Costamere proteins and their involvement in myopathic processes

Abstract

Muscle fibres are very specialised cells with a complex structure that requires a high level of organisation of the constituent proteins. For muscle contraction to function properly, there is a need for not only sarcomeres, the contractile structures of the muscle fibre, but also costameres. These are supramolecular structures associated with the sarcolemma that allow muscle adhesion to the extracellular matrix. They are composed of protein complexes that interact and whose functions include maintaining cell structure and signal transduction mediated by their constituent proteins. It is important to improve our understanding of these structures, as mutations in various genes that code for costamere proteins cause many types of muscular dystrophy. In this review, we provide a description of costameres detailing each of their constituent proteins, such as dystrophin, dystrobrevin, syntrophin, sarcoglycans, dystroglycans, vinculin, talin, integrins, desmin, plectin, etc. We describe as well the diseases associated with deficiency thereof, providing a general overview of their importance.

Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells

“…In fact, both F-actin and dynamin-2 are required for focal adhesion assembly/disassembly, which in skeletal muscle fibers are concentrated at specialized adhesives structures critical to maintain the sarcomere integrity 47 . As the sarcomere stability is highly influenced by its association to costameres 48 , which are muscle-specific adhesion sites enriched in actin 49 and dynamin-2 50 , it is possible that focal areas of disorganization in HTZ-mouse myofibers are a consequence of an altered costamere organization. The latter might be yet another mechanism that contributes to the pathogenesis of CNM caused by dynamin-2 mutations.…”

Overview of the Muscle Cytoskeleton

“…16). The IPP complex then activates signaling pathways involved in hypertrophy and resistance to apoptosis [reviewed in (292)].…”

“…Utrophin (ubiquitously expressed dystrophin) is highly homologous to dystrophin and is down-regulated in adult muscle where dystrophin is expressed, except in myotendinous and neuromuscular junctions (63,422). Through interactions with actin, microtubules, and intermediate filament proteins such as syntrophin, dystrophin forms a link to the extracellular matrix at the costamere [(323, 324, 781), reviewed in (292)] (Figs. 3 and 16).…”

Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies

“…However, the deletion 45-46 has been recently reported to be accompanied by a DMD phenotype [75] and to produce no dystrophin (personal communication). On contrast, there are no patients reported for the deletion of exons [44][45], signifying that the deletion may be asymptomatic. Therefore, the therapy of these two DMD deletions may not result in the same cure effect even though we anticipate that patients will all be transformed in BMD-like patients.…”

“…As such, dystrophin constitutes a major scaffolding protein of normal muscle which links cytoskeletal actin, microtubules and intermediate filaments to the extracellular matrix. This dystrophin scaffolding network is present at specific structures of the skeletal and heart muscle named costameres situated at the periphery of the fibers along with the transverse M-and Z-lines [44,45]. Costameres are specifically involved in the lateral transmission of forces from the cytosol to the extracellular matrix by which they prevent plasma membrane ruptures during muscle contractions [41,[46][47][48][49].…”