Abstract
Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies. The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness. Besides EBS-MD, PLEC mutations lead to EBS with nail dystrophy, EBS-MD with a myasthenic syndrome, EBS with pyloric atresia, limb-girdle muscular dystrophy type R17, or EBS-Ogna. In this review, we focus on the clinical and pathological manifestations caused by PLEC mutations on skeletal and cardiac muscle. Skeletal muscle biopsies from EBS-MD patients and plectin-deficient mice revealed severe dystrophic features with variation in fiber size, degenerative myofibrillar changes, mitochondrial alterations, and pathological desmin-positive protein aggregates. Ultrastructurally, PLEC mutations lead to a disorganization of myofibrils and sarcomeres, Z- and I-band alterations, autophagic vacuoles and cytoplasmic bodies, and misplaced and degenerating mitochondria. We also summarize a variety of genetically manipulated mouse and cell models, which are either plectin-deficient or that specifically lack a skeletal muscle-expressed plectin isoform. These models are powerful tools to study functional and molecular consequences of PLEC defects and their downstream effects on the skeletal muscle organization.
Highlights
We summarize a variety of genetically manipulated mouse and cell models, which are either plectin-deficient or that lack a skeletal muscle-expressed plectin isoform
In muscle fibers that are deficient for P1d, the association of residual plectin with mitochondria and the colocalization of collapsed desmin intermediate filaments (IFs) with organelle aggregates were reported, indicating that mitochondria-associated P1b was still able to fulfill its function as a linker between the IF network and mitochondria [9,79]
Increased protein levels of various heat shock proteins (HSPs), molecular chaperones that assist in the establishment of proper protein conformation and that prevent the aggregation of partially denaturated proteins [88], were observed in skeletal muscle specimens from muscle creatine kinase (MCK)-Cre/cKO mice and, to some extent, during the differentiation of Plec−/− myotubes, indicating that chaperones might represent a first line of defense against desmin network aggregation [80]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Desmin intermediate filaments (IFs), which are structurally organized by plectin in myoblasts (Figure 1A) and muscle fibers, constitute the principal component of the extrasarcomeric cytoskeleton. Plectin harbors a functional actin-binding domain (ABD); binds to microtubule-associated proteins (MAPs); and interacts with transmembrane receptors, proteins of the subplasma membrane protein skeleton, components of the nuclear envelope, and several kinases with known roles in the migration, proliferation, and energy metabolism of cells (Figure 1B) [4,5]. Plectin acts as a multi-functional linker and signaling scaffold, centrally orchestrating the structural and functional organization of filamentous cytoskeletal networks and thereby substantially contributing to the fundamental biomechanical properties of stress-bearing tissues such as muscle. Binding partners are indicated below the scheme; binding partners which were experimentally found in myoblasts/skeletal muscle are highlighted in bold. * Interaction was shown for isoform P1f. ** Interaction was shown for isoform P1
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