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 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.
Konieczny
Patryk
P
Max F. Perutz Laboratories, Department of Molecular Cell Biology, University of Vienna, A-1030 Vienna, Austria.
Fuchs
Peter
P
Reipert
Siegfried
S
Kunz
Wolfram S
WS
Zeöld
Anikó
A
Fischer
Irmgard
I
Paulin
Denise
D
Schröder
Rolf
R
Wiche
Gerhard
G
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
D003893:Desmin; C495333:Plec protein, mouse; D051190:Plectin; D020033:Protein Isoforms