivo genome editing in mouse restores dystrophin expression in Duchenne muscular dystrophy patient muscle fibers

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Menglong Chen ◽  
Hui Shi ◽  
Shixue Gou ◽  
Xiaomin Wang ◽  
Lei Li ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Genome Editing ◽  
Large Scale ◽  
Gene Editing ◽  
High Efficiency ◽  
Muscle Fibers ◽  
Muscle Cells

Abstract Background Mutations in the DMD gene encoding dystrophin—a critical structural element in muscle cells—cause Duchenne muscular dystrophy (DMD), which is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. Methods In this study, we developed a novel strategy for reframing DMD mutations via CRISPR-mediated large-scale excision of exons 46–54. We compared this approach with other DMD rescue strategies by using DMD patient-derived primary muscle-derived stem cells (DMD-MDSCs). Furthermore, a patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Results Results demonstrated that the large-scale excision of mutant DMD exons showed high efficiency in restoring dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cas12a)-mediated genome editing could correct DMD mutation with the same efficiency as CRISPR-associated protein 9 (Cas9). In addition, more than 10% human DMD muscle fibers expressed dystrophin in the PDX DMD mouse model after treated by the large-scale excision strategies. The restored dystrophin in vivo was functional as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan. Conclusions We demonstrated that the clinically relevant CRISPR/Cas9 could restore dystrophin in human muscle cells in vivo in the PDX DMD mouse model. This study demonstrated an approach for the application of gene therapy to other genetic diseases.

Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy

2021 ◽  
Vol 13 (588) ◽  
pp. eabb0319
Author(s):  
Peiling Luan ◽  
Davide D’Amico ◽  
Pénélope A. Andreux ◽  
Pirkka-Pekka Laurila ◽  
Martin Wohlwend ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Mitochondrial Dysfunction ◽  
Muscle Function ◽  
Experimental Models ◽  
Muscle Stem Cells ◽  
Expression Of Genes ◽  
Primary Myoblasts ◽  
Urolithin A ◽  
Regenerative Ability

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy, and despite advances in genetic and pharmacological disease-modifying treatments, its management remains a major challenge. Mitochondrial dysfunction contributes to DMD, yet the mechanisms by which this occurs remain elusive. Our data in experimental models and patients with DMD show that reduced expression of genes involved in mitochondrial autophagy, or mitophagy, contributes to mitochondrial dysfunction. Mitophagy markers were reduced in skeletal muscle and in muscle stem cells (MuSCs) of a mouse model of DMD. Administration of the mitophagy activator urolithin A (UA) rescued mitophagy in DMD worms and mice and in primary myoblasts from patients with DMD, increased skeletal muscle respiratory capacity, and improved MuSCs’ regenerative ability, resulting in the recovery of muscle function and increased survival in DMD mouse models. These data indicate that restoration of mitophagy alleviates symptoms of DMD and suggest that UA may have potential therapeutic applications for muscular dystrophies.

scholarly journals How origin stories shape children's social reasoning

2020 ◽  
Author(s):  
Emily Foster-Hanson ◽  
Marjorie Rhodes
Keyword(s):  
Social World ◽  
Social Reasoning ◽  
Common Mechanism ◽  
Social Category ◽  
Cultural Contexts ◽  
Explicit Information ◽  
Origin Stories ◽  
Embedded Knowledge ◽  
The Social ◽  
The Many

How do we explain the behavior of the many people we meet throughout our lives? Children and adults sometimes consider other people in terms of their social category memberships (e.g., assuming that a girl likes pink because she is a girl), but people view some categories as more informative than others, and which people think of as informative varies across cultural contexts. One type of culturally-embedded knowledge that appears to shape whether people view particular categories as providing explanations for behavior are beliefs about how the category came to be. In the current studies with 4- to 5-year-old children (N = 206), we ask how learning about quasi-scientific or supernatural causal origins of a category shapes young children’s use of categories to predict and explain what category members are like. In Study 1, children more often used a category to explain behavior when they heard the category described as intentionally created by a powerful being than when they heard no explicit information about its origins. In Studies 2 and 3, learning about both quasi-scientific and supernatural causal origins shaped children’s social category beliefs via a common mechanism: by signaling that the category marked a non-arbitrary way of dividing up the social world.

Removal of dystroglycan causes severe muscular dystrophy in zebrafish embryos

Development ◽  
2002 ◽  
Vol 129 (14) ◽  
pp. 3505-3512 ◽  
Author(s):  
Michael J. Parsons ◽  
Isabel Campos ◽  
Elizabeth M. A. Hirst ◽  
Derek L. Stemple
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Muscular Dystrophy ◽  
Muscle Cells ◽  
Laminin Receptor ◽  
Central Component ◽  
Zebrafish Embryos ◽  
Term Survival ◽  
Α Subunit ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex

Muscular dystrophy is frequently caused by disruption of the dystrophin-glycoprotein complex (DGC), which links muscle cells to the extracellular matrix. Dystroglycan, a central component of the DGC, serves as a laminin receptor via its extracellular α subunit, and interacts with dystrophin (and thus the actin cytoskeleton) through its integral membrane β subunit. We have removed the function of dystroglycan in zebrafish embryos. In contrast to mouse, where dystroglycan mutations lead to peri-implantation lethality, dystroglycan is dispensable for basement membrane formation during early zebrafish development. At later stages, however, loss of dystroglycan leads to a disruption of the DGC, concurrent with loss of muscle integrity and necrosis. In addition, we find that loss of the DGC leads to loss of sarcomere and sarcoplasmic reticulum organisation. The DGC is required for long-term survival of muscle cells in zebrafish, but is dispensable for muscle formation. Dystroglycan or the DGC is also required for normal sarcomere and sarcoplasmic reticulum organisation. Because zebrafish embryos lacking dystroglycan share several characteristics with human muscular dystrophy, they should serve as a useful model for the disease. In addition, knowing the dystroglycan null phenotype in zebrafish will facilitate the isolation of other molecules involved in muscular dystrophy pathogenesis.

scholarly journals Cyclophilin a as a Mediator of Tissue Injure and Nephrotoxicity

2012 ◽  
Vol 4 (2) ◽  
pp. 42-44
Author(s):  
Grace Moscoso-Solorzano ◽  
Gianna Mastroianni-Kirsztajn
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Cyclophilin A ◽  
Common Mechanism ◽  
Ppiase Activity ◽  
Expression Of Genes ◽  
Inflammatory Stimuli ◽  
Genes Encoding ◽  
Inflammatory Processes

Cyclophilin A (CypA) belongs to the peptidyl-prolil isomerase (PPlase) family of proteins and it is also known as the cellular receptor for cyclosporine A (CsA). CsA binds to CypA and inhibits the PPIase activity, but the CypA-CsA complex also binds to calcineurin that promotes the expression of genes encoding cytokines and other proteins required for immune response. In addition, the polymorphism variation of CypA promoter seems to have an influence on the expression of CypA in in vitro studies. CypA was also implicated in inflammatory processes (such as, among others, those observed in rheumatoid arthritis, atherosclerotic disease, nephrotoxicity) and it can be secreted by cells in response to inflammatory stimuli. CypA can also have a role in the molecular mechanisms by which CsA induces nephroxicity but these remain poorly understood. Recent studies suggest that CsA inhibition of CypA PPlase activity is a possible mechanism of this drug toxicity. In addition, CypA overexpression could be protective against CsA nephrotoxicity. Finally, the putative common mechanism by which CypA could be involved in CsA nephrotoxicity and tissue injury is related to its proinflammatory effects in cells.

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