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PubMed1994

Truncated desmin in PtK2 cells induces desmin-vimentin-cytokeratin coprecipitation, involution of intermediate filament networks, and nuclear fragmentation: a model for many degenerative diseases.

The earliest expression of truncated desmin in transfected PtK2 cells results in the formation of dispersed microprecipitates containing not only the truncated desmin, but also endogenous vimentin and cytokeratin proteins. Desmin microprecipitates without vimentin or vimentin microprecipitates without desmin are not observed. The microprecipitates involving cytokeratin invariably are also positive for desmin and vimentin. Over time, the precipitates enlarge into 1- to 2-microns spheroids and then fuse into amorphous chimeric juxtanuclear masses that can occupy > 30% of the cell volume. Concurrently, first the vimentin and then the cytokeratin networks are resorbed. The chimeric precipitates are not recognized or marked for degradation by the lysosomal system. Ultimately the cell nucleus fragments and the cell dies. Similar protein complexes appear in many human and animal pathologies, suggesting that a similar protein-precipitation sequence initiated by the introduction of a mutationally or environmentally altered protein molecule is at work.

Alzheimer Disease↗
PubMed2001

Abnormal desmin protein in myofibrillar myopathies caused by desmin gene mutations.

Muscle proteins were extracted in various sodium dodecyl sulfate buffers from 6 patients with myofibrillar myopathy (MFM) and previously identified with mutations in the desmin gene (desmin myopathy; DesM), 6 with MFM without mutations, and 14 disease controls to search for alterations in biochemistry and solubility of mutated desmin filaments. In the 1% posthigh-speed pellet fraction, desmin was detected with immunoblots only in DesM and not the other MFM. We conclude that mutant desmin forms insoluble aggregates that are specific for the DesM and can be detected with Western blots.

Blotting, Western↗
PubMed1999

Desmin phosphorylation abnormalities in cytoplasmic body and desmin-related myopathies.

Cytoplasmic body myopathy (CBM) and desmin-related myopathy (DRM) are both characterized by an abnormal accumulation of desmin. To determine whether these abnormalities involve similar or different forms of desmin, we performed desmin two-dimensional electrophoresis: our results showed an increase in the two acidic isoforms in CBM muscles as compared with an increase in the number of acidic isovariants in DRM samples. A process of hyperphosphorylation involved in these acidic forms was confirmed by alkaline phosphatase application onto the muscle samples in both pathological conditions.

Cytoplasm↗
PubMed1986

Immunocytochemical studies of endothelial cells in vivo. I. The presence of desmin only, or of desmin plus vimentin, or vimentin only, in the endothelial cells of different capillaries of the adult chicken.

It is currently believed that the intermediate filaments of endothelial cells contain vimentin subunits exclusively. This inference, however, is derived from studies of only a few types of endothelial cells. By double indirect immunofluorescence and immunoelectron microscopy, we have now examined the endothelial cells of the micro- and macrovasculature of a variety of tissues and organs of adult chicken in vivo for their content of desmin and vimentin. Endothelial cells of the peritubular capillary in the renal cortex, the hepatic sinusoid, and the splenic sinusoid were found to contain only desmin; those of the exocrine pancreas capillary contained both desmin and vimentin; and the endothelial cells of the macrovasculatures and of all the other microvasculatures examined, including the vasa recta of the renal medulla, contained only vimentin. Such heterogeneity suggests that different types of adult chicken endothelial cells may have different embryological origins. To the extent that desmin and vimentin intermediate filaments may be functionally distinct, these results also suggest that different capillary endothelial cells may have different functional properties.

Animals↗
PubMed2006

Forced expression of desmin and desmin mutants in cultured cells: impact of myopathic missense mutations in the central coiled-coil domain on network formation.

