What does desmin do: A bibliometric assessment of the functions of the muscle intermediate filament

Abstract

Intermediate filaments were first described in muscle in 1968, and desmin was biochemically identified about 10 years afterwards. Its importance grew after the identification of desminopathies and desmin mutations that cause mostly cardiopathies. Since its characterization until recently, different functions have been attributed to desmin. Here, we use bibliometric tools to evaluate the articles published about desmin and to assess its several putative functions. We identified the most productive authors and the relationships between research groups. We studied the more frequent words among 9734 articles (September 2021) containing “desmin” on the title and abstract, to identify the major research focus. We generated an interactive spreadsheet with the 934 papers that contain “desmin” only on the title that can be used to search and quantify terms in the abstract. We further selected the articles that contained the terms “function” or “role” from the spreadsheet, which we then classified according to type of function, organelle, or tissue involved. Based on the bibliographic analysis, we assess comparatively the putative functions, and we propose an alternative explanation for the desmin function.

Keywords

Desmin intermediate filaments cytoskeleton

Impact Statement

More than 50 years after the identification of intermediate filaments, there is still a debate about their functions. While on one hand, several knockouts and genetic variants have been studied, on the other hand, there is still a tendency to mix together functions that are related to all intermediate filaments, dismissing the fact that desmin is specific to muscle cells. The present review uses a bibliometric approach to assess the research on desmin, and to compare its alleged functions. Based on the interpretation of the comparative list of functions we organized, we propose a new approach to interpret the function of desmin. This review should be useful to those interested in cytoskeleton, particularly in intermediate filaments, and in myogenesis and muscle structure and function, by providing a comprehensive view of the research on desmin.

Introduction

The cytoskeletal component “intermediate filament” (IF) has been characterized by Holtzer in 1968¹ because of its diameter of 10 nm, based on his observation of chick muscle cells in culture. He pointed out that other similarly sized filaments have been described in other cell types, and he assumed that these structures were related. Later it was shown that, while IFs form the nuclear lamina in all cell types, not all cell types have cytoplasmic IFs. Furthermore, IFs are composed of different proteins in different tissues.² Here, we will focus on the muscle- (and endothelial) specific filament protein desmin. The first purification of muscle IF protein has been reported by Cooke in 1976,³ followed by Lazarides,⁴ who suggested the name “desmin” for its ability to join structures, and Small, who suggested the name “skeletin.”⁵ This sequence of events, from structure to biochemistry, is the opposite of what happened to microfilaments, where the biochemical identification of actin and myosin took place around 50 years before the visualization of contractile filaments, and similar to microtubules, that were first identified by electron microscopy and only biochemically purified 20 years afterwards. Yet the fundamental role of actin and myosin in contraction and tubulin in chromosome movement during mitosis, in all eukaryotic cells, appeared quite early in research, explaining why all cell types express actin and tubulin. The most obvious function assigned to IF is vaguely categorized as “mechanical integration.”⁶ While this mechanical function can be undoubtedly observed in epithelial cells, the concept that all cell types have the same IF function is somewhat contradictory with the fact that each cell type has a different set of IF proteins.

Contrary to actin and tubulin, which are compact globular proteins that have to undergo an extra chaperone processing step before they assume their final form,⁷ IF proteins are elongated molecules, with two varying globular domains and a conserved central rod domain. Polymerization of actin and tubulin involves a smaller region of the subunit than IFs, which first assemble as antiparallel dimers throughout their central domain.² While the polymerization of actin and tubulin involves nTP hydrolysis, the polymerization of IF is regulated by phosphorylation. In the immunofluorescence image of cultured cells (Figure 1), desmin filaments spread in every direction of the muscle cells, contrary to actin filaments which are mostly oriented in the direction of contraction along the major axis of the cell. We used the radiality-based processing (SRRF⁸) to better visualize both desmin and actin filaments. This method is based on the direction of changes in brightness among several images of the same field, much like the stochastic position determining microscopies such as STORM. Actin in these embryonic chicken primary cultures of skeletal myotubes⁹ is still distributed in non-periodical stress fibers, while desmin is clearly distributed around the nuclei (visible in the interference contrast figure).

Many diseases have been related to mutations in IFs.¹⁰ The hereditary disease epidermolysis bullosa simplex (EBS) is caused by alterations on the genes of cytokeratins.¹¹ The pathophysiology of EBS has been clearly established, with the symptoms of skin fragility combining to the loss of structural continuity between the cytokeratin network of adjacent skin cells. The disease is well modeled by cytokeratins K5 and K14 knockout mice, and a similar phenotype can be observed in alterations in desmosomes (IF-related cell–cell adhesion structures), such as pemphigus. Desminopathy has been characterized as a disease caused by alterations in the desmin gene or alterations that lead to the abnormal distribution and/or accumulation of desmin inside the cells.¹² As it happens to many other diseases, there is a gap between medical and basic cell biology knowledge,¹³ and the desmin-related physiopathological mechanisms are not clearly characterized: it is still not clear whether the disease is caused by the lack of function of altered desmin or to the accumulation of unprocessed molecular aggregates.

Here, we used bibliometrics, the quantitative study of publications, to review desmin function. Until September 2021, 10,570 articles have been published in PubMed citing desmin on the title or abstract, and 970 articles cite desmin on the title (Figure 2). Among the first category, 797 articles were classified as “review,” and about 7.5% of the total also mentioned the words “role” or “function.” The annual number of articles on desmin has been growing sharply, and there is a change in the total number of articles concerning “function” since 2005, at about the same time when the field of desminopathies became better investigated. The growth in the number of articles, however, should be kept in perspective because when we compared with the whole PubMed production, the proportion of articles about desmin actually became smaller over time (blue line on graph). Since there are numerous excellent reviews on several aspects of desmin, we decided to concentrate on the putative function(s) of desmin.

Patients

The quest for the function of desmin is ever more important because the identification of new cases of desminopathies that are being frequently identified and can have severe consequences for patients. In these cases, the literature either focuses on medical case-descriptions or on trying to establish details of each mutation at the cellular and molecular levels. From the medical point of view, the lack of awareness regarding desminopathies may represent a serious bias in determining the prevalence of desminopathies in different countries. Indeed, there is a huge difference in the number of diagnosed cases in different countries, which suggests an under-notification of cases and that the number of cases reported per country is more dependent on the local medical expertise than on the country’s human development index (data not shown) or possibly the population’s genetic background. Assuming that all the desmin mutation cases in the world should be registered in the Leiden Open Variation Database (LOVD, https://databases.lovd.nl/shared/genes/DES, maintained by the University of Leiden at https://www.dmd.nl/), we analyzed the worldwide incidence of desmin mutations (Figure 3). There is a large variation in the incidence from country to country, even considering the differences in population size. For instance, we could find only two descriptions of desminopathy in Brazil, which are not listed on the Leiden database nor on PubMed. Based on the average incidence of 0.25 cases per million habitants (calculated from the sum of cases in the LOVD database), we should expect about 53 cases in Brazil.

