scholarly journals Muscle-Related Plectinopathies

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2480
Author(s):  
Michaela M. Zrelski ◽  
Monika Kustermann ◽  
Lilli Winter
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Epidermolysis Bullosa Simplex ◽  
Progressive Muscle Weakness ◽  
Mitochondrial Alterations ◽  
Cytoplasmic Bodies ◽  
Downstream Effects ◽  
Myasthenic Syndrome ◽  
Genetically Manipulated ◽  
Muscle Biopsies

Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies. The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness. Besides EBS-MD, PLEC mutations lead to EBS with nail dystrophy, EBS-MD with a myasthenic syndrome, EBS with pyloric atresia, limb-girdle muscular dystrophy type R17, or EBS-Ogna. In this review, we focus on the clinical and pathological manifestations caused by PLEC mutations on skeletal and cardiac muscle. Skeletal muscle biopsies from EBS-MD patients and plectin-deficient mice revealed severe dystrophic features with variation in fiber size, degenerative myofibrillar changes, mitochondrial alterations, and pathological desmin-positive protein aggregates. Ultrastructurally, PLEC mutations lead to a disorganization of myofibrils and sarcomeres, Z- and I-band alterations, autophagic vacuoles and cytoplasmic bodies, and misplaced and degenerating mitochondria. We also summarize a variety of genetically manipulated mouse and cell models, which are either plectin-deficient or that specifically lack a skeletal muscle-expressed plectin isoform. These models are powerful tools to study functional and molecular consequences of PLEC defects and their downstream effects on the skeletal muscle organization.

scholarly journals DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

2020 ◽  
Vol 21 (3) ◽  
pp. 729 ◽  
Author(s):  
Kenji Rowel Q. Lim ◽  
Quynh Nguyen ◽  
Toshifumi Yokota
Keyword(s):  
Skeletal Muscle ◽  
Cell Death ◽  
Transcription Factor ◽  
Muscular Dystrophy ◽  
Embryonic Development ◽  
Disease Onset ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Signalling Pathways ◽  
Progressive Muscle Weakness ◽  
Homeobox Protein

Facioscapulohumeral muscular dystrophy (FSHD) is a disabling inherited muscular disorder characterized by asymmetric, progressive muscle weakness and degeneration. Patients display widely variable disease onset and severity, and sometimes present with extra-muscular symptoms. There is a consensus that FSHD is caused by the aberrant production of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. DUX4 is normally expressed during early embryonic development, and is then effectively silenced in all tissues except the testis and thymus. Its reactivation in skeletal muscle disrupts numerous signalling pathways that mostly converge on cell death. Here, we review studies on DUX4-affected pathways in skeletal muscle and provide insights into how understanding these could help explain the unique pathogenesis of FSHD.

scholarly journals Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

2016 ◽  
Vol 113 (39) ◽  
pp. 10992-10997 ◽  
Author(s):  
Erik P. Rader ◽  
Rolf Turk ◽  
Tobias Willer ◽  
Daniel Beltrán ◽  
Kei-ichiro Inamori ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Pathological Feature ◽  
Passive Tension ◽  
Lengthening Contractions ◽  
Mechanistic Insight ◽  
The Stability ◽  
Muscle Biopsies ◽  
Insight Into

Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contraction-induced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contraction-induced injury was not accompanied by increased necrosis, excitation–contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions.

scholarly journals Case Reports: Emery-Dreifuss Muscular Dystrophy Presenting as a Heart Rhythm Disorders in Children

2021 ◽  
Vol 8 ◽  
Author(s):  
Tatiana Kovalchuk ◽  
Elena Yakovleva ◽  
Svetlana Fetisova ◽  
Tatiana Vershinina ◽  
Viktoriya Lebedeva ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Case Reports ◽  
Sinus Node ◽  
Heart Rhythm ◽  
Cardiac Abnormalities ◽  
Progressive Muscle Weakness ◽  
Cardiac Phenotype ◽  
Cardiac Symptoms ◽  
Heart Rhythm Disorders

Emery-Dreifuss muscular dystrophy (EDMD) is inherited muscle dystrophy often accompanied by cardiac abnormalities in the form of supraventricular arrhythmias, conduction defects and sinus node dysfunction. Cardiac phenotype typically arises years after skeletal muscle presentation, though, could be severe and life-threatening. The defined clinical manifestation with joint contractures, progressive muscle weakness and atrophy, as well as cardiac symptoms are observed by the third decade of life. Still, clinical course and sequence of muscle and cardiac signs may be variable and depends on the genotype. Cardiac abnormalities in patients with EDMD in pediatric age are not commonly seen. Here we describe five patients with different forms of EDMD (X-linked and autosomal-dominant) caused by the mutations in EMD and LMNA genes, presented with early onset of cardiac abnormalities and no prominent skeletal muscle phenotype. The predominant forms of cardiac pathology were atrial arrhythmias and conduction disturbances that progress over time. The presented cases discussed in the light of therapeutic strategy, including radiofrequency ablation and antiarrhythmic devices implantation, and the importance of thorough neurological and genetic screening in pediatric patients presenting with complex heart rhythm disorders.

scholarly journals Clinical and Experimental Results on Cardiac Troponin Expression in Duchenne Muscular Dystrophy

2001 ◽  
Vol 47 (3) ◽  
pp. 451-458 ◽  
Author(s):  
Angelika Hammerer-Lercher ◽  
Petra Erlacher ◽  
Reginald Bittner ◽  
Rudolf Korinthenberg ◽  
Daniela Skladal ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Western Blot ◽  
Blot Analysis ◽  
Cardiac Troponin ◽  
Western Blot Analysis ◽  
Clinical Evidence ◽  
Mdx Mouse ◽  
Muscle Biopsies

Abstract Background: Because of controversial earlier studies, the purpose of this study was to provide novel experimental and additional clinical data regarding the possible reexpression of cardiac troponin T (cTnT) in regenerating skeletal muscle in Duchenne muscular dystrophy (DMD). Methods: Plasma from 14 patients (mean age, 7.5 years; range, 5.7–19.4 years) with DMD was investigated for creatine kinase (CK), the CK MB isoenzyme (CKMB), cTnT and cardiac troponin I (cTnI), and myoglobin. cTnT concentrations were measured by an ELISA (second-generation assay; Roche) using the ES 300 Analyzer. cTnI, myoglobin, and CKMB were measured by an ELISA using the ACCESS System (Beckman Diagnostics). Troponin isoform expression was studied by Western blot analysis in remnants of skeletal muscle biopsies of three patients with DMD and in an animal model of DMD (mdx mice; n = 6). Results: There was no relation of cTnT and cTnI to clinical evidence for cardiac failure. cTnI concentrations remained below the upper reference limit in all patients. cTnT was increased (median, 0.11 μg/L; range, 0.06–0.16 μg/L) in 50% of patients. The only significant correlation was found for CK (median, 3938 U/L; range, 2763–5030 U/L) with age (median, 7.5 years; range, 6.8–10.9 years; r = −0.762; P = 0.042). Western blot analysis of human or mouse homogenized muscle specimens showed no evidence for cardiac TnT and cTnI expression, despite strong signals for skeletal muscle troponin isoforms. Conclusions: We found no evidence for cTnT reexpression in human early-stage DMD and in mdx mouse skeletal muscle biopsies. Discrepancies of cTnT and cTnI in plasma samples of DMD patients were found, but neither cTnT nor cTnI plasma concentrations were related with other clinical evidence for cardiac involvement.

scholarly journals Lamin-related congenital muscular dystrophy alters mechanical signaling and skeletal muscle growth

2020 ◽  
Author(s):  
Daniel J. Owens ◽  
Julien Messéant ◽  
Sophie Moog ◽  
Mark Viggars ◽  
Arnaud Ferry ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Disease Severity ◽  
Myogenic Differentiation ◽  
Muscle Growth ◽  
Congenital Muscular Dystrophy ◽  
Skeletal Muscle Growth ◽  
Muscle Biopsies

AbstractBackgroundLaminopathies 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 impair skeletal muscle growth may contribute to the disease severity.MethodsWe used human muscle stem cells (MuSCs) carrying 4 different LMNA mutations and two mouse models of muscle laminopathies, representing a spectrum of disease severity, to investigate the ability of skeletal muscle to differentiate and to hypertrophy in response to mechanical challenges. We extended these finding to individuals with LMNA-related muscular dystrophy using muscle biopsies.ResultsIn vitro, we observe impaired myogenic differentiation with disorganized cadherin/β catenin adhesion complexes in MuSCs carrying LMNA-CMD. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective accretion of activated MuSCs, defective protein synthesis and defective remodeling of the neuro-muscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the Yes-Associated Protein (YAP), a key sensor and mediator of mechanical cues. 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 EDMD models.ConclusionsCombining studies in vitro, in vivo and patient samples, we find that LMNA-CMD mutations interfere with mechano-signaling pathways in skeletal muscle, implicating defective skeletal muscle growth as a pathogenic contributor for the severity of LMNA-related muscular dystrophy.

scholarly journals Duchenne muscular dystrophy: alpha-dystroglycan immunoexpression in skeletal muscle and cognitive performance