We recently demonstrated that inherited disease-causing mutations clustered in the alpha-helical coiled-coil "rod" domain of the muscle-specific intermediate filament (IF) protein desmin display a wide range of inhibitory effects on regular in vitro assembly. In these studies, we showed that individual mutations exhibited phenotypes that were not, with respect to the severity of interference, predictable by our current knowledge of the structural design of IF proteins. Moreover, the behavior of some mutated proteins in a standard tissue culture cell expression system was found to be even more complex. Here, we systematically investigate the behavior of these disease mutants in four different cell types: three not containing desmin or the related IF protein vimentin and the standard fibroblast line 3T3, which has an extensive vimentin system. The ability of the mutants to form filaments in the vimentin-free cells varies considerably, and only the mutants forming IFs in vitro generate extended filamentous networks. Furthermore, these latter mutants integrate into the 3T3 vimentin network but all the others do not. Instead, they cause the endogenous network of 3T3 vimentin to reorganize into perinuclear bundles. In addition, most of these assembly-deficient mutant desmins completely segregate from the vimentin system. Instead, the small round to fibrillar particles formed distribute independently throughout the cytoplasm as well as between the collapsed vimentin filament arrays in the perinuclear area.

3T3 Cells↗
PubMed1980

Purification of smooth-muscle desmin and a protein-chemical comparison of desmins from chicken gizzard and hog stomach.

A fast and convenient procedure for the purification of polymerization-competent smooth-muscle desmin is described. Desmin from chicken gizzard and hog stomach were compared by fingerprint techniques. The two proteins show extensive amino acid sequence homology, although some clear differences in the peptide patterns are indicated. Comparative amino acid sequence analysis of some of the peptides obtained in pure form directly proves this conclusion.

Amino Acid Sequence↗
PubMed1991

Desmin is present in proliferating rat muscle satellite cells but not in bovine muscle satellite cells.

The presence of desmin was characterized in cultured rat and bovine satellite cells and its potential usefulness as a marker for identifying satellite cells in vitro was evaluated. In primary cultures, positive immunohistochemical staining for desmin and skeletal muscle myosin was observed in rat and bovine myotubes. A small number of mononucleated cells (20% of rat satellite cells and 5% of bovine satellite cells) were myosin-positive, indicative of post-mitotic differentiated myocytes. In bovine satellite cell cultures 13% of the mononucleated cells were desmin-positive, while 84% of the mononucleated cells in rat satellite cell cultures were desmin-positive. Rat satellite cell mass cultures and bovine satellite cell clonal density cultures were pulsed with 3H-thymidine, and autoradiographic data revealed that greater than 94% of dividing rat cells were desmin-positive, suggesting that desmin is synthesized in proliferating rat satellite cells. However, no desmin was seen in cells that incorporated labeled thymidine in bovine satellite cell clones. Analysis of clonal density cultures revealed that only 14% of the mononucleated cells in bovine satellite cell colonies were desmin-positive, whereas 98% of the cells in rat satellite cell colonies were desmin-positive. Fibroblast colonies from both species were desmin-negative. In order to further examine the relationship between satellite cell differentiation and desmin expression, 5-bromo-2'-deoxyuridine (BrdU) was added to culture medium at the time of plating to inhibit differentiation. Fusion was inhibited in rat and bovine cultures, and cells continued to divide. Very few desmin-positive cells were found in bovine cultures, but greater than 90% of the cells in rat cultures stained positive for desmin. The presence of desmin and sarcomeric myosin was also evaluated in regenerating rat tibialis anterior five days after bupivacaine injection. In regenerating areas of the muscle many desmin-positive cells were present, and only a few cells stained positive for skeletal muscle myosin. Application of desmin staining to rat satellite cell growth assays indicated that rat satellite cells cultured in serum-containing medium were contaminated with fibroblasts at levels that ranged from approximately 5% in 24 hr cultures to 15% in mature cultures. In defined medium 4 day cultures contain approximately 95% to 98% desmin-positive satellite cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation with compromised systolic function.

