title: Myofiber integrity depends on desmin network targeting to Z-disks and costameres via distinct plectin isoforms.
abstract: Dysfunction of plectin, a 500-kD cytolinker protein, leads to skin blistering and muscular dystrophy. Using conditional gene targeting in mice, we show that plectin deficiency results in progressive degenerative alterations in striated muscle, including aggregation and partial loss of intermediate filament (IF) networks, detachment of the contractile apparatus from the sarcolemma, profound changes in myofiber costameric cytoarchitecture, and decreased mitochondrial number and function. Analysis of newly generated plectin isoform-specific knockout mouse models revealed that IF aggregates accumulate in distinct cytoplasmic compartments, depending on which isoform is missing. Our data show that two major plectin isoforms expressed in muscle, plectin 1d and 1f, integrate fibers by specifically targeting and linking desmin IFs to Z-disks and costameres, whereas plectin 1b establishes a linkage to mitochondria. Furthermore, disruption of Z-disk and costamere linkages leads to the pathological condition of epidermolysis bullosa with muscular dystrophy. Our findings establish plectin as the major organizer of desmin IFs in myofibers and provide new insights into plectin- and desmin-related muscular dystrophies.
authors.affiliation: Max F. Perutz Laboratories, Department of Molecular Cell Biology, University of Vienna, A-1030 Vienna, Austria.
authors.forename: Patryk
authors.initials: P
authors.lastname: Konieczny
authors.forename: Peter
authors.initials: P
authors.lastname: Fuchs
authors.forename: Siegfried
authors.initials: S
authors.lastname: Reipert
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: Anikó
authors.initials: A
authors.lastname: Zeöld
authors.forename: Irmgard
authors.initials: I
authors.lastname: Fischer
authors.forename: Denise
authors.initials: D
authors.lastname: Paulin
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wiche
mesh_terms: D000818:Animals; D003893:Desmin / Q000378:metabolism*; D018450:Disease Progression; D007382:Intermediate Filaments / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D008954:Models, Biological; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D054792:Muscle, Striated / Q000473:pathology / Q000648:ultrastructure; D010807:Physical Endurance; D051190:Plectin / Q000172:deficiency / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D012508:Sarcolemma / Q000473:pathology / Q000648:ultrastructure; D012518:Sarcomeres / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D003893:Desmin; C495333:Plec protein, mouse; D051190:Plectin; D020033:Protein Isoforms