Myofiber integrity depends on desmin network targeting to Z-disks and costameres via distinct plectin isoforms

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 f...

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Bibliographic Details
Published in:The Journal of cell biology 2008-05, Vol.181 (4), p.667-681
Main Authors: Konieczny, Patryk, Fuchs, Peter, Reipert, Siegfried, Kunz, Wolfram S, Zeöld, Anikó, Fischer, Irmgard, Paulin, Denise, Schröder, Rolf, Wiche, Gerhard
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Cellular biology
Costameres
Creatine
Desmin - metabolism
Disease Progression
Intermediate Filaments - metabolism
Intermediate Filaments - ultrastructure
Mice
Mice, Knockout
Mitochondria
Mitochondria - pathology
Mitochondria - ultrastructure
Models, Biological
Muscle Contraction
Muscle fibers
Muscle Fibers, Skeletal - metabolism
Muscle Fibers, Skeletal - pathology
Muscle, Striated - pathology
Muscle, Striated - ultrastructure
Muscular dystrophy
Pathology
Phenotypes
Physical Endurance
Plectin - deficiency
Plectin - metabolism
Protein isoforms
Protein Isoforms - metabolism
Proteins
Rodents
Sarcolemma
Sarcolemma - pathology
Sarcolemma - ultrastructure
Sarcomeres - metabolism
Skeletal muscle
Survival Analysis
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200711058