Desmin is the muscle-specific member of the intermediate filament family of cytoskeletal proteins, expressed both in striated and smooth muscle tissues. In mature striated muscle fibers, the desmin filament lattice surrounds the Z-discs, interconnects them to each other and links the entire contractile apparatus to the sarcolemmal cytoskeleton, cytoplasmic organelles and the nucleus. There have been increasing reports of human cardiomyopathies associated with abnormal accumulation and aggregation of desmin filaments. Recently identified desmin mutations in humans suffering from skeletal muscle myopathy and cardiomyopathy suggest that these diseases might arise as a consequence of impaired function of desmin filaments. Previous generation of desmin null mice in our laboratory demonstrated that the absence of desmin results in myocyte ultrastructural defects and myocyte cell death leading to fibrosis and calcification of the myocardium. However, the effects that these defects have on cardiac function were not addressed. To further our understanding of desmin function in vivo, and in order to address the direct involvement of desmin in cardiomyopathy, we investigated the effect of the absence of desmin on myocardial mass, myocyte size and shape, changes in gene expression and cardiac systolic and diastolic function in mice. Morphometric characterization of isolated cardiomyocytes demonstrated a 24% increase in cell volume in the desmin null mice, solely due to an increase in transverse section area, suggesting for the first time that mice lacking the intermediate filament protein desmin develop concentric cardiomyocyte hypertrophy. This type of hypertrophy was accompanied by induction of embryonic gene expression and later by ventricular dilatation, and compromised systolic function. These results demonstrate that desmin is essential for normal cardiac function, and they suggest that the absence of an intact desmin filament system, rather than accumulation of the protein, may be responsible for the pathology seen in some of the desmin associated cardiomyopathies.

Animals↗
PubMed1994

Differential organization of desmin and vimentin in muscle is due to differences in their head domains.

In most myogenic systems, synthesis of the intermediate filament (IF) protein vimentin precedes the synthesis of the muscle-specific IF protein desmin. In the dorsal myotome of the Xenopus embryo, however, there is no preexisting vimentin filament system and desmin's initial organization is quite different from that seen in vimentin-containing myocytes (Cary and Klymkowsky, 1994. Differentiation. In press.). To determine whether the organization of IFs in the Xenopus myotome reflects features unique to Xenopus or is due to specific properties of desmin, we used the injection of plasmid DNA to drive the synthesis of vimentin or desmin in myotomal cells. At low levels of accumulation, exogenous vimentin and desmin both enter into the endogenous desmin system of the myotomal cell. At higher levels exogenous vimentin forms longitudinal IF systems similar to those seen in vimentin-expressing myogenic systems and massive IF bundles. Exogenous desmin, on the other hand, formed a reticular IF meshwork and non-filamentous aggregates. In embryonic epithelial cells, both vimentin and desmin formed extended IF networks. Vimentin and desmin differ most dramatically in their NH2-terminal "head" regions. To determine whether the head region was responsible for the differences in the behavior of these two proteins, we constructed plasmids encoding chimeric proteins in which the head of one was attached to the body of the other. In muscle, the vimentin head-desmin body (VDD) polypeptide formed longitudinal IFs and massive IF bundles like vimentin. The desmin head-vimentin body (DVV) polypeptide, on the other hand, formed IF meshworks and non-filamentous structures like desmin. In embryonic epithelial cells DVV formed a discrete filament network while VDD did not. Based on the behavior of these chimeric proteins, we conclude that the head domains of vimentin and desmin are structurally distinct and not interchangeable, and that the head domain of desmin is largely responsible for desmin's muscle-specific behaviors.

Amino Acid Sequence↗
PubMed1989

[Immunocytochemical studies on the appearance and distribution of desmin during myogenesis in the embryos of Cynops orientalis].