Researchers

One of the questions that can be analyzed bibliometrically is who the main researchers in the desmin field are, and how the research groups are related. We built from PubMed (September 2021) a database of 9731 articles with the word “desmin” in the title or abstract (including “skeletin” and excluding the dermatan sulfate “Desmin 370”). Using the software Vosviewer, we assembled a diagram showing the number of publications per authors and their relationship on Figure 4 (the files that allow interactive visualization with Vosviewer app: https://app.vosviewer.com can be provide upon request). While more than 72% of the 39,450 authors published less than five articles about desmin, 175 authors published more than 10 articles. The five authors with most papers are: Christopher Fletcher (Brigham and Women’s Hospital, US), Markku Miettinen (Nat Cancer Inst, US), Denise Paulin (Université Pierre et Marie Curie Paris 6, FR), Zhenlin Li (Université Pierre et Marie Curie Paris 6, FR), and Giulio Gabbiani (Université de Genève, SW), with more than 50 articles published each. While Fletcher and Miettinen publish mostly on tumor pathology, the others usually publish on basic cell biology science: the major focus of the articles will be discussed in the next section.

Research themes

Bibliometric analysis also allows the visualization of the most frequent words, which can be assumed to represent the main subjects in a field. The software Vosviewer identified the most frequent words in the desmin PubMed database, organized them according to their relationship (co-occurrence), and displayed them in a map (Figure 5, the files that allow interactive visualization with Vosviewer app: https://app.vosviewer.com can be provide upon request). From the association between these words, we can try to identify the major research areas (marked in the diagram): (1) articles that use desmin as a tumor marker, (2) articles on desmin-related diseases, (3) articles on the cell biology of desmin, and (4) articles on desmin biochemistry. The first group includes several medical cases and other articles in which desmin is used as a marker for the identification of a given cell type. Frequent words in this group are “expression,” “immunohistochemistry,” “staining” and “marker,” and medical terms such as “diagnosis,” “case,” and “treatment.” The second group (mostly colored in blue) includes articles on desmin-related diseases, with words such as “myopathy,” “cardiomyopathy,” “patient,” “mutation,” and “desmin gene” highly frequent. The third group (mostly colored in green) has been tentatively composed of words related to cell biology, with high frequency of words such as “cell,” “differentiation,” “vimentin,” and “keratin.” Interestingly, words related to immunostain (“monoclonal antibody,” “antibody,” and “immunofluorescence”) are also frequently used, but distinct from the first cluster. Finally, the fourth cluster (mostly colored in red) is tentatively associated with biochemistry, centered in the word “protein,” and including as frequent words “intermediate filament,” “filament” but also “myotube” and “myoblast.” In the center of the figure there are some words colored in yellow, which are linked to all the groups, such as “muscle,” “heart,” and “function.” Since these words link to words in all clusters, we considered them to be in an intersection between all groups and to not constitute an independent cluster.

Functions

Since the classification of all 10-nm filaments previously observed in several tissues as intermediate filaments, there has been a tendency to assume that they all have similar functions. The central core of all the IFs proteins, through which they polymerize, is conserved and they can be considered quite similar. However, it should be kept in mind that the head and tail of each of the tissue-specific IFs proteins are different, which must confer different properties to the filaments themselves, which in turn enable them to have different functions.¹⁴ There should be a reason for the cell-type specificity of the IF proteins. Here we used a bibliographic protocol to select articles on desmin to comparatively assess the putative functions. First, based on the EuropePMC search for articles with “desmin” on the Title, we manually assembled a spreadsheet including the abstract of each article that can be made available upon request. The spreadsheet can be used to search and quantify terms in the abstract or authors fields, and spreadsheet cells can be classified according to the desired criteria, such as number of citations or publication year. Using this spreadsheet, we could observe that the impact of articles with “function” or “role” on the abstract is significantly higher than the rest of the papers: the average number of citations of “desmin” + “function” articles is 34.4, while the average number of “desmin” articles is 26.4. This difference could be justified because the scientific community has been emphasizing research focused on mechanisms of action rather than description of cases or observations.¹³

We then used the spreadsheet to further analyze the articles that contained “function” or “role” in their abstract and that were not Reviews. We extracted the papers listed on Table 1 among those 164 articles. We classified each article according to: (1) alleged function, (2) conceptual approach (pathological, physiological, or structural), (3) level (subcellular, cellular, or tecidual), (4) model had a genetic modification such as knockouts, mutant (naturally occurring), and variant (experimentally constructed), (5) biological model, and (6) tissue type.

Table 1.

List of desmin functions, with the respective articles, classified according to alleged function, conceptual approach, structural level, genetic modification, biological model, and tissue type.

