Muscle intermediate filaments and their links to membranes and membranous organelles. Exp Cell Res

Cell Biology Division, Center of Basic Research, Biomedical Research Foundation Academy of Athens, Soranou Efessiou 4, 12965 Athens, Greece.
Experimental Cell Research (Impact Factor: 3.25). 07/2007; 313(10):2063-76. DOI: 10.1016/j.yexcr.2007.03.033
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Intermediate filaments (IFs) play a key role in the integration of structure and function of striated muscle, primarily by mediating mechanochemical links between the contractile apparatus and mitochondria, myonuclei, the sarcolemma and potentially the vesicle trafficking apparatus. Linkage of all these membranous structures to the contractile apparatus, mainly through the Z-disks, supports the integration and coordination of growth and energy demands of the working myocyte, not only with force transmission, but also with de novo gene expression, energy production and efficient protein and lipid trafficking and targeting. Desmin, the most abundant and intensively studied muscle intermediate filament protein, is linked to proper costamere organization, myoblast and stem cell fusion and differentiation, nuclear shape and positioning, as well as mitochondrial shape, structure, positioning and function. Similar links have been established for lysosomes and lysosome-related organelles, consistent with the presence of widespread links between IFs and membranous structures and the regulation of their fusion, morphology and stabilization necessary for cell survival.

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Available from: Robert J Bloch, Feb 26, 2015
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    • "AGEs and lipid peroxidation end-products accumulate in PAD muscle and, particularly, in PAD myofibers (Norgren et al. 2007; Pipinos et al. 2008, 2007). Desmin links neighboring myofibrils into bundles through their Z-discs (Capetanaki et al. 2007; Dalakas et al. 2000), aligns the Z-discs of neighboring myofibers (Capetanaki et al. 1997; Carlsson and Thornell 2001; Lazarides 1980), organizes the mitochondria into a welldefined functional network around the myofibrils (Capetanaki et al. 1997; Milner et al. 2000) and facilitates transmission of the force of sarcomere contraction to the ECM (Bloch and Gonzalez-Serratos 2003; Capetanaki et al. 2007; Carlsson and Thornell 2001; Goldfarb et al. 2004; Paulin et al. 2004). Mitochondrial dysfunction in PAD skeletal muscle is well documented (Makris et al. 2007; Pipinos et al. 2006; Pipinos et al. 2003; Pipinos et al. 2000). "
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    ABSTRACT: Patients with peripheral artery disease (PAD) develop a myopathy in their ischemic lower extremities, which is characterized by myofiber degeneration, mitochondrial dysfunction and impaired limb function. Desmin, a protein of the cytoskeleton, is central to maintenance of the structure, shape and function of the myofiber and its organelles, especially the mitochondria, and to translation of sarcomere contraction into muscle contraction. In this study, we investigated the hypothesis that disruption of the desmin network occurs in gastrocnemius myofibers of PAD patients and correlates with altered myofiber morphology, mitochondrial dysfunction, and impaired limb function. Using fluorescence microscopy, we evaluated desmin organization and quantified myofiber content in the gastrocnemius of PAD and control patients. Desmin was highly disorganized in PAD but not control muscles and myofiber content was increased significantly in PAD compared to control muscles. By qPCR, we found that desmin gene transcripts were increased in the gastrocnemius of PAD patients as compared with control patients. Increased desmin and desmin gene transcripts in PAD muscles correlated with altered myofiber morphology, decreased mitochondrial respiration, reduced calf muscle strength and decreased walking performance. In conclusion, our studies identified disruption of the desmin system in gastrocnemius myofibers as an index of the myopathy and limitation of muscle function in patients with PAD.
