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International Journal of Molecular... Aug 2023Cardiac muscle contraction is distinct from the contraction of other muscle types. The heart continuously undergoes contraction-relaxation cycles throughout an animal's... (Review)
Review
Cardiac muscle contraction is distinct from the contraction of other muscle types. The heart continuously undergoes contraction-relaxation cycles throughout an animal's lifespan. It must respond to constantly varying physical and energetic burdens over the short term on a beat-to-beat basis and relies on different mechanisms over the long term. Muscle contractility is based on actin and myosin interactions that are regulated by cytoplasmic calcium ions. Genetic variants of sarcomeric proteins can lead to the pathophysiological development of cardiac dysfunction. The sarcomere is physically connected to other cytoskeletal components. Actin filaments, microtubules and desmin proteins are responsible for these interactions. Therefore, mechanical as well as biochemical signals from sarcomeric contractions are transmitted to and sensed by other parts of the cardiomyocyte, particularly the nucleus which can respond to these stimuli. Proteins anchored to the nuclear envelope display a broad response which remodels the structure of the nucleus. In this review, we examine the central aspects of mechanotransduction in the cardiomyocyte where the transmission of mechanical signals to the nucleus can result in changes in gene expression and nucleus morphology. The correlation of nucleus sensing and dysfunction of sarcomeric proteins may assist the understanding of a wide range of functional responses in the progress of cardiomyopathic diseases.
Topics: Animals; Myocytes, Cardiac; Mechanotransduction, Cellular; Cell Nucleus; Nuclear Envelope; Cytosol
PubMed: 37686151
DOI: 10.3390/ijms241713341 -
Current Opinion in Cell Biology Dec 2023The intermediate filament (IF) cytoskeleton supports cellular structural integrity, particularly in response to mechanical stress. The most abundant IF proteins in... (Review)
Review
The intermediate filament (IF) cytoskeleton supports cellular structural integrity, particularly in response to mechanical stress. The most abundant IF proteins in mature cardiomyocytes are desmin and lamins. The desmin network tethers the contractile apparatus and organelles to the nuclear envelope and the sarcolemma, while lamins, as components of the nuclear lamina, provide structural stability to the nucleus and the genome. Mutations in desmin or A-type lamins typically result in cardiomyopathies and recent studies emphasized the synergistic roles of desmin and lamins in the maintenance of nuclear integrity in cardiac myocytes. Here we explore the emerging roles of the interdependent relationship between desmin and lamins in providing resilience to nuclear structure while transducing extracellular mechanical cues into the nucleus.
Topics: Intermediate Filaments; Lamins; Desmin; Cytoskeleton; Nuclear Lamina
PubMed: 37972529
DOI: 10.1016/j.ceb.2023.102280 -
Circulation. Genomic and Precision... Aug 2023
Topics: Humans; Cardiomyopathies; Cardiomyopathy, Dilated
PubMed: 37191012
DOI: 10.1161/CIRCGEN.122.003998 -
Cells Mar 2024Understanding the structure and function of intermediate filaments (IFs) is necessary in order to explain why more than 70 related IF genes have evolved in vertebrates...
Understanding the structure and function of intermediate filaments (IFs) is necessary in order to explain why more than 70 related IF genes have evolved in vertebrates while maintaining such dramatically tissue-specific expression. Desmin is a member of the large multigene family of IF proteins and is specifically expressed in myocytes. In an effort to elucidate its muscle-specific behavior, we have used a yeast two-hybrid system in order to identify desmin's head binding partners. We described a mitochondrial and a lysosomal protein, NADH ubiquinone oxidoreductase core subunit S2 (NDUFS2), and saposin D, respectively, as direct desmin binding partners. In silico analysis indicated that both interactions at the atomic level occur in a very similar way, by the formation of a three-helix bundle with hydrophobic interactions in the interdomain space and hydrogen bonds at R16 and S32 of the desmin head domain. The interactions, confirmed also by GST pull-down assays, indicating the necessity of the desmin head domain and, furthermore, point out its role in function of mitochondria and lysosomes, organelles which are disrupted in myopathies due to desmin head domain mutations.
Topics: Animals; Desmin; Intermediate Filaments; Muscles; Muscular Diseases; Mutation; Humans
PubMed: 38607042
DOI: 10.3390/cells13070603 -
Hua Xi Kou Qiang Yi Xue Za Zhi = Huaxi... Aug 2023To analyze the clinicopathological features of maxillofacial granular cell tumors (GCT) with the aid of immunohistochemical staining.
