Unknown

Dataset Information

0

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.

SUBMITTER: Winter L 

PROVIDER: S-EPMC4512624 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC2426950 | BioStudies
1000-01-01 | S-EPMC4263455 | BioStudies
2011-01-01 | S-EPMC3228830 | BioStudies
2016-01-01 | S-EPMC4847350 | BioStudies
1000-01-01 | S-EPMC507309 | BioStudies
2010-01-01 | S-EPMC3023027 | BioStudies
1000-01-01 | S-EPMC4664173 | BioStudies
2018-01-01 | S-EPMC5775598 | BioStudies
1000-01-01 | S-EPMC507667 | BioStudies
2014-01-01 | S-EPMC3934181 | BioStudies