#	Authors	Function	Type	Level	Genetic modification	Biological model	Tissue
1	Alam et al.¹⁵	Regulates mitochondrial fission	Pathological	Mitochondria	Mutant	Mouse	Cardiac muscle
2	Balogh et al.¹⁶	Regulates sarcomere alignment	Structural	Myofibril	KO	Mouse	Cardiac muscle
3	Boriek et al.¹⁷	Regulates stiffness and force production	Structural	Myofibril	KO	Mouse	Skeletal muscle
4	Bouvet et al.¹⁸	Induce toxic aggregates formation	Physiological	Degradation systems	Variant molecule	Rat	Cardiac muscle
5	Cao et al.¹⁹	Regulates intercellular electrical coupling	Physiological	Gap junctions	–	Human/rat	Cardiac muscle
6	Capetanaki et al.²⁰	Regulates cellular structural and functional integrity	Physiological/structural	Myofibril	Variant molecule	Mouse	Skeletal, cardiac and smooth muscle
7	Charrier et al.²¹	Regulates myoblast stiffness	Physiological	Cell stiffness	–	Mouse	Skeletal muscle
8	Chaurasia et al.²²	Remodeling of chorneal myofibroblasts	Physiological	Myofibroblast	–	Rabbit	Other
9	Chen et al.²³	Regulates mechanoelectric feedback	Physiological	Cell signaling	Variant molecule	Rat	Cardiac muscle
10	Conover et al.²⁴	Regulates actin microfilament and nebulin size	Pathological	Myofibril	Mutant	Chicken/rat	Skeletal and cardiac muscle
11	Dagvadorj et al.²⁵	Support respiration	Physiological	Respiratory system	Mutant	Human	Skeletal muscle
12	D’Amati et al.²⁶	Allows contraction	Physiological	Myofibril	–	Human	Cardiac muscle
13	Datta et al.²⁷	Prevent cytoskeletal remodeling	Pathological	Heart	–	Rat	Cardiac muscle
14	Di Somma et al.²⁸	Regulates cardiac function	Physiological	Heart	–	Human	Cardiac muscle
15	Diermeier et al.²⁹	Regulates stiffness	Pathological	Myofibril	Mutant	Mouse	Skeletal muscle
16	Diguet et al.³⁰	Regulates mitochondrial function	Physiological	Mitochondria	KO	Mouse	Cardiac muscle
17	Eiber et al.³¹	Regulates cellular structural and functional integrity	Physiological/structural	Neuromuscular junction	KO	Mouse	Skeletal muscle
18	Galata et al.³²	Interferes with laminopathy phenotype severity	Pathological	Nucleus	Variant molecule	Mouse	Cardiac muscle
19	Gard and Lazarides³³	Regulates myofibril lateral organization	Structural	Myofibril	–	Chicken	Skeletal muscle
20	Gard et al.³⁴	Prevents cardiac arrhythmogenesis	Physiological	Heart	Variant molecule	Mouse	Cardiac muscle
21	Heckmann et al.³⁵	Allows contraction	Physiological	Myofibril	KO	Mouse	Cardiac muscle
22	Hijikata et al.³⁶	Stabilizes the subsarcolemmal cytoskeleton	Structural	Cytoskeleton	–	Rat	Skeletal muscle
23	Hofner et al.³⁷	Regulates mesodermal differentiation into cardiomyoblast	Physiological	Heart	Variant molecule	Mouse	Cardiac muscle
24	Höllrigl et al.³⁸	Regulates myoblast fusion, but hampers cardiomyogenesis and blocks smooth muscle development	Physiological/pathological	Myoblast fusion	KO	Mouse	Cardiac and smooth muscle
25	Huang et al.³⁹	Regulates myofibril alignment	Pathological	Myofibril	Mutant	Hamster	Cardiac muscle
26	Joanne et al.⁴⁰	Interferes with myofibril, mitochondria and autophagy	Physiological	Myofibril	KO	Mouse	Skeletal muscle
27	Kayman et al.⁴¹	Regulates calcium flux in myofibers	Physiological	Calcium homeostasis	KO	Zebrafish	Skeletal muscle
28	Kostareva et al.⁴²	Interferes with heart remodeling	Pathological	Heart	Mutant	Human	Cardiac muscle
29	Kouloumenta et al.⁴³	Regulates lysosome positioning	Structural	Lysosome and endoplasmic reticulum	Variant molecule	Yeast/mouse	Cardiac muscle
30	Lapouge et al.⁴⁴	Regulates cytoarchitecture in cardiomyocytes	Structural	Cell adhesion	Variant molecule	Yeast	Cardiac muscle
31	Lazarides⁴⁵	Regulates nuclei positioning	Structural	Nucleus	–	Chicken	Cardiac muscle
32	Li et al.⁴⁶	Prevent idiopathic dilated cardiomyopathy	Pathological	Heart	Mutant	Human	Cardiac muscle
33	Liu et al.⁴⁷	Impairs proteolytic function if aggregated	Physiological	Degradation systems	Variant molecule	Rat	Cardiac muscle
34	Loufrani et al.⁴⁸	Regulates vascular tone and blood flow	Physiological	Arteries	KO	Mouse	Other
35	Loufrani et al.⁴⁹	Regulates arteries diameter and flow	Structural	Endothelial cells	KO	Mouse	Other
36	Lovering et al.⁵⁰	Regulates muscle tension	Pathological	Myofibril	Mutant/KO	Mouse	Skeletal muscle
37	Mackiewicz et al.⁵¹	Regulates heart contractile function	Physiological	Heart	Variant molecule	Mouse	Cardiac muscle
38	Maloyan et al.⁵²	Regulates mitochondrial function	Pathological	Mitochondria	Mutant	Mouse	Cardiac muscle
39	Mavroidis et al.⁵³	Induces Z disk alterations	Pathological	Myofibril	Mutant	Mouse	Cardiac muscle
40	Mermelstein et al.⁵⁴	Regulates myoblast cell shape	Physiological	Calcium homeostasis	–	Mouse	Skeletal muscle
41	Meyer et al.⁵⁵	Regulates Z disk stabilization	Structural	Myofibril	–	Theoretical prediction	Skeletal muscle
42	Milner et al.⁵⁶	Regulates cellular structural and functional integrity	Physiological/structural	Myofibril	Variant molecule	Mouse	Skeletal, cardiac and smooth muscle
43	Milner et al.⁵⁷	Regulates mitochondrial function and positioning	Physiological/structural	Mitochondria	KO	Mouse	Skeletal and cardiac muscle
44	Mitsui et al.⁵⁸	Regulates contraction	Physiological	Myofibril	–	Rabbit	Skeletal muscle
45	Mohamed et al.⁵⁹	Regulates smooth muscle hypertrophy	Physiological	Bronchi	KO	Mouse	Smooth muscle
46	Nag et al.⁶⁰	Regulates organelle positioning	Structural	Nucleus	–	Rat	Cardiac muscle
47	Oliveira et al.⁶¹	Regulates decidualization of endometrial cells	Physiological	Nucleus	–	Mouse	Other
48	Otten et al.⁶²	Regulates intercalated disk maintenance	Pathological	Myofibril	Mutant	Human	Cardiac muscle
49	Panagopoulou et al.⁶³	Regulates ventricular wall thickness	Physiological	Heart	Variant molecule	Mouse	Cardiac muscle
50	Ralston et al.⁶⁴	Regulates nuclei positioning	Structural	Nucleus	KO	Rat	Skeletal muscle
51	Russ and Grandy⁶⁵	Regulates muscular function	Physiological	Muscle	–	Rat	Skeletal muscle
52	Sam et al.⁶⁶	Increases vulnerability to mechanical injury	Structural	Myofibril	Variant molecule	Rat	Cardiac muscle
53	Schultheiss et al.⁶⁷	Not necessary for myofibril organization	Structural	Myofibril	Variant molecule	Chicken	Skeletal muscle
54	Shah et al.⁶⁸	Prevents respiratory problems	Pathological	Respiratory system	Variant molecule	Human	Skeletal muscle
55	Shah et al.⁶⁹	Regulates sarcomere arrangement	Structural	Myofibril	KO	Mouse	Skeletal muscle
56	Shah et al.⁷⁰	Regulates myofibrillar mobility	Structural	Myofibril	KO	Mouse	Skeletal muscle
57	Shah et al.⁷¹	Regulates nuclei positioning	Structural	Nucleus	KO	Mouse	Skeletal muscle
58	Sheng et al.⁷²	Regulates blood pressure	Physiological	Myofibril	Variant molecule	Mouse	Cardiac muscle
59	Singh et al.^73,a	Protects muscle from damage	Physiological	Degradation systems	–	–	–
60	Smythe et al.⁷⁴	Regulates myoblast proliferation and fusion	Physiological	Myoblast fusion	KO	Mouse	Skeletal muscle
61	Tao and Ip⁷⁵	Regulates myoblast fusion	Physiological	Myoblast fusion	Variant molecule	Chicken/quail	Smooth muscle
62	Tassin et al.⁷⁶	Not necessary for myofibril organization	Pathological	Myofibril	Mutant	Mouse	Skeletal muscle
63	Tokuyasu et al.⁷⁷	Regulates myofibril organization	Structural	Myofibril	–	Chicken	Skeletal and cardiac muscle
64	Tolstonog et al.⁷⁸	Contributes to genomic integrity	Physiological	Gene expression	–	Mouse	Other
65	Vermeer et al.⁷⁹	Regulates cellular structural and functional integrity	Pathological	Mitochondria	Mutant	Human	Cardiac muscle
66	Wang et al.⁸⁰	Regulates myofibril assembly	Structural	Myofibril	–	Chicken	Cardiac muscle
67	Wede et al.⁸¹	Regulates tension in micro arteries	Structural	Myofibril	KO	Mouse	Smooth muscle
68	Wieneke et al.⁸²	Necessary for myofiber activation	Physiological	Myofibril	KO	Mouse	Skeletal muscle
69	Woolstenhulme et al.⁸³	Regulates force generation	Physiological	Myofibril	–	Human	Skeletal muscle
70	Yamamoto et al.⁸⁴	Regulates myosin maturation	Physiological	Myofibril	–	Human	Cardiac muscle

OBS: Although this article is a review, it does propose a new function for desmin.

