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Cells Sep 2021Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene () cause several rare diseases that are... (Review)
Review
Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene () 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, 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 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, 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 defects and their downstream effects on the skeletal muscle organization.
Topics: Animals; Epidermolysis Bullosa Simplex; Humans; Muscle, Skeletal; Muscular Dystrophies; Plectin
PubMed: 34572129
DOI: 10.3390/cells10092480 -
Immunity Sep 2020Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic...
Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD.
Topics: Animals; Biomarkers; Bone Marrow Cells; Cells, Cultured; Desmin; Female; Kupffer Cells; Liver; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Osteopontin; Proteome; Transcriptome
PubMed: 32888418
DOI: 10.1016/j.immuni.2020.08.004 -
Frontiers in Cell and Developmental... 2022Desmin () is a classical type III intermediate filament protein encoded by the gene. Desmin is abundantly expressed in cardiac, skeletal, and smooth muscle cells. In... (Review)
Review
Desmin () is a classical type III intermediate filament protein encoded by the gene. Desmin is abundantly expressed in cardiac, skeletal, and smooth muscle cells. In these cells, desmin interconnects several protein-protein complexes that cover cell-cell contact, intracellular organelles such as mitochondria and the nucleus, and the cytoskeletal network. The extra- and intracellular localization of the desmin network reveals its crucial role in maintaining the structural and mechanical integrity of cells. In the heart, desmin is present in specific structures of the cardiac conduction system including the sinoatrial node, atrioventricular node, and His-Purkinje system. Genetic variations and loss of desmin drive a variety of conditions, so-called desminopathies, which include desmin-related cardiomyopathy, conduction system-related atrial and ventricular arrhythmias, and sudden cardiac death. The severe cardiac disease outcomes emphasize the clinical need to understand the molecular and cellular role of desmin driving desminopathies. As the role of desmin in cardiomyopathies has been discussed thoroughly, the current review is focused on the role of desmin impairment as a trigger for cardiac arrhythmias. Here, the molecular and cellular mechanisms of desmin to underlie a healthy cardiac conduction system and how impaired desmin triggers cardiac arrhythmias, including atrial fibrillation, are discussed. Furthermore, an overview of available (genetic) desmin model systems for experimental cardiac arrhythmia studies is provided. Finally, potential implications for future clinical treatments of cardiac arrhythmias directed at desmin are highlighted.
PubMed: 36158202
DOI: 10.3389/fcell.2022.986718 -
The FEBS Journal May 2022Desmin is the primary intermediate filament (IF) of cardiac, skeletal, and smooth muscle. By linking the contractile myofibrils to the sarcolemma and cellular... (Review)
Review
Desmin is the primary intermediate filament (IF) of cardiac, skeletal, and smooth muscle. By linking the contractile myofibrils to the sarcolemma and cellular organelles, desmin IF contributes to muscle structural and cellular integrity, force transmission, and mitochondrial homeostasis. Mutations in desmin cause myofibril misalignment, mitochondrial dysfunction, and impaired mechanical integrity leading to cardiac and skeletal myopathies in humans, often characterized by the accumulation of protein aggregates. Recent evidence indicates that desmin filaments also regulate proteostasis and cell size. In skeletal muscle, changes in desmin filament dynamics can facilitate catabolic events as an adaptive response to a changing environment. In addition, post-translational modifications of desmin and its misfolding in the heart have emerged as key determinants of homeostasis and disease. In this review, we provide an overview of the structural and cellular roles of desmin and propose new models for its novel functions in preserving the homeostasis of striated muscles.
Topics: Desmin; Homeostasis; Humans; Muscle, Skeletal; Muscular Diseases; Myofibrils
PubMed: 33825342
DOI: 10.1111/febs.15864 -
Turkish Journal of Biology = Turk... 2021It has been a long time since researchers have focused on the cytoskeletal proteins' unconventional functions in the nucleus. Subcellular localization of a protein not... (Review)
Review
It has been a long time since researchers have focused on the cytoskeletal proteins' unconventional functions in the nucleus. Subcellular localization of a protein not only affects its functions but also determines the accessibility for cellular processes. Desmin is a muscle-specific, cytoplasmic intermediate filament protein, the cytoplasmic roles of which are defined. Yet, there is some evidence pointing out nuclear functions for desmin. In silico and wet lab analysis shows that desmin can enter and function in the nucleus. Furthermore, the candidate nuclear partners of desmin support the notion that desmin can serve as a transcriptional regulator inside the nucleus. Uncovering the nuclear functions and partners of desmin will provide a new insight into the biological significance of desmin.
PubMed: 35068951
DOI: 10.3906/biy-2107-54 -
African Journal of Paediatric Surgery :... 2022Rhabdomyosarcoma (RMS) is one of the common malignant soft-tissue sarcomas affecting children. It originates from the embryonic mesenchyme precursor of striated muscle...
