The costamere bridges sarcomeres to the sarcolemma in striated muscle

Abstract

Costameres are sub-membranous, Z-line associated structures found in striated muscle. They have been shown to have important roles in transmission of force from the sarcomere to the sarcolemma and extracellular matrix, maintaining mechanical integrity of the sarcolemma, and orchestrating mechanically related signaling. The costamere is akin to the more well-known focal adhesion complex present in most cells. The Z-line is a critical structural anchor for the sarcomere, but it is also a hot-spot for muscle cell signaling. Therefore functionally, the costamere represents a two-way signaling highway tethered between the Z-line and the extracellular matrix, relaying mechanical stress signals from outside the cell to intracellular signaling networks. In this role it can modulate myofibril growth and contraction. The major force generated by sarcomeres is transduced in the lateral direction from the sarcomere to the extracellular matrix through the costamere. Two major protein complexes have been described at the costamere: the dystrophin-glycoprotein complex and the integrin-vinculin-talin complex. The importance of these two protein complexes in striated muscle function has between demonstrated both in human disease and mouse models. Members of the dystrophin glycoprotein complex and integrins have both been reported to interact directly with filamin-C, thus linking costameric complexes with those present at the Z-line. Moreover, studies from our labs and others have shown that the Z-line proteins belonging to the PDZ-LIM domain protein family, enigma homolog (ENH) and cypher, may directly or indirectly be involved in this linkage. The following review will focus on the protein components of this linkage, their function in force transmission, and how the dysfunction or loss of proteins within these complexes contributes to muscular disease.

Keywords: Costamere; Cypher/ZASP; Integrin; Mechanotransduction; Vinculin; Z-line.

Fig. 1

Costameric proteins associated with Z-lines. Dystrophin glycoprotein complex and integrin–vinculin–talin complex are two major costameric protein complexes. Members of the dystrophin glycoprotein complex and integrin were reported to directly interact with protein components at the Z-line, such as filamin-C. Filamin-C (γ-filamin, filamin2) physically links the costamere and the sarcomere by interacting with two major costameric protein complexes: the sarcoglycans in the dystrophin glycoprotein complex and integrin. In addition, filamin-C interacts with the Z-line proteins calsarcin-1 and myotilin. Vinculin, the founding member of the costamere, interacts with multiple proteins including talin, paxillin, and α-actinin. Integrin interacts with the ILK-pinch-parvin complex and FAK. Dystrophin binds to ankyrin B and G, which are essential to organize the dystrophin and dystroglycan complex. Titin is the largest known protein and crosses longitudinally from the Z-line to the M-line. The N-terminus of titin at the Z-line binds to ankyrin. Not all costameric proteins or Z-line proteins are illustrated in this figure for simplicity. Key proteins are shown to highlight the bridges between the sarcomere and the costamere.