OBJECTIVES
To analyze the clinicopathological features of maxillofacial granular cell tumors (GCT) with the aid of immunohistochemical staining.
METHODS
Seven cases of maxillofacial GCT were retrospectively collated, and the microscopic morphology of maxillofacial GCT was analyzed. The expression of S-100, neuron-specific enolase (NSE), SOX-10, CD68, actin, desmin, and Ki-67 in GCT was detected by immunohistochemical staining. The cases were observed in the follow-ups after clinical treatment.
RESULTS
All seven GCT tumors lacked envelopes and were poorly defined. Microscopically, the sizes of the tumor cells were large and appeared with inconspicuous cell membranes, forming a syncytium-like appearance. The cytoplasm was filled with characteristic eosinophilic granules. The immunohistochemical results showed that six cases were NSE-positive, five cases were S-100-positive, seven cases were CD68-positive, five cases were SOX-10-positive, one case was actin-positive, and seven cases were desmin-negative. The Ki-67 index did not exceed 5% in all cases. In the follow-up sessions, none of the six cases presented a recurrence.
CONCLUSIONS
Maxillofacial GCT has a characteristic histological structure. Immunohistochemical S-100, CD68, and other indicators can assist in diagnosis, and the prognosis is good after clinical resection.
Topics: Humans; Ki-67 Antigen; Granular Cell Tumor; Retrospective Studies; Actins; Desmin; S100 Proteins
PubMed: 37474473
DOI: 10.7518/hxkq.2023.2023035 -
International Journal of Molecular... Feb 2024Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is... (Review)
Review
Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is known to function as a molecular chaperone, particularly for desmin, but also interacts with a wide variety of additional proteins. The molecular chaperone function is also enhanced by signal-dependent phosphorylation at specific residues under stress conditions. Naturally occurring mutations in , the gene that encodes alpha-B-crystallin, have been suggested to alter ionic intermolecular interactions that affect dimerization and chaperone function. These mutations have been associated with myofibrillar myopathy, restrictive cardiomyopathy, and hypertrophic cardiomyopathy and promote pathological hypertrophy through different mechanisms such as desmin aggregation, increased reductive stress, or activation of calcineurin-NFAT signaling. This review will discuss the known mechanisms by which alpha-B-crystallin functions in cardiac homeostasis and the pathogenesis of cardiomyopathies and provide insight into potential future areas of exploration.
Topics: Humans; Desmin; Cardiomyopathies; Mutation; Cardiomyopathy, Restrictive; Molecular Chaperones
PubMed: 38474073
DOI: 10.3390/ijms25052826 -
Journal of Ginseng Research Jul 2023Ginsenoside Rg1, a bioactive component of Ginseng, has demonstrated anti-inflammatory, anti-cancer, and hepatoprotective effects. It is known that the...
BACKGROUND
Ginsenoside Rg1, a bioactive component of Ginseng, has demonstrated anti-inflammatory, anti-cancer, and hepatoprotective effects. It is known that the epithelial-mesenchymal transition (EMT) plays a key role in the activation of hepatic stellate cells (HSCs). Recently, Rg1 has been shown to reverse liver fibrosis by suppressing EMT, although the mechanism of Rg1-mediated anti-fibrosis effects is still largely unclear. Interestingly, Smad7, a negative regulator of the transforming growth factor β (TGF-β) pathway, is often methylated during liver fibrosis. Whether Smad7 methylation plays a vital role in the effects of Rg1 on liver fibrosis remains unclear.
METHODS
Anti-fibrosis effects were examined after Rg1 processing and . Smad7 expression, Smad7 methylation, and microRNA-152 (miR-152) levels were also analyzed.
RESULTS
Rg1 significantly reduced the liver fibrosis caused by carbon tetrachloride, and reduced collagen deposition was also observed. Rg1 also contributed to the suppression of collagenation and HSC reproduction in vitro. Rg1 caused EMT inactivation, reducing Desmin and increasing E-cadherin levels. Notably, the effect of Rg1 on HSC activation was mediated by the TGF-β pathway. Rg1 induced Smad7 expression and demethylation. The over-expression of DNA methyltransferase 1 (DNMT1) blocked the Rg1-mediated inhibition of Smad7 methylation, and miR-152 targeted DNMT1. Further experiments suggested that Rg1 repressed Smad7 methylation via miR-152-mediated DNMT1 inhibition. MiR-152 inhibition reversed the Rg1-induced promotion of Smad7 expression and demethylation. In addition, miR-152 silencing led to the inhibition of the Rg1-induced EMT inactivation.
CONCLUSION
Rg1 inhibits HSC activation by epigenetically modulating Smad7 expression and at least by partly inhibiting EMT.