Rhabdomyosarcoma (RMS) is one of the common malignant soft-tissue sarcomas affecting children. It originates from the embryonic mesenchyme precursor of striated muscle and is frequently seen in the head-and-neck region, genitourinary system and extremities. Occasionally, it arises from the retroperitoneum, biliary tract and abdomen and is rarely seen in the sacrococcygeal area. A 4-month-male child presented with a nodule over the sacrum. Based on histopathology and immunohistochemical marker studies, a final diagnosis of RMS was rendered. There was no evidence of any teratomatous elements.
Topics: Child; Humans; Male; Rhabdomyosarcoma; Sacrococcygeal Region; Soft Tissue Neoplasms; Teratoma
PubMed: 36018208
DOI: 10.4103/ajps.ajps_69_21 -
Frontiers in Cell and Developmental... 2022Cellular adhesion and migration are key functions that are disrupted in numerous diseases. We report that desmin, a type-III muscle-specific intermediate filament, is a...
Cellular adhesion and migration are key functions that are disrupted in numerous diseases. We report that desmin, a type-III muscle-specific intermediate filament, is a novel cell adhesion regulator. Expression of p.R406W mutant desmin, identified in patients with desmin-related myopathy, modified focal adhesion area and expression of adhesion-signaling genes in myogenic C2C12 cells. Satellite cells extracted from desmin-knock-out (DesKO) and desmin-knock-in-p.R405W (DesKI-R405W) mice were less adhesive and migrated faster than those from wild-type mice. Moreover, we observed mislocalized and aggregated vinculin, a key component of cell adhesion, in DesKO and DesKI-R405W muscles. Vinculin expression was also increased in desmin-related myopathy patient muscles. Together, our results establish a novel role for desmin in cell-matrix adhesion, an essential process for strength transmission, satellite cell migration and muscle regeneration. Our study links the patho-physiological mechanisms of desminopathies to adhesion/migration defects, and may lead to new cellular targets for novel therapeutic approaches.
PubMed: 35350386
DOI: 10.3389/fcell.2022.783724 -
Free Neuropathology Jan 2021Heart disease is an integral part of Friedreich ataxia (FA) and the most common cause of death in this autosomal recessive disease. The result of the mutation is lack of...
Heart disease is an integral part of Friedreich ataxia (FA) and the most common cause of death in this autosomal recessive disease. The result of the mutation is lack of frataxin, a small mitochondrial protein. The clinical and pathological phenotypes of FA are complex, involving brain, spinal cord, dorsal root ganglia, sensory nerves, heart, and endocrine pancreas. The hypothesis is that frataxin deficiency causes downstream changes in the proteome of the affected tissues, including the heart. A proteomic analysis of heart proteins in FA cardiomyopathy by antibody microarray, Western blots, immunohistochemistry, and double-label laser scanning confocal immunofluorescence microscopy revealed upregulation of desmin and its chaperone protein, αB-crystallin. In normal hearts, these two proteins are co-localized at intercalated discs and Z discs. In FA, desmin and αB-crystallin aggregate, causing chaotic modification of intercalated discs, clustering of mitochondria, and destruction of the contractile apparatus of cardiomyocytes. Western blots of tissue lysates in FA cardiomyopathy reveal a truncated desmin isoprotein that migrates at a lower molecular weight range than wild type desmin. While desmin and αB-crystallin are not mutated in FA, the accumulation of these proteins in FA hearts allows the conclusion that FA cardiomyopathy is a desminopathy akin to desmin myopathy of skeletal muscle.
PubMed: 37284625
DOI: 10.17879/freeneuropathology-2021-3679 -
Frontiers in Physiology 2023The sarcomere is the smallest functional unit of muscle contraction. It is delineated by a protein-rich structure known as the Z-disk, alternating with M-bands. The... (Review)
Review
The sarcomere is the smallest functional unit of muscle contraction. It is delineated by a protein-rich structure known as the Z-disk, alternating with M-bands. The Z-disk anchors the actin-rich thin filaments and plays a crucial role in maintaining the mechanical stability of the cardiac muscle. A multitude of proteins interact with each other at the Z-disk and they regulate the mechanical properties of the thin filaments. Over the past 2 decades, the role of the Z-disk in cardiac muscle contraction has been assessed widely, however, the impact of genetic variants in Z-disk proteins has still not been fully elucidated. This review discusses the various Z-disk proteins (alpha-actinin, filamin C, titin, muscle LIM protein, telethonin, myopalladin, nebulette, and nexilin) and Z-disk-associated proteins (desmin, and obscurin) and their role in cardiac structural stability and intracellular signaling. This review further explores how genetic variants of Z-disk proteins are linked to inherited cardiac conditions termed cardiomyopathies.
PubMed: 36935760
DOI: 10.3389/fphys.2023.1143858