    Journal of Histochemistry and Cytochemistry 01/2015; DOI:10.1369/0022155415569348 · 1.96 Impact Factor
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    • "Based on reported physical interactions in the literature and protein-protein interaction databases (BioGRID, MINT, GeneMANIA; Mostafavi et al. 2008; Stark et al. 2006), we established an interaction network for desmin (Fig. 2b). Desmin interactors include other members of the IF family, cytolinkers bridging organelles and cytoskeleton, chaperones and adaptor proteins and proteins that have been implicated in proteolysis, posttranslational modifications and signaling important for proper skeletal or cardiac muscle functions (Capetanaki et al. 2007; Costa et al. 2004). The architectural role of desmin filaments has been enriched by these new findings suggesting that desmin serves as a platform for signaling events perturbed upon desmin misfolding/ aggregation under pathological conditions. "
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    ABSTRACT: Desmin is a muscle-specific type III intermediate filament essential for proper muscular structure and function. In human, mutations affecting desmin expression or promoting its aggregation lead to skeletal (desmin-related myopathies), or cardiac (desmin-related cardiomyopathy) phenotypes, or both. Patient muscles display intracellular accumulations of misfolded proteins and desmin-positive insoluble granulofilamentous aggregates, leading to a large spectrum of molecular alterations. Increasing evidence shows that desmin function is not limited to the structural and mechanical integrity of cells. This novel perception is strongly supported by the finding that diseases featuring desmin aggregates cannot be easily associated with mechanical defects, but rather involve desmin filaments in a broader spectrum of functions, such as in organelle positioning and integrity and in signaling. Here, we review desmin functions and related diseases affecting striated muscles. We detail emergent cellular functions of desmin based on reported phenotypes in patients and animal models. We discuss known desmin protein partners and propose an overview of the way that this molecular network could serve as a signal transduction platform necessary for proper muscle function.
    Cell and Tissue Research 10/2014; 360(3). DOI:10.1007/s00441-014-2016-4 · 3.57 Impact Factor
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    • "Genetic defects in humans, as well as gene-targeted elimination of K5, K14, plectin, or BPAG1e in mice, cause cytoskeletal disorganization and loss of cytokeratin anchorage to hemidesmosomes , resulting in an epidermolysis bullosa simplex phenotype (Guo et al., 1995; Andrä et al., 1997; Coulombe and Omary, 2002; Porter and Lane, 2003; Intong and Murrell, 2012; Liu et al., 2012; Winter and Wiche, 2013). Plectin or desmin gene defects also result in muscular dystrophy (Andrä et al., 1997; Winter and Wiche, 2013), accompanied by disorganization of the desmin IF network and malposition of mitochondria (Capetanaki et al., 2007). These findings unequivocally demonstrate the importance of the interplay between IFs and plakins for the maintenance of the cytoarchitecture in the skin and in skeletal muscle. "
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    ABSTRACT: Plectin, a cytolinker of the plakin family, anchors the intermediate filament (IF) network formed by keratins 5 and 14 (K5/K14) to hemidesmosomes, junctional adhesion complexes in basal keratinocytes. Genetic alterations of these proteins cause epidermolysis bullosa simplex (EBS) characterized by disturbed cytoarchitecture and cell fragility. The mechanisms through which mutations located after the documented plectin IF-binding site, composed of the plakin repeat domain (PRD) B5 and the linker, as well as mutations in K5 or K14 lead to EBS remain unclear. We investigated the interaction of plectin C-terminus, encompassing four domains, the PRD B5, the linker, the PRD C and the C-extremity, with K5/K14 using different approaches, including a rapid and sensitive fluorescent protein-binding assay, based on EGFP-tagged proteins (FluoBACE). Our results demonstrate that all four plectin C-terminal domains contribute to its association with K5/K14 and act synergistically to ensure efficient IF-binding. The plectin C-terminus predominantly interacted with the K5/K14 coil 1 domain and bound more extensively to K5/K14 filaments compared to monomeric keratins or IF assembly intermediates. These findings indicate a multimodular association of plectin with K5/K14 filaments and give insights into the molecular basis of EBS associated with pathogenic mutations in plectin, K5 or K14 genes.Journal of Investigative Dermatology accepted article preview online, 18 June 2014; doi:10.1038/jid.2014.255.
    Journal of Investigative Dermatology 06/2014; 134(11). DOI:10.1038/jid.2014.255 · 7.22 Impact Factor
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