KO: knockout.

The long list of functions of Table 1 suggests some interpretations.

There are important differences among the cell types that express desmin, the three muscle types and endothelial cells. In the table, we can observe that most (61%) of the alleged functions are described only in a single muscle cell type: 45% on cardiac muscle, 34% on skeletal muscle, and only 3% on smooth muscle. Since the muscles are quite different, should we expect that the same desmin molecule performs the same function(s) in the different muscle types? It should be kept in mind that desmin can have several post-translational modifications, related to several circumstances in the cell, but there are no tissue-specific isoforms in the desmin molecule among the various muscle cell types.⁸⁵ It is worth mentioning that among several desmin partners, some are tissue-specific, such as cardiac muscle troponin I (TNNI3) and skeletal muscle nebulin (NEB), which could be an indication of tissue-specific desmin functions. Several desmin-interacting molecules have been previously discussed by us¹⁴ and by others, such as Klymkowsky,⁸⁶ and can be identified with automated databases such as STRING (https://string-db.org/), and therefore will not be further discussed here. Furthermore, some of the functions that could be attributed to desmin, like mechanical resistance, are in fact attributed to IFs in general, sometimes from observations in other cell types such as epithelia. Our previous bibliographic search method did not analyze articles on IF, but a PubMed search for IF on title/abstract selected 11,052 papers, among them 3329 (30%) containing “function” or “role.” Comparatively, there are 9737 papers with desmin on the title/abstract and among them only 1803 papers (18%) containing “function” or “role.” Just to compare, there are 5512 papers with “GFAP” and “function” and 7,427 with “vimentin” and “function” on PubMed.

Papers investigate at different levels: some focus on human physiology such as respiration, others focus on a single organ, like the heart, others in general cell behavior, other at subcellular level for instance in myofibrils. It is therefore difficult to compare these results.

Several (68%) of the articles rely on genetic modifications of desmin, either engineered or naturally occurring (mutations), assuming that the comparison with normal will highlight the (lack of) functions. Two groups constructed desmin mice knockouts: Capetanaki²⁰ and Paulin.⁸⁷ Desmin KO are viable and have somewhat subtle phenotypes. More recently, a zebrafish knockout model has been created using CRISPR: fish are also viable but with a subtle phenotype of calcium sensitivity.⁴¹ These results contrast the previous results obtained with zebrafish morpholino-based desmin knockdown⁸⁸ or with knockins,⁸⁹ which showed a highly damaged phenotype. Some of the alterations could be attributed to the morpholinos because they are known to disturb development. On the contrary, it is not possible to discard putative gene compensations in the CRISPR models because they are checked only for the affected genes: it is not unusual to have divergent results with morpholinos and CRISPR. Several papers study mutants, and many of them actually try to relate the affected part of the molecule with a specific function or phenotype.

Several (23%) of the alleged functions actually describe pathological situations, either using naturally occurring mutants or experimentally created modifications. As we mentioned before, in all these cases, the observed pathological alterations could be due to the loss of function of desmin, and their study can contribute to the identification of the desmin function. Alternatively, abnormal processing or mutant molecules could lead to the formation and accumulation of molecular aggregates which are pathological by themselves. Aggregates can be formed by changes in desmin sequence, in patients/mutants, by changes in desmin processing molecules, such as calpain and caspases or by changes in associated proteins, such as the heat-shock protein alphaBcrystallin.⁹⁰ It has been shown that some regions of the desmin molecules (which include regions where mutations have been reported) are prone to aggregation. Furthermore, there are already studies on the structural alterations caused by specific mutations.¹²

One interesting type of alteration in muscle development are the electric organs of fish. These muscle-derived organs specialized to produce electric discharges, and they lose their contractile filaments during development. They are related to the Purkinje fibers in the heart of large mammals, which also are muscle-derived cells specialized to conduct electricity, and which also have several desmin isoforms. We could show that the intermediate filaments of electric organs of the electric eel Electrophorus electricus are composed of desmin.⁹¹ Desmin was also identified in the electric organs of the ray Torpedo marmorata.⁹² Recently, proteome analysis of the electric eel confirmed the biochemical identification and demonstrated that there are about 78 phosphorylated variants of desmin in the electric organs.⁹³ Phosphorylation of IFs has been linked to their disassembly, in the case of the nuclear lamina for instance.⁸⁵ Nevertheless, there are several phosphorus binding sites in desmin, and it is probable that phosphorylation could be involved in other activities such as signal transduction. Desmin is also linked to connexin 43, which is important for electrical coupling among cells.¹⁹

5. Several (40%) of the functions focus on myofibrils. Since the visualization that desmin is distributed around the Z-lines and dense bodies in cultured cells in 1985,⁹⁴ it has been suggested that desmin has a role in the organization of myofibrils, particularly during myogenesis. Yet there are several other places where desmin is concentrated. This progressive change in desmin distribution is well illustrated in the zebrafish embryo myogenesis,⁹⁵ where it is possible to follow the initial distribution of desmin around the nuclei, then in striations, then accumulated at the myotendinous junction near the somite’s septa (a distribution that does not happen in cultured cells, probably because they do not make strong directional adhesions like actual muscle). Moreover, several muscle organelles, such as endoplasmic reticulum, due to the cytoplasm compression during contraction, not only have a periodical distribution but concentrate at regions that are not compressed, such as the Z line. Furthermore, myofibrillogenesis can happen in desmin KO or in cells transfected with truncated desmin.⁶⁷

6. Some of the alleged functions focus on mechanical forces, sometimes relating the IF network to the microfilaments. Boriek points out the desmin is oriented in all dimensions, while actin has only a single orientation (see Figure 1), and therefore, desmin can dissipate energy in all directions.¹⁷ Besides interacting with myofibrils, desmin has been shown to interact with actin. Actually, actin was a contaminant in the initial desmin purification by Lazarides. More recently, the protein nebullete has been shown to link desmin with the actin cytoskeleton.⁹⁶ Another mechanical role is regulation of stiffness. Charrier shows that desmin mutations and the amount of functional desmin alters mechanical properties of the cell,²¹ and Diermeier studied stiffness in mutant desmin,²⁹ besides the aforementioned work of Boriek.¹⁷

