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20 pages, 2389 KiB

Open AccessArticle

Molecular Fingerprint of BMD Patients Lacking a Portion in the Rod Domain of Dystrophin

by Daniele Capitanio, Manuela Moriggi, Pietro Barbacini, Enrica Torretta, Isabella Moroni, Flavia Blasevich, Lucia Morandi, Marina Mora and Cecilia Gelfi

Int. J. Mol. Sci. 2022, 23(5), 2624; https://doi.org/10.3390/ijms23052624 - 27 Feb 2022

Cited by 7 | Viewed by 2782

Abstract

BMD is characterized by a marked heterogeneity of gene mutations resulting in many abnormal dystrophin proteins with different expression and residual functions. The smaller dystrophin molecules lacking a portion around exon 48 of the rod domain, named the D8 region, are related to [...] Read more.

BMD is characterized by a marked heterogeneity of gene mutations resulting in many abnormal dystrophin proteins with different expression and residual functions. The smaller dystrophin molecules lacking a portion around exon 48 of the rod domain, named the D8 region, are related to milder phenotypes. The study aimed to determine which proteins might contribute to preserving muscle function in these patients. Patients were subdivided, based on the absence or presence of deletions in the D8 region, into two groups, BMD1 and BMD2. Muscle extracts were analyzed by 2-D DIGE, label-free LC-ESI-MS/MS, and Ingenuity pathway analysis (IPA). Increased levels of proteins typical of fast fibers and of proteins involved in the sarcomere reorganization characterize BMD2. IPA of proteomics datasets indicated in BMD2 prevalence of glycolysis and gluconeogenesis and a correct flux through the TCA cycle enabling them to maintain both metabolism and epithelial adherens junction. A 2-D DIGE analysis revealed an increase of acetylated proteoforms of moonlighting proteins aldolase, enolase, and glyceraldehyde-3-phosphate dehydrogenase that can target the nucleus promoting stem cell recruitment and muscle regeneration. In BMD2, immunoblotting indicated higher levels of myogenin and lower levels of PAX7 and SIRT1/2 associated with a set of proteins identified by proteomics as involved in muscle homeostasis maintenance. Full article

(This article belongs to the Special Issue Cell Signaling and Omics in Muscular Dystrophies)

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15 pages, 4534 KiB

Open AccessArticle

Transcriptome Analysis in a Primary Human Muscle Cell Differentiation Model for Myotonic Dystrophy Type 1

by Vanessa Todorow, Stefan Hintze, Alastair R. W. Kerr, Andreas Hehr, Benedikt Schoser and Peter Meinke

Int. J. Mol. Sci. 2021, 22(16), 8607; https://doi.org/10.3390/ijms22168607 - 10 Aug 2021

Cited by 9 | Viewed by 2837

Abstract

Myotonic dystrophy type 1 (DM1) is caused by CTG-repeat expansions leading to a complex pathology with a multisystemic phenotype that primarily affects the muscles and brain. Despite a multitude of information, especially on the alternative splicing of several genes involved in the pathology, [...] Read more.

Myotonic dystrophy type 1 (DM1) is caused by CTG-repeat expansions leading to a complex pathology with a multisystemic phenotype that primarily affects the muscles and brain. Despite a multitude of information, especially on the alternative splicing of several genes involved in the pathology, information about additional factors contributing to the disease development is still lacking. We performed RNAseq and gene expression analyses on proliferating primary human myoblasts and differentiated myotubes. GO-term analysis indicates that in myoblasts and myotubes, different molecular pathologies are involved in the development of the muscular phenotype. Gene set enrichment for splicing reveals the likelihood of whole, differentiation stage specific, splicing complexes that are misregulated in DM1. These data add complexity to the alternative splicing phenotype and we predict that it will be of high importance for therapeutic interventions to target not only mature muscle, but also satellite cells. Full article

(This article belongs to the Special Issue Cell Signaling and Omics in Muscular Dystrophies)

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17 pages, 3382 KiB

Open AccessArticle

Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control

by Byongsun Lee, Seungjae Lee, Younggwang Lee, Yongjin Park and Jaekyung Shim

Int. J. Mol. Sci. 2021, 22(13), 6669; https://doi.org/10.3390/ijms22136669 - 22 Jun 2021

Cited by 6 | Viewed by 2938

Abstract

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery–Dreifuss muscular dystrophy (EDMD). Evidence is accumulating that emerin regulation of specific gene expression is associated with this disease, but [...] Read more.

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery–Dreifuss muscular dystrophy (EDMD). Evidence is accumulating that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has not been fully elucidated. Here, we show that emerin downregulates Signal transducer and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus kinase (JAK). Deletion mutation experiments show that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacts directly and co-localizes with STAT3 in the nuclear membrane. Emerin knockdown induces STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin, by assembling with BAF and lamin A/C, acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induces STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and may be a new therapeutic target for treatment. Full article

(This article belongs to the Special Issue Cell Signaling and Omics in Muscular Dystrophies)

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12 pages, 2505 KiB

Open AccessArticle

Separating the Wheat from the Chaff: The Use of Upstream Regulator Analysis to Identify True Differential Expression of Single Genes within Transcriptomic Datasets

by Jeremiah Hadwen, Sarah Schock, Faraz Farooq, Alex MacKenzie and Julio Plaza-Diaz

Int. J. Mol. Sci. 2021, 22(12), 6295; https://doi.org/10.3390/ijms22126295 - 11 Jun 2021

Cited by 1 | Viewed by 3418

Abstract

The development of DNA microarray and RNA-sequencing technology has led to an explosion in the generation of transcriptomic differential expression data under a wide range of biologic systems including those recapitulating the monogenic muscular dystrophies. Data generation has increased exponentially due in large [...] Read more.

