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.