7. Seventeen percent of the functions focus on mitochondria and nucleus. While it is quite clear that alterations in desmin changes the distribution and function of mitochondria,^{15,30,52,57,79} it should be noted that other cytoskeletal filaments participate on mitochondria positioning, and other organelles such as endoplasmic reticulum also interact with mitochondria. To further complicate the matter, mitochondria are involved in several cellular processes, including respiration, apoptosis, and calcium control. A few papers point to an involvement of desmin on calcium regulation. Again, calcium is involved in several pathways, and in muscle, the regulation of contraction and regulation of protein degradation (through calpain, for example). Desmin has been implicated in the positioning of other organelles: lysosomes and endoplasmic reticulum⁴³ and particularly nuclei.^45,60,64,71 Desmin filaments are stably associated with the outer nuclear membrane of muscle cells.⁹⁷ Recently, the perinuclear region of muscle cells has been characterized as a membraneless organelle, rich in several cytoskeletal proteins, including desmin.⁹ The perinuclear distribution of desmin could indicate a role in mechanotransduction.

8. Some of the listed functions correlate desmin to stress conditions. One could argue that the IF system in muscle is not necessary under normal conditions because muscle has a hypertrophied acto-myosin-based mechanical support, and only when the myofibrils are affected for some reason, like in electric organ differentiation, or in muscular dystrophies, the function of desmin becomes prominent. Several of the desmin KO features could be explained in this way: only when muscle is stressed, like after repeated contractions, does the difference between KO and wild type appear. Most of the human disease symptoms also appear in older persons, which could be related to the long-term stress of the myofibrillar system. The formation of desmin aggregates has been considered the cause of muscle diseases. However, a recent paper by Singh addressed aggregation as actually an adaptive response to stress.⁷³ It seems that desmin can involve other cytoskeleton components such as microtubules and gene regulation as stress response.⁹⁸ The gene regulatory role of desmin has been confirmed in heart formation through the regulation of the gene Nkx.⁹⁹

It is interesting to compare the alleged functions of desmin to the functions attributed to vimentin, the intermediate filament protein that is highly expressed in the beginning of myogenesis. Besides some functions already mentioned for intermediate filaments in general, vimentin participates in vascular remodeling¹⁰⁰ and epithelial-mesenchymal transition (EMT).¹⁰¹ Through its linkage to adhesion structures and gene regulation, vimentin is one of the hallmarks of EMT and is related to cancer and cell differentiation.

We show the distribution of intermediate filaments proteins in smooth, cardiac, and skeletal muscle in the scheme in Figure 6. We tried to depict the relative distribution of desmin, vimentin, cytokeratin, nestin, synemin, paranemin, and syncoilin, in previous characterized muscular structures: dense body, intercalated disk, neuromuscular junction, perimitochondrial, perinuclear, sarcomere, myotendinous junction, costamere, cytoplasm, and desmosome. While the only IF protein that has been described in all these structures is desmin, there are a few IF proteins that have been described only in specific cellular regions, such as nestin concentrated in neuromuscular and myotendinous junctions, and cytokeratin concentrated in desmosomes.

Conclusions

It is arguable that the muscular program is quite strong, in the sense that it prevails over other cell differentiation programs in experimental conditions. We showed that the forced expression of the MyoD gene in other cell types convert them to muscle.¹⁰² Another sign of the robustness of the muscle gene regulation program is its redundancy, based on the compensatory expression of MyoD and Myf5 in mice knockouts.¹⁰³ It is tempting to include in this robustness concept the fact that muscle has an inhibitory differentiation and growth system, based on myostatin, rather than a stimulatory system. Would it be possible that desmin intermediate filaments are part of this “muscle back-up system”? Indeed, experiments such as with the double knockout of desmin and dystrophin¹⁰⁴ are pointing in this direction. They show that desmin can in some ways compensate for the damages of the lack of dystrophin. The function of desmin will probably be understood in the global picture of muscle structure and physiology.

Footnotes

Authors’ Contributions

M.L.C. conceived the work. M.L.C., A.D.J., C.M., G.G., K.A., M.S., and S.A. contributed to the acquisition of data and their analysis. M.L.C. wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, funding no. 302115/2017-0 for CM, 301443/2018-1 for MLC) and Fundação de Apoio à Pesquisa do Estado do Rio de Janeiro (FAPERJ, funding no. E-26/202.920/2019 for CM and E26/210.220/2018 for MLC). A.D.J. is a fellow of the Estácio de Sá University (UNESA) Research Productivity Program and Institutos Nacionais de Ciência e Tecnologia (INCT/CAPES, grant no. 88887.568853/2020-00).

ORCID iDs

Sarah Azevedo

Manoel Luis Costa

References

Ishikawa

Bischoff

Holtzer

. Mitosis and intermediate-sized filaments in developing skeletal muscle. J Cell Biol 1968;38:538–55

Herrmann

Aebi

. Intermediate filaments: structure and assembly. Cold Spring Harb Perspect Biol 2016;8:a018242

Cooke

. A filamentous cytoskeleton in vertebrate smooth muscle fibers. J Cell Biol 1976;68:539–56

Lazarides

Hubbard

. Immunological characterization of the subunit of the 100 A filaments from muscle cells. Proc Natl Acad Sci USA 1976;73:4344–8

Small

Sobieszek

. Studies on the function and composition of the 10-NM(100-A) filaments of vertebrate smooth muscle. J Cell Sci 1977;23:243–68

Lazarides

. Intermediate filaments as mechanical integrators of cellular space. Nature 1980;283:249–56

Lewis

Tian

Vainberg

Cowan

. Chaperonin-mediated folding of actin and tubulin. J Cell Biol 1996;132:1–4

Culley

Tosheva

Matos Pereira

Henriques

. SRRF: universal live-cell super-resolution microscopy. Int J Biochem Cell Biol 2018;101: 74–9

do Amaral

de Andrade Rosa

Andrade

Fang

Andrade

Costa

Mermelstein

. The perinuclear region concentrates disordered proteins with predicted phase separation distributed in a 3D network of cytoskeletal filaments and organelles. Biochim Biophys Acta Mol Cell Res 2022;1869:119161

10.

Omary

. “IF-pathies”: a broad spectrum of intermediate filament-associated diseases. J Clin Invest 2009;119:1756–62

11.

Homberg

Magin

. Beyond expectations: novel insights into epidermal keratin function and regulation. Int Rev Cell Mol Biol 2014;311:265–306

12.

Clemen

Herrmann

Strelkov

Schröder

. Desminopathies: pathology and mechanisms. Acta Neuropathol 2013;125:47–75

13.

Azevedo

Seixas

Jurberg

Mermelstein

Costa

. Do medicine and cell biology talk to each other? A study of vocabulary similarities between fields. Braz J Med Biol Res 2021;54:e11728

14.

Costa

Escaleira

Cataldo

Oliveira

Mermelstein

. Desmin: molecular interactions and putative functions of the muscle intermediate filament protein. Braz J Med Biol Res 2004;37:1819–30

15.