Indirect immunofluorescence was used to study the temporal appearance and spatial distribution of desmin during the myogenesis of the embryos of Cynops orientalis. Desmin is undetectable until stage 25. In stage 25 embryo, it can be seen that desmin is restrictively distributed at both ends of columnar cells, near the boundary between two somites and intense in the cells near by the notochord. From stage 26 to stage 30, the amount of desmin is increased and its distribution pattern shows little change (Plate I, Figs. 1-2). At stage 32 desmin can be detected in the cells more distal to the notochord and forms filaments on the inside of the cell membrane parallel to the long axis of the cell (Plate I, Fig. 3 and 5). Desmin filaments extend gradually from the both ends toward the mid-part of the cell (Plate I, Fig. 6 and Plate II, Figs. 7, 11-13). At about stage 40 the whole cell is filled with desmin filaments and the attachment of desmin to Z line can occasionally be detected (Plate II, Fig. 8). Desmin attached to Z line is increased at stage 41 (Plate II, Fig. 9) and at stage 43 most of the desmin is found attached to Z line (Plate II, Fig.10). According to EM observation, Z line structure can be seen in stage 33 embryo (Wang[18]), but desmin remains in the filament form till stage 40. The transference of desmin distribution pattern from filament to Z line occurs somewhat later than the appearance of scattered sarcomeres. The possibility that notochord may be the main factor which influences the spatial localization of desmin was analyzed. The relationship between the transference of desmin from filament to Z line attached form and the quantitative changes of both desmin and sarcomere was discussed.

Animals↗
PubMed1998

Distribution and organization of desmin in cultured adult cardiac muscle cells: reflection on function.

The cell-culture model for the study of desmin in adult cardiac muscle cells has provided insight into the function of desmin based on its distribution and structural organization. Initially, desmin emerged as a filamentous network from the existing amorphous form in the growing adult cardiac myocytes in vitro. Later, desmin became organized in various forms. In addition to the presence of a periodic array of desmin in the Z-line regions as observed in cardiac myocytes in vivo, longitudinally and transversely oriented strands of desmin were observed along the length of myofibrils in cardiac myocytes in vitro. These desmin strands and transverse perodicities formed a complex interwoven network, interlacing myofibrils of cells. Desmin and alpha-actinin were organized in ribbon- or aponeuroses-like structures that appeared as sheet-like, supportive structures for the cell body. The cellular cytoplasmic processes containing myofibrils were supported by desmin bars. The complex desmin network, desmin bars, transverse strands and ribbons or aponeuroses were observed in in vitro cardiac myocytes in contrast to in vivo cardiac myocytes. The functional implication of desmin, as indicated by in vivo studies, required more information concerning the organization of desmin for its supportive function, and is addressed in the present study. The elaborate organization of desmin provides evidence for its supportive function for the maintenance of the structural integrity and function of cardiac muscle cells.

Actinin↗
PubMed2004

Desmin myopathy.

Desmin myopathy is a recently identified disease associated with mutations in desmin or alphaB-crystallin. Typically, the illness presents with lower limb muscle weakness slowly spreading to involve truncal, neck-flexor, facial, bulbar and respiratory muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks and arrhythmias resulting in premature sudden death. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing amorphous eosinophilic deposits seen as granular or granulofilamentous material on electron microscopic examination. Immuno-staining for desmin is positive in each region containing abnormal structures. The inheritance pattern in familial desmin myopathy is autosomal dominant or autosomal recessive, but many cases have no family history. At least some, and probably most, non-familial desmin myopathy cases are associated with de novo desmin mutations. Age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Multiple mutations have been identified in the desmin gene: point substitutions, insertion, small in-frame deletions and a larger exon-skipping deletion. The majority of these mutations are located in conserved alpha-helical segments of desmin. Many of the missense mutations result in changing the original amino acid into proline, which is known as a helix breaker. Studies of transfected cell cultures indicate that mutant desmin is assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. Disease-associated desmin mutations in humans or transgenic mice cause accumulation of chimeric intracellular aggregates containing desmin and other cytoskeletal proteins. alphaB-crystallin serves in the muscle as a chaperone preventing desmin aggregation under various forms of stress. If mutated, alphaB-crystallin may cause a myopathy similar to those resulting from desmin mutations. Routine genetic testing of patients for mutations in desmin and alphaB- crystallin genes is now available and necessary for establishing an accurate diagnosis and providing appropriate genetic counselling. Better understanding of disease pathogenesis would stimulate research focused on developing specific treatments for these conditions.

Amino Acid Sequence↗
PubMed2001

Mouse model of desmin-related cardiomyopathy.