PubMed: 37397418
DOI: 10.1016/j.jgr.2022.12.005 -
Journal of Comparative Physiology. B,... Oct 2023Employing animal models to study heart failure (HF) has become indispensable to discover and test novel therapies, but their translatability remains challenging....
Employing animal models to study heart failure (HF) has become indispensable to discover and test novel therapies, but their translatability remains challenging. Although cytoskeletal alterations are linked to HF, the tubulin signature of common experimental models has been incompletely defined. Here, we assessed the tubulin signature in a large set of human cardiac samples and myocardium of animal models with cardiac remodeling caused by pressure overload, myocardial infarction or a gene defect. We studied levels of total, acetylated, and detyrosinated α-tubulin and desmin in cardiac tissue from hypertrophic (HCM) and dilated cardiomyopathy (DCM) patients with an idiopathic (n = 7), ischemic (n = 7) or genetic origin (n = 59), and in a pressure-overload concentric hypertrophic pig model (n = 32), pigs with a myocardial infarction (n = 28), mature pigs (n = 6), and mice (n = 15) carrying the HCM-associated MYBPC3 mutation. In the human samples, detyrosinated α-tubulin was increased 4-fold in end-stage HCM and 14-fold in pediatric DCM patients. Acetylated α-tubulin was increased twofold in ischemic patients. Across different animal models, the tubulin signature remained mostly unaltered. Only mature pigs were characterized by a 0.5-fold decrease in levels of total, acetylated, and detyrosinated α-tubulin. Moreover, we showed increased desmin levels in biopsies from NYHA class II HCM patients (2.5-fold) and the pressure-overload pig model (0.2-0.3-fold). Together, our data suggest that desmin levels increase early on in concentric hypertrophy and that animal models only partially recapitulate the proliferated and modified tubulin signature observed clinically. Our data warrant careful consideration when studying maladaptive responses to changes in the tubulin content in animal models.
PubMed: 37644284
DOI: 10.1007/s00360-023-01509-1 -
International Journal of Molecular... Jul 2023Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene...
Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene () result in a variety of diseases, including cardiomyopathies and myofibrillar myopathy, collectively called desminopathies. Here we describe the clinical, histological and radiological features of a Greek patient with a myofibrillar myopathy and cardiomyopathy linked to the c.734A>G,p.(Glu245Gly) heterozygous variant in the gene. Moreover, through ribonucleic acid sequencing analysis in skeletal muscle we show that this variant provokes a defect in exon 3 splicing and thus should be considered clearly pathogenic.
Topics: Humans; Desmin; Greece; Cardiomyopathies; Myopathies, Structural, Congenital; Muscle, Skeletal; Mutation; Muscular Diseases
PubMed: 37446359
DOI: 10.3390/ijms241311181 -
Molecular Therapy. Nucleic Acids Dec 2023Exon-skipping therapy is a promising treatment strategy for Duchenne muscular dystrophy (DMD), which is caused by loss-of-function mutations in the gene encoding...
Exon-skipping therapy is a promising treatment strategy for Duchenne muscular dystrophy (DMD), which is caused by loss-of-function mutations in the gene encoding dystrophin, leading to progressive cardiomyopathy. In-frame deletion of exons 3-9 (Δ3-9), manifesting a very mild clinical phenotype, is a potential targeted reading frame for exon-skipping by targeting actin-binding domain 1 (ABD1); however, the efficacy of this approach for DMD cardiomyopathy remains uncertain. In this study, we compared three isogenic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing Δ3-9, frameshifting Δ3-7, or intact RNA sequencing revealed a resemblance in the expression patterns of mechano-transduction-related genes between Δ3-9 and wild-type samples. Furthermore, we observed similar electrophysiological properties between Δ3-9 and wild-type hiPSC-CMs; Δ3-7 hiPSC-CMs showed electrophysiological alterations with accelerated CaMKII activation. Consistently, Δ3-9 hiPSC-CMs expressed substantial internally truncated dystrophin protein, resulting in maintaining F-actin binding and desmin retention. Antisense oligonucleotides targeting exon 8 efficiently induced skipping exons 8-9 to restore functional dystrophin and electrophysiological parameters in Δ3-7 hiPSC-CMs, bringing the cell characteristics closer to those of Δ3-9 hiPSC-CMs. Collectively, exon-skipping targeting ABD1 to convert the reading frame to Δ3-9 may become a promising therapy for DMD cardiomyopathy.
PubMed: 38028197
DOI: 10.1016/j.omtn.2023.102060