Alam

Abdullah

Aishwarya

Miriyala

Panchatcharam

Peretik

Orr

James

Robbins

Bhuiyan

. Aberrant mitochondrial fission is maladaptive in desmin mutation-induced cardiac proteotoxicity. J Am Heart Assoc 2018;7:e009289

16.

Balogh

Merisckay

Paulin

Arner

. Hearts from mice lacking desmin have a myopathy with impaired active force generation and unaltered wall compliance. Cardiovasc Res 2002;53:439–50

17.

Boriek

Capetanaki

Hwang

Officer

Badshah

Rodarte

Tidball

. Desmin integrates the three-dimensional mechanical properties of muscles. Am J Physiol Cell Physiol 2001;280:C46–52

18.

Bouvet

Dubois-Deruy

Turkieh

Mulder

Peugnet

Chwastyniak

Beseme

Dechaumes

Amouyel

Richard

Lamblin

Pinet

. Desmin aggrephagy in rat and human ischemic heart failure through PKCζ and GSK3β as upstream signaling pathways. Cell Death Discov 2021;7:153

19.

Cao

Gao

Chen

Wang

Zhang

Wang

. Desmin correlated with Cx43 may facilitate intercellular electrical coupling during chronic heart failure. Evid Based Complement Alternat Med 2021;2021:6621132

20.

Capetanaki

Milner

Weitzer

. Desmin in muscle formation and maintenance: knockouts and consequences. Cell Struct Funct 1997;22:103–16

21.

Charrier

Montel

Asnacios

Delort

Vicart

Gallet

Batonnet-Pichon

Hénon

. The desmin network is a determinant of the cytoplasmic stiffness of myoblasts. Biol Cell 2018;110:77–90

22.

Chaurasia

Kaur

de Medeiros

Smith

Wilson

. Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury. Exp Eye Res 2009;89:133–9

23.

Chen

Wang

Hong

Cao

. The role of desmin alterations in mechanical electrical feedback in heart failure. Life Sci 2020;241:117119

24.

Conover

Henderson

Gregorio

. A myopathy-linked desmin mutation perturbs striated muscle actin filament architecture. Mol Biol Cell 2009;20:834–45

25.

Dagvadorj

Goudeau

Hilton-Jones

Blancato

Shatunov

Simon-Casteras

Squier

Nagle

Goldfarb

Vicart

. Respiratory insufficiency in desminopathy patients caused by introduction of proline residues in desmin c-terminal alpha-helical segment. Muscle Nerve 2003;27:669–75

26.

D’Amati

Kahn

Butany

Silver

. Altered distribution of desmin filaments in hypertrophic cardiomyopathy: an immunohistochemical study. Mod Pathol 1992;5:165–8

27.

Datta

Basak

Varshney

Sengupta

Sarkar

. Quantitative proteomic changes during post myocardial infarction remodeling reveals altered cardiac metabolism and Desmin aggregation in the infarct region. J Proteomics 2017;152:283–99

28.

Di Somma

Di Benedetto

Salvatore

Agozzino

Ferranti

Esposito

La Dogana

Scarano

Caputo

Cotrufo

Santo

de Divitiis

. Desmin-free cardiomyocytes and myocardial dysfunction in end stage heart failure. Eur J Heart Fail 2004;6:389–98

29.

Diermeier

Iberl

Vetter

Haug

Pollmann

Reischl

Buttgereit

Schürmann

Spörrer

Goldmann

Fabry

Elhamine

Stehle

Pfitzer

Winter

Clemen

Herrmann

Schröder

Friedrich

. Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desmin-mutant knock-in mice. Sci Rep 2017;7:1391

30.

Diguet

Mallat

Ladouce

Clodic

Prola

Tritsch

Blanc

Larcher

Delcayre

Samuel

Friguet

Bolbach

Mericskay

. Muscle creatine kinase deficiency triggers both actin depolymerization and desmin disorganization by advanced glycation end products in dilated cardiomyopathy. J Biol Chem 2011;286:35007–19

31.

Eiber

Fröb

Schowalter

Thiel

Clemen

Schröder

Hashemolhosseini

. Lack of desmin in mice causes structural and functional disorders of neuromuscular junctions. Front Mol Neurosci 2020;13:567084

32.

Galata

Kloukina

Kostavasili

Varela

Davos

Makridakis

Bonne

Capetanaki

. Amelioration of desmin network defects by αB-crystallin overexpression confers cardioprotection in a mouse model of dilated cardiomyopathy caused by LMNA gene mutation. J Mol Cell Cardiol 2018;125:73–86

33.

Gard

Lazarides

. The synthesis and distribution of desmin and vimentin during myogenesis in vitro. Cell 1980;19:263–75

34.

Gard

Yamada

Green

Eloff

Rosenbaum

Wang

Robbins

Schuessler

Yamada

Saffitz

. Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy. Cardiovasc Res 2005;67:539–47

35.

Heckmann

Bauer

Jungmann

Winter

Rapti

Strucksberg

Clemen

Schröder

Katus

Müller

. AAV9-mediated gene transfer of desmin ameliorates cardiomyopathy in desmin-deficient mice. Gene Ther 2016;23:673–9

36.

Hijikata

Murakami

Ishikawa

Yorifuji

. Plectin tethers desmin intermediate filaments onto subsarcolemmal dense plaques containing dystrophin and vinculin. Histochem Cell Biol 2003;119:109–23

37.

Hofner

Höllrigl

Puz

Stary

Weitzer

. Desmin stimulates differentiation of cardiomyocytes and up-regulation of brachyury and nkx2.5. Differentiation 2007;75:605–15

38.

Höllrigl

Puz

Al-Dubai

Kim

Capetanaki

Weitzer

. Amino-terminally truncated desmin rescues fusion of des(-/-) myoblasts but negatively affects cardiomyogenesis and smooth muscle development. FEBS Lett 2002;523:229–33

39.

Huang

Foster

Lemanski

Dube

Zhang

Lemanski

. Protein kinase C-mediated desmin phosphorylation is related to myofibril disarray in cardiomyopathic hamster heart. Exp Biol Med 2002;227:1039–46

40.

Joanne

Hovhannisyan

Bencze

Daher

Parlakian

Toutirais

Gao-Li

Lilienbaum

Kordeli

Ferry

Agbulut

. Absence of desmin results in impaired adaptive response to mechanical overloading of skeletal muscle. Front Cell Dev Biol 2021;9:662133

41.

Kayman Kürekçi

Kural Mangit

Koyunlar

Unsal

Saglam

Ergin

Gizer

Uyanik

Boustanabadimaralan Düz

Korkusuz

Talim

Purali

Hughes

Dincer

. Knockout of zebrafish desmin genes does not cause skeletal muscle degeneration but alters calcium flux. Sci Rep 2021;11:7505

42.

Kostareva

Sjoberg

Gudkova

Smolina

Semernin

Shlyakhto

Sejersen

. Desmin A213V substitution represents a rare polymorphism but not a mutation and is more prevalent in patients with heart dilation of various origins. Acta Myol 2011;30:42–5

43.

Kouloumenta

Mavroidis

Capetanaki

. Proper perinuclear localization of the TRIM-like protein myospryn requires its binding partner desmin. J Biol Chem 2007;282:35211–21

44.

Lapouge

Fontao

Champliaud

Jaunin

Frias

Favre

Paulin

Green

Borradori

. New insights into the molecular basis of desmoplakin- and desmin-related cardiomyopathies. J Cell Sci 2006;119:4974–85

45.

Lazarides

. The distribution of desmin (100 A) filaments in primary cultures of embryonic chick cardiac cells. Exp Cell Res 1978;112:265–73

46.

Tapscoft

Gonzalez

Burch

Quiñones

Zoghbi

Hill

Bachinski

Mann

Roberts

. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation 1999;100:461–4

47.

Liu

Tang

Mestril

Wang

. Aberrant protein aggregation is essential for a mutant desmin to impair the proteolytic function of the ubiquitin-proteasome system in cardiomyocytes. J Mol Cell Cardiol 2006;40:451–4

48.

Loufrani

Lévy

Paulin

Henrion

. Excessive microvascular adaptation to changes in blood flow in mice lacking gene encoding for desmin. Arterioscler Thromb Vasc Biol 2002;22:1579–84

49.

Loufrani

Matrougui

Levy

Lacolley

Paulin

Henrion

. Selective microvascular dysfunction in mice lacking the gene encoding for desmin. FASEB J 2002;16:117–9

50.

Lovering

O’Neill

Muriel

Prosser

Strong

Bloch

. Physiology, structure, and susceptibility to injury of skeletal muscle in mice lacking keratin 19-based and desmin-based intermediate filaments. Am J Physiol Cell Physiol 2011;300:C803–13

51.

Mackiewicz

Czarnowska

Brudek

Pająk

Duda

Emanuel

Csanyi

Fedorowicz

Grochal

Tyrankiewicz

Skórka

Mende

Lewartowski

Chłopicki

. Preserved cardiomyocyte function and altered desmin pattern in transgenic mouse model of dilated cardiomyopathy. J Mol Cell Cardiol 2012;52:978–87

52.

Maloyan

Sanbe

Osinska

Westfall

Robinson

Imahashi

Murphy

Robbins

. Mitochondrial dysfunction and apoptosis underlie the pathogenic process in alpha-B-crystallin desmin-related cardiomyopathy. Circulation 2005;112:3451–61

53.

Mavroidis

Panagopoulou

Kostavasili

Weisleder

Capetanaki

. A missense mutation in desmin tail domain linked to human dilated cardiomyopathy promotes cleavage of the head domain and abolishes its Z-disc localization. FASEB J 2008;22:3318–27

54.

Mermelstein

Amaral

Rebello

Reis

Borojevic

Costa

. Changes in cell shape and desmin intermediate filament distribution are associated with down-regulation of desmin expression in C2C12 myoblasts grown in the absence of extracellular Ca2+. Braz J Med Biol Res 2005;38:1025–32

55.

Meyer

Kiss

Ward

Morgan

Kellermayer

Lieber

. Theoretical predictions of the effects of force transmission by desmin on intersarcomere dynamics. Biophys J 2010;98:258–66

56.

Milner

Weitzer

Tran

Bradley

Capetanaki

. Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J Cell Biol 1996;134:1255–70

57.

Milner

Mavroidis

Weisleder

Capetanaki

. Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. J Cell Biol 2000;150:1283–98

58.

Mitsui

Kawajiri

Kunishige

Endo

Akaike

Aki

Matsumoto

. Functional association between nicotinic acetylcholine receptor and sarcomeric proteins via actin and desmin filaments. J Cell Biochem 2000;77:584–95

59.

Mohamed

Hajira

Paulin

Boriek

. Desmin regulates airway smooth muscle hypertrophy through early growth-responsive protein-1 and microRNA-26a. J Biol Chem 2011;286:43394–404

60.

Nag

Krehel

Cheng

. Distributions of vimentin and desmin filaments in embryonic cardiac muscle cells in culture. Cytobios 1986;45:195–209

61.

Oliveira

Greca

Abrahamsohn

Reis

Zorn

. Organization of desmin-containing intermediate filaments during differentiation of mouse decidual cells. Histochem Cell Biol 2000;113:319–27

62.

Otten

Asimaki

Maass

van Langen

van der Wal

de Jonge

van den Berg

Saffitz

Wilde

Jongbloed

van Tintelen

. Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks. Heart Rhythm 2010;7:1058–64

63.

Panagopoulou

Davos

Milner

Varela

Cameron

Mann

Capetanaki

. Desmin mediates TNF-alpha-induced aggregate formation and intercalated disk reorganization in heart failure. J Cell Biol 2008;181:761–75

64.

Ralston

Biscocho

Soumaka

Mavroidis

Prats

Lømo

Capetanaki

Ploug

. Blood vessels and desmin control the positioning of nuclei in skeletal muscle fibers. J Cell Physiol 2006;209:874–82

65.

Russ

Grandy

. Increased desmin expression in hindlimb muscles of aging rats. J Cachexia Sarcopenia Muscle 2011;2:175–80

66.

Sam

Shah

Fridén

Milner

Capetanaki

Lieber

. Desmin knockout muscles generate lower stress and are less vulnerable to injury compared with wild-type muscles. Am J Physiol Cell Physiol 2000;279:C1116–22

67.

Schultheiss

Lin

Ishikawa

Zamir

Stoeckert

Holtzer

. Desmin/vimentin intermediate filaments are dispensable for many aspects of myogenesis. J Cell Biol 1991;114:953–66

68.

Shah

Franklin

Holmlund

Levring Jäghagen

Berggren

Forsgren

Stål

. Desmin and dystrophin abnormalities in upper airway muscles of snorers and patients with sleep apnea. Respir Res 2019;20:31

69.

Shah

Peters

Jordan

Milner

Fridén

Capetanaki

Lieber

. Sarcomere number regulation maintained after immobilization in desmin-null mouse skeletal muscle. J Exp Biol 2001;204:1703–10

70.

Shah

Jordan

Milner

Fridén

Capetanaki

Lieber

. Evidence for increased myofibrillar mobility in desmin-null mouse skeletal muscle. J Exp Biol 2002;205:321–5

71.

Shah

Davis

Weisleder

Kostavassili

McCulloch

Ralston

Capetanaki

Lieber

. Structural and functional roles of desmin in mouse skeletal muscle during passive deformation. Biophys J 2004;86:2993–3008

72.

Sheng

Feng

Pinto

Wei

Jin

. Increases of desmin and α-actinin in mouse cardiac myofibrils as a response to diastolic dysfunction. J Mol Cell Cardiol 2016;99:218–29

73.

Singh

Kadioglu

Patel

Carrier

Agnetti

. Is desmin propensity to aggregate part of its protective function? Cells 2020;9:491

74.