BACKGROUND: The consequence of upregulation of desmin in the heart is unknown. Mutations in desmin have been linked to desmin-related myopathy (DRM), which is characterized by abnormal intrasarcoplasmic accumulation of desmin, but direct causative evidence that a desmin mutation leads to aberrant intrasarcoplasmic desmin accumulation, aggregation, and cardiomyopathy is lacking. METHODS AND RESULTS: Multiple transgenic mouse lines that expressed either murine wild-type desmin or a 7-amino acid deletion (R173 through E179) desmin (D7-des) mutation linked to DRM were made. The distribution of desmin protein was unchanged, and no overt phenotype was detected in the wild-type desmin transgenic mice. In contrast, the D7-des mouse heart showed aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates that were desmin-positive and characteristic of human DRM. The desmin filament network was significantly disrupted, and myofibril alignment was visibly compromised. Although systolic function at the whole-organ level was substantially conserved in the young adult animals, the ability of the heart to respond to beta-agonist stimulation, as measured in the intact animal, was significantly blunted. CONCLUSIONS: Upregulation of desmin protein at moderate levels is not detrimental. However, the D7-des mutation is dominant negative, and expression of the mutant protein leads to the appearance of aggregates that are characteristic of and diagnostic for human desmin-related cardiomyopathy.

Amino Acid Sequence↗
PubMed1996

Immunocytochemical colocalization of desmin and vimentin in human fetal skeletal muscle cells.

BACKGROUND: Desmin and vimentin are the major intermediate filaments in muscle. They have been extensively studied in animal experiments. This study is the first to identify the distribution and to analyse the correlation of desmin and vimentin in human fetal skeletal muscle. Vimentin might be replaced by or transformed into desmin during myogenesis in chick embryo, although the precise process remains to be elucidated. The aim of this report is to evaluate the ratio of desmin to vimentin in human fetal muscle. METHODS: By double-labeling immunoelectron microscopy, desmin and vimentin intermediate filaments were localized in developing skeletal muscles of 20-29-week-old human fetuses. The ratio of desmin and vimentin was analyzed statistically. RESULTS: Two sizes of colloidal gold particles, 5 nm (vimentin) and 10 nm (desmin), were distributed along the intermediate filaments. The commonest distance between gold particles was approximately 40-50 nm. Desmin and vimentin labeled with gold particles were arranged very close together in the same intermediate filament. The ratio of vimentin to desmin varied but the amount of vimentin decreased progressively from the undifferentiated myoblast to the differentiated myocytes. As the fetuses developed, desmin increased and vimentin decreased. Desmin and vimentin intermediate filaments were identified in the intermyofibrils of differentiated myocytes, in subsarcolemmal space, and in myoblast. CONCLUSIONS: Desmin and vimentin were colocalized in the same intermediate filaments. More vimentin existed in the less differentiated myocytes, although a small number of desmin filaments were already found in undifferentiated myoblasts. These intermediate filaments may not only connect myofibril bundles, cell organelles, and cell membrane but also provide a basis for myofibrillogenesis that is similar to relation between connective fibers and parenchymal cells.

Desmin↗
PubMed2004

Desmin: a major intermediate filament protein essential for the structural integrity and function of muscle.

Desmin is a muscle-specific protein and a key subunit of the intermediate filament in cardiac, skeletal and smooth muscles. Desmin filaments are mainly located at the periphery of Z-disk of striated muscles and at the dense bodies of smooth muscle cells, and they have been postulated to play a critical role in the maintenance of structural and mechanical integrity of the contractile apparatus in muscle tissues. This review summarizes the findings in the regulation of the desmin gene and function of the desmin protein. The expression of desmin gene is regulated by a combination of different transcription control regions in muscle cells. The results from mice deficient in desmin reveal the fundamental role of desmin filaments in cell architecture, force transmission and mitochondrial function. Mice lacking desmin postnatally develop a dilated cardiomyopathy, a skeletal myopathy and smooth muscle defects. Some of desmin-related myopathies are attributable to a missense mutations and deletions in the desmin gene. Other desmin-related myopathies, in which the desmin gene is not mutated, could be related to mutations of the genes encoding the proteins that interact with desmin.

