Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle

Lilli Winter, Andrey V. Kuznetsov, Michael Grimm, A. Zeöld, Irmgard Fischer, Gerhard Wiche

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Article numberddv184
Pages (from-to)4530-4544
Number of pages15
JournalHuman Molecular Genetics
Volume24
Issue number16
DOIs
Publication statusPublished - Apr 28 2015

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Plectin
Protein Isoforms
Skeletal Muscle
Muscles
Mitochondrial Dynamics
Mitochondria
Knockout Mice
Plakins
Citrate (si)-Synthase
Desmin
Muscular Dystrophies
Adenosine Diphosphate

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle. / Winter, Lilli; Kuznetsov, Andrey V.; Grimm, Michael; Zeöld, A.; Fischer, Irmgard; Wiche, Gerhard.

In: Human Molecular Genetics, Vol. 24, No. 16, ddv184, 28.04.2015, p. 4530-4544.

Research output: Contribution to journalArticle

Winter, Lilli ; Kuznetsov, Andrey V. ; Grimm, Michael ; Zeöld, A. ; Fischer, Irmgard ; Wiche, Gerhard. / Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 16. pp. 4530-4544.
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