The development of DNA microarray and RNA-sequencing technology has led to an explosion in the generation of transcriptomic differential expression data under a wide range of biologic systems including those recapitulating the monogenic muscular dystrophies. Data generation has increased exponentially due in large part to new platforms, improved cost-effectiveness, and processing speed. However, reproducibility and thus reliability of data remain a central issue, particularly when resource constraints limit experiments to single replicates. This was observed firsthand in a recent rare disease drug repurposing project involving RNA-seq-based transcriptomic profiling of primary cerebrocortical cultures incubated with clinic-ready blood–brain penetrant drugs. Given the low validation rates obtained for single differential expression genes, alternative approaches to identify with greater confidence genes that were truly differentially expressed in our dataset were explored. Here we outline a method for differential expression data analysis in the context of drug repurposing for rare diseases that incorporates the statistical rigour of the multigene analysis to bring greater predictive power in assessing individual gene modulation. Ingenuity Pathway Analysis upstream regulator analysis was applied to the differentially expressed genes from the Care4Rare Neuron Drug Screen transcriptomic database to identify three distinct signaling networks each perturbed by a different drug and involving a central upstream modulating protein: levothyroxine (DIO3), hydroxyurea (FOXM1), dexamethasone (PPARD). Differential expression of upstream regulator network related genes was next assessed in in vitro and in vivo systems by qPCR, revealing 5× and 10× increases in validation rates, respectively, when compared with our previous experience with individual genes in the dataset not associated with a network. The Ingenuity Pathway Analysis based gene prioritization may increase the predictive value of drug–gene interactions, especially in the context of assessing single-gene modulation in single-replicate experiments. Full article

(This article belongs to the Special Issue Cell Signaling and Omics in Muscular Dystrophies)

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21 pages, 6992 KiB

Open AccessArticle

by Daniel J. Owens, Julien Messéant, Sophie Moog, Mark Viggars, Arnaud Ferry, Kamel Mamchaoui, Emmanuelle Lacène, Norma Roméro, Astrid Brull, Gisèle Bonne, Gillian Butler-Browne and Catherine Coirault

Int. J. Mol. Sci. 2021, 22(1), 306; https://doi.org/10.3390/ijms22010306 - 30 Dec 2020

Cited by 18 | Viewed by 4691

Abstract

Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal [...] Read more.

Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/β catenin adhesion complexes. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective fusion of activated MuSCs, defective protein synthesis and defective remodeling of the neuromuscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the yes-associated protein (YAP). We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely related but less severe EDMD models. In conclusion, combining studies in vitro, in vivo, and patient samples, we find that LMNA-CMD mutations interfere with mechanosignaling pathways in skeletal muscle, implicating A-type lamins in the regulation of skeletal muscle growth. Full article

(This article belongs to the Special Issue Cell Signaling and Omics in Muscular Dystrophies)

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Review

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19 pages, 572 KiB

Open AccessReview

Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy

by Aoife Gowran, Maura Brioschi, Davide Rovina, Mattia Chiesa, Luca Piacentini, Sara Mallia, Cristina Banfi, Giulio Pompilio and Rosaria Santoro

Int. J. Mol. Sci. 2021, 22(16), 8954; https://doi.org/10.3390/ijms22168954 - 19 Aug 2021

Cited by 4 | Viewed by 2829

Abstract

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The [...] Read more.

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date. Full article

(This article belongs to the Special Issue Cell Signaling and Omics in Muscular Dystrophies)

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20 pages, 2750 KiB

Open AccessReview

Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies

by Coralie Croissant, Romain Carmeille, Charlotte Brévart and Anthony Bouter

Int. J. Mol. Sci. 2021, 22(10), 5276; https://doi.org/10.3390/ijms22105276 - 17 May 2021

Cited by 22 | Viewed by 5105

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Cell Signaling and Omics in Muscular Dystrophies)

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19 pages, 4772 KiB

Open AccessReview

Caenorhabditis elegans as a Model System for Duchenne Muscular Dystrophy

by Rebecca A. Ellwood, Mathew Piasecki and Nathaniel J. Szewczyk

Int. J. Mol. Sci. 2021, 22(9), 4891; https://doi.org/10.3390/ijms22094891 - 5 May 2021

Cited by 7 | Viewed by 4962

Abstract

The nematode worm Caenorhabditis elegans has been used extensively to enhance our understanding of the human neuromuscular disorder Duchenne Muscular Dystrophy (DMD). With new arising clinically relevant models, technologies and treatments, there is a need to reconcile the literature and collate the key [...] Read more.

The nematode worm Caenorhabditis elegans has been used extensively to enhance our understanding of the human neuromuscular disorder Duchenne Muscular Dystrophy (DMD). With new arising clinically relevant models, technologies and treatments, there is a need to reconcile the literature and collate the key findings associated with this model. Full article

(This article belongs to the Special Issue Cell Signaling and Omics in Muscular Dystrophies)

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