Smythe

Davies

Paulin

Grounds

. Absence of desmin slightly prolongs myoblast proliferation and delays fusion in vivo in regenerating grafts of skeletal muscle. Cell Tissue Res 2001;304:287–94

75.

Tao

. Site-specific antibodies block kinase A phosphorylation of desmin in vitro and inhibit incorporation of myoblasts into myotubes. Cell Motil Cytoskeleton 1991;19:109–20

76.

Tassin

Pinçon-Raymond

Paulin

Rieger

. Unusual organization of desmin intermediate filaments in muscular dysgenesis and TTX-treated myotubes. Dev Biol 1988;129:37–47

77.

Tokuyasu

Dutton

Singer

. Immunoelectron microscopic studies of desmin (skeletin) localization and intermediate filament organization in chicken cardiac muscle. J Cell Biol 1983;96:1736–42

78.

Tolstonog

Wang

Shoeman

Traub

. Intermediate filaments reconstituted from vimentin, desmin, and glial fibrillary acidic protein selectively bind repetitive and mobile DNA sequences from a mixture of mouse genomic DNA fragments. DNA Cell Biol 2000;19:647–77

79.

Vermeer

Bolling

Bliley

Arevalo Gomez

Pavez-Giani

Kramer

Romero-Herrera

Westenbrink

Diercks

van den Berg

Feinberg

Silljé

HHW

van der Meer

. Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues. J Clin Invest 2021;131:e140615

80.

Wang

Huang

Tseng

. Role of desmin filaments in chicken cardiac myofibrillogenesis. J Cell Biochem 2000;77:635–44

81.

Wede

Löfgren

Paulin

Arner

. Mechanical function of intermediate filaments in arteries of different size examined using desmin deficient mice. J Physiol 2002;540:941–9

82.

Wieneke

Stehle

Jockusch

. Generation of tension by skinned fibers and intact skeletal muscles from desmin-deficient mice. Biochem Biophys Res Commun 2000;278:419–25

83.

Woolstenhulme

Jutte

Drummond

Parcell

. Desmin increases with high-intensity concentric contractions in humans. Muscle Nerve 2005;31:20–4

84.

Yamamoto

Abe

Rodríguez-Vázquez

Fujimiya

Murakami

Ide

. Immunohistochemical distribution of desmin in the human fetal heart. J Anat 2011;219:253–8

85.

Winter

Paulin

Mericskay

. Posttranslational modifications of desmin and their implication in biological processes and pathologies. Histochem Cell Biol 2014;141:1–16

86.

Klymkowsky

. Filaments and phenotypes: cellular roles and orphan effects associated with mutations in cytoplasmic intermediate filament proteins. F1000Res 2019;8:F1000 Faculty Rev-1703

87.

Mericskay

Agbulut

Butler-Browne

Carlsson

Thornell

Babinet

Paulin

. Desmin is essential for the tensile strength and integrity of myofibrils but not for myogenic commitment, differentiation, and fusion of skeletal muscle. J Cell Biol 1997;139:129–44

88.

Andersson-Lendahl

Sejersen

Arner

. Knockdown of desmin in zebrafish larvae affects interfilament spacing and mechanical properties of skeletal muscle. J Gen Physiol 2013;141:335–45

89.

Ramspacher

Steed

Boselli

Ferreira

Faggianelli

Roth

Spiegelhalter

Messaddeq

Trinh

Liebling

Chacko

Tessadori

Bakkers

Laporte

Hnia

Vermot

. Developmental alterations in heart biomechanics and skeletal muscle function in desmin mutants suggest an early pathological root for desminopathies. Cell Rep 2015;11:1564–76

90.

Kedia

Arhzaouy

Pittman

Sun

Batchelor

Weihl

Bieschke

. Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers. Proc Natl Acad Sci USA 2019;116:16835–40

91.

Costa

Moura Neto

Chagas

. Desmin heterogeneity in the main electric organ of Electrophorus electricus. Biochimie 1988;70:783–9

92.

Walker

Boustead

Witzemann

Shaw

Weber

Osborn

. Cytoskeletal proteins at the cholinergic synapse: distribution of desmin, actin, fodrin, neurofilaments, and tubulin in Torpedo electric organ. Eur J Cell Biol 1985;38:123–33

93.

Traeger

Sabat

Barrett-Wilt

Wells

Sussman

. A tail of two voltages: proteomic comparison of the three electric organs of the electric eel. Sci Adv 2017;3:e1700523

94.

Tokuyasu

Maher

Singer

. Distributions of vimentin and desmin in developing chick myotubes in vivo. II. Immunoelectron microscopic study. J Cell Biol 1985;100:1157–66

95.

Costa

Escaleira

Rodrigues

Manasfi

Mermelstein

. Some distinctive features of zebrafish myogenesis based on unexpected distributions of the muscle cytoskeletal proteins actin, myosin, desmin, alpha-actinin, troponin and titin. Mech Dev 2002;116:95–104

96.

Hernandez

Bennett

Dunina-Barkovskaya

Wedig

Capetanaki

Herrmann

Conover

. Nebulette is a powerful cytolinker organizing desmin and actin in mouse hearts. Mol Biol Cell 2016;27:3869–82

97.

Mermelstein

Andrade

Portilho

Costa

. Desmin filaments are stably associated with the outer nuclear surface in chick myoblasts. Cell Tissue Res 2006;323:351–7

98.

Giovarelli

Zecchini

Martini

Garrè

Barozzi

Ripolone

Napoli

Coazzoli

Vantaggiato

Roux-Biejat

Cervia

Moscheni

Perrotta

Parazzoli

Clementi

De Palma

. Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle. Cell Death Differ 2020;27:2383–401

99.

Fuchs

Gawlas

Heher

Nikouli

Paar

Ivankovic

Schultheis

Klammer

Gottschamel

Capetanaki

Weitzer

. Desmin enters the nucleus of cardiac stem cells and modulates Nkx2.5 expression by participating in transcription factor complexes that interact with the nkx2.5 gene. Biol Open 2016;5:140–53

100.

Tang

Dai

Liu

Huang

Wang

Yao

. RhoA/ROCK signaling regulates smooth muscle phenotypic modulation and vascular remodeling via the JNK pathway and vimentin cytoskeleton. Pharmacol Res 2018;133:201–12

101.

Usman

Waseem

Nguyen

TKN

Mohsin

Jamal

Teh

Waseem

. Vimentin is at the heart of epithelial mesenchymal transition (EMT) mediated metastasis. Cancers 2021;13:4985

102.

Choi

Costa

Mermelstein

Chagas

Holtzer

. MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. Proc Natl Acad Sci USA 1990;87:7988–92

103.

Rudnicki

Schnegelsberg

Stead

Braun

Arnold

Jaenisch

. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 1993;75:1351–9

104.

Ferry

Messéant

Parlakian

Lemaitre

Roy

Delacroix

Lilienbaum

Hovhannisyan

Furling

Klein

Agbulut

. Desmin prevents muscle wasting, exaggerated weakness and fragility, and fatigue in dystrophic mdx mouse. J Physiol 2020;598:3667–89