Sarcolemmal organization in skeletal muscle lacking desmin: evidence for cytokeratins associated with the membrane skeleton at costameres.

The sarcolemma of fast-twitch muscle is organized into "costameres," structures that are oriented transversely, over the Z and M lines of nearby myofibrils, and longitudinally, to form a rectilinear lattice. Here we examine the role of desmin, the major intermediate filament protein of muscle in organizing costameres. In control mouse muscle, desmin is enriched at the sarcolemmal domains that lie over nearby Z lines and that also contain beta-spectrin. In tibialis anterior muscle from mice lacking desmin due to homologous recombination, most costameres are lost. In myofibers from desmin -/- quadriceps, by contrast, most costameric structures are stable. Alternatively, Z line domains may be lost, whereas domains oriented longitudinally or lying over M lines are retained. Experiments with pan-specific antibodies to intermediate filament proteins and to cytokeratins suggest that control and desmin -/- muscles express similar levels of cytokeratins. Cytokeratins concentrate at the sarcolemma at all three domains of costameres when the latter are retained in desmin -/- muscle and redistribute with beta-spectrin at the sarcolemma when costameres are lost. Our results suggest that desmin associates with and selectively stabilizes the Z line domains of costameres, but that cytokeratins associate with all three domains of costameres, even in the absence of desmin.

Costameres: repeating structures at the sarcolemma of skeletal muscle.

Costameres, structures at the plasma membrane of skeletal muscle, are present in a rectilinear array that parallels the organization of the underlying contractile apparatus. Costameres have three major functions: to keep the plasma membrane, or sarcolemma, aligned and in register with nearby contractile structures; to protect the sarcolemma against contraction-induced damage; and to transmit some of the forces of contraction laterally, to the extracellular matrix. These functions require that costameres link the contractile apparatus through the membrane to the extracellular matrix. Mutations to key components of costameres cause these structures to lose their rectilinear organization and can result in muscle weakness or death. This article summarizes the evidence that costameres are composed of large complexes of integral and peripheral membrane proteins that are linked to the contractile apparatus by intermediate filaments and to the extracellular matrix by laminin. They also present evidence that costameres are altered when key costameric components are missing, as in a murine form of muscular dystrophy.