2005 ◽  
Vol 63 (4) ◽  
pp. 984-989 ◽  
Author(s):  
Conceição Campanario da Silva Pereira ◽  
Beatriz Hitomi Kiyomoto ◽  
Ricardo Cardoso ◽  
Acary Souza Bulle Oliveira
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Cognitive Performance ◽  
Intelligence Quotient ◽  
Intelligence Scale ◽  
Verbal Iq ◽  
Alpha Dystroglycan ◽  
The Relationship ◽  
Muscle Biopsies ◽  
Low Expression

The Duchenne muscular systrophy (DMD) is a muscular dystrophy with cognitive impairment present in 20-30% of the cases. In the present study, in order to study the relationship between the alpha-dystroglycan (alpha-DG) immunostaining in skeletal muscle and cognitive performance in DMD patients, 19 were assessed. Twelve patients performed the intelligence quotient (IQ) below the average. Among the 19 patients, two were assessed by the Stanford-Binet test and 17 by Wechsler Intelligence Scale for Children-III (WISC-III). Nine patients performed a verbal IQ below the average, only three patients performed an average verbal IQ. The muscle biopsies immunostained with antibodies to alpha-DG showed that 17 patients presented a low expression, below 25% of the total fibers. Two patients presented alpha-DG immunostaining above 40% and an IQ within the average. No significant statistical relationship was demonstrated among total IQ, verbal IQ and execution IQ and alpha-DG immunostaining at these patients muscle samples.

scholarly journals Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy

2016 ◽  
Vol 4 (1) ◽  
Author(s):  
Lilli Winter ◽  
Matthias Türk ◽  
Patrick N. Harter ◽  
Michel Mittelbronn ◽  
Cornelia Kornblum ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Epidermolysis Bullosa ◽  
Epidermolysis Bullosa Simplex ◽  
Downstream Effects

Time course of ultrastructural changes in skeletal muscle after two types of exercise

1982 ◽  
Vol 52 (4) ◽  
pp. 910-913 ◽  
Author(s):  
M. A. Nimmo ◽  
D. H. Snow
Keyword(s):  
Skeletal Muscle ◽  
Endurance Exercise ◽  
Ultrastructural Study ◽  
Time Course ◽  
Ultrastructural Changes ◽  
Mitochondrial Structure ◽  
Mitochondrial Alterations ◽  
Thoroughbred Horses ◽  
Muscle Biopsies

To ascertain the effects of sprint and endurance exercise on the time course of skeletal muscle mitochondrial changes, an ultrastructural study was conducted on four Thoroughbred horses. Skeletal muscle biopsies were taken at various intervals during and after the exercise. Transient mitochondrial alterations of varying degrees were observed following both types of exercise and were considered to be related to the development of fatigue. The degree of distortion of mitochondrial structure is considered not to represent the in vivo condition but the state of responsiveness to the fixation medium.

scholarly journals Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth

2020 ◽  
Vol 22 (1) ◽  
pp. 306
Author(s):  
Daniel J. Owens ◽  
Julien Messéant ◽  
Sophie Moog ◽  
Mark Viggars ◽  
Arnaud Ferry ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Muscle Growth ◽  
Congenital Muscular Dystrophy ◽  
Muscle Stem Cells ◽  
Skeletal Muscle Growth ◽  
Mechanical Signaling ◽  
Muscle Biopsies

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.

scholarly journals Circadian Genes as Exploratory Biomarkers in DMD: Results From Both the mdx Mouse Model and Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Rachele Rossi ◽  
Maria Sofia Falzarano ◽  
Hana Osman ◽  
Annarita Armaroli ◽  
Chiara Scotton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Circadian Rhythm ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Expression Profiles ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Muscle Biopsies

Duchenne muscular dystrophy (DMD) is a rare genetic disease due to dystrophin gene mutations which cause progressive weakness and muscle wasting. Circadian rhythm coordinates biological processes with the 24-h cycle and it plays a key role in maintaining muscle functions, both in animal models and in humans. We explored expression profiles of circadian circuit master genes both in Duchenne muscular dystrophy skeletal muscle and in its animal model, the mdx mouse. We designed a customized, mouse-specific Fluidic-Card-TaqMan-based assay (Fluid-CIRC) containing thirty-two genes related to circadian rhythm and muscle regeneration and analyzed gastrocnemius and tibialis anterior muscles from both unexercised and exercised mdx mice. Based on this first analysis, we prioritized the 7 most deregulated genes in mdx mice and tested their expression in skeletal muscle biopsies from 10 Duchenne patients. We found that CSNK1E, SIRT1, and MYOG are upregulated in DMD patient biopsies, consistent with the mdx data. We also demonstrated that their proteins are detectable and measurable in the DMD patients’ plasma. We suggest that CSNK1E, SIRT1, and MYOG might represent exploratory circadian biomarkers in DMD.

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