Animals↗
PubMed1990

Assembly of amino-terminally deleted desmin in vimentin-free cells.

To study the role of the amino-terminal domain of the desmin subunit in intermediate filament (IF) formation, several deletions in the sequence encoding this domain were made. The deleted hamster desmin genes were fused to the RSV promoter. Expression of such constructs in vimentin-free MCF-7 cells as well as in vimentin-containing HeLa cells, resulted in the synthesis of mutant proteins of the expected size. Single- and double-label immunofluorescence assays of transfected cells showed that in the absence of vimentin, desmin subunits missing amino acids 4-13 are still capable of filament formation, although in addition to filaments large numbers of desmin dots are present. Mutant desmin subunits missing larger portions of their amino terminus cannot form filaments on their own. It may be concluded that the amino-terminal region comprising amino acids 7-17 contains residues indispensable for desmin filament formation in vivo. Furthermore it was shown that the endogenous vimentin IF network in HeLa cells masks the effects of mutant desmin on IF assembly. Intact and mutant desmin colocalized completely with endogenous vimentin in HeLa cells. Surprisingly, in these cells endogenous keratin also seemed to colocalize with endogenous vimentin, even if the endogenous vimentin filaments were disturbed after expression of some of the mutant desmin proteins. In MCF-7 cells some overlap between endogenous keratin and intact exogenous desmin filaments was also observed, but mutant desmin proteins did not affect the keratin IF structures. In the absence of vimentin networks (MCF-7 cells), the initiation of desmin filament formation seems to start on the preexisting keratin filaments. However, in the presence of vimentin (HeLa cells) a gradual integration of desmin in the preexisting vimentin filaments apparently takes place.

Amino Acid Sequence↗
PubMed1991

Comparative immunohistochemical staining for desmin and muscle-specific actin. A study of 576 cases.

Muscle-specific actin (MSA) and desmin are considered to be sensitive and specific markers for muscle differentiation. The authors compared staining patterns for these markers in 576 samples of normal, reactive, and neoplastic tissues. The standard avidin-biotin-peroxidase complex technique was performed with the use of two commercial antibodies against MSA (HHF35; Enzo Biochemical, Inc., New York, NY) and desmin (DER11; DAKO Corporation, Santa Barbara, CA), respectively, on consecutive paraffin-embedded tissue sections from these cases. Both MSA and desmin were found in all 80 normal muscle samples. Although MSA appeared diffusely in all vascular smooth muscle samples, desmin was demonstrated focally in vascular smooth muscle cells in 100 of 196 samples. MSA but not desmin always was found in myoepithelial cells (25 samples), pericytes (286 samples), and decidual cells (7 samples). Among 76 cases of myofibroblast-containing lesions, 14 and 54 were found to have desmin and MSA, respectively. MSA and desmin were found in 4 of 4 cardiac rhabdomyomas, 34 of 34 rhabdomyosarcomas, and 5 of 6 leiomyomas. Among 22 leiomyosarcomas, 7 displayed either MSA or desmin and 7 showed both markers. In general, more tumor cells showed staining for MSA than desmin, but the reverse was true in some cases. Tissue fixed in Zenker's solution seemed to show a significant decrease in MSA immunoreactivity, but no significant change for desmin staining was observed. None of the 154 normal tissues and 22 benign nonmyogenic tumors expressed MSA or desmin. Among 133 malignant nonmyogenic tumors, positive staining for both desmin and MSA was found in 3 of 8 cases of glioblastoma multiforme, 1 of 10 malignant schwannomas, and 1 of 14 malignant fibrous histiocytomas; staining for only MSA was found in 3 of 14 malignant fibrous histiocytomas, 1 of 10 malignant schwannomas, 6 of 6 fibromatoses, 1 of 1 mammary myofibroblastoma, and 1 of 7 malignant mesotheliomas; and staining for desmin only was seen in 1 of 7 malignant mesotheliomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Actins↗