title: Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle.
abstract: Plectin, a versatile 500-kDa cytolinker protein, is essential for muscle fiber integrity and function. The most common disease caused by mutations in the human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), is characterized by severe skin blistering and progressive muscular dystrophy. Besides displaying pathological desmin-positive protein aggregates and degenerative changes in the myofibrillar apparatus, skeletal muscle specimens of EBS-MD patients and plectin-deficient mice are characterized by massive mitochondrial alterations. In this study, we demonstrate that structural and functional alterations of mitochondria are a primary aftermath of plectin deficiency in muscle, contributing to myofiber degeneration. We found that in skeletal muscle of conditional plectin knockout mice (MCK-Cre/cKO), mitochondrial content was reduced, and mitochondria were aggregated in sarcoplasmic and subsarcolemmal regions and were no longer associated with Z-disks. Additionally, decreased mitochondrial citrate synthase activity, respiratory function and altered adenosine diphosphate kinetics were characteristic of plectin-deficient muscles. To analyze a mechanistic link between plectin deficiency and mitochondrial alterations, we comparatively assessed mitochondrial morphology and function in whole muscle and teased muscle fibers of wild-type, MCK-Cre/cKO and plectin isoform-specific knockout mice that were lacking just one isoform (either P1b or P1d) while expressing all others. Monitoring morphological alterations of mitochondria, an isoform P1b-specific phenotype affecting the mitochondrial fusion-fission machinery and manifesting with upregulated mitochondrial fusion-associated protein mitofusin-2 could be identified. Our results show that the depletion of distinct plectin isoforms affects mitochondrial network organization and function in different ways.
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna, 1030 Vienna, Austria, Institute of Neuropathology, University Hospital Erlangen, 91054 Erlangen, Germany and.
authors.forename: Lilli
authors.initials: L
authors.lastname: Winter
authors.affiliation: Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kuznetsov
authors.affiliation: Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Grimm
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna, 1030 Vienna, Austria.
authors.forename: Anikó
authors.initials: A
authors.lastname: Zeöld
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna, 1030 Vienna, Austria.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Fischer
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna, 1030 Vienna, Austria, gerhard.wiche@univie.ac.at.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wiche
mesh_terms: D000818:Animals; D002460:Cell Line; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051190:Plectin / Q000172:deficiency*; D020033:Protein Isoforms / Q000172:deficiency
chemical_list: C495333:Plec protein, mouse; D051190:Plectin; D020033:Protein Isoforms; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse