Costameric proteins in human skeletal muscle during muscular inactivity

Abstract

Costameres are regions that are associated with the sarcolemma of skeletal muscle fibres and comprise proteins of the dystrophin-glycoprotein complex and vinculin-talin-integrin system. Costameres play both a mechanical and a signalling role, transmitting force from the contractile apparatus to the extracellular matrix in order to stabilize skeletal muscle fibres during contraction and relaxation. Recently, it was shown that bidirectional signalling occurs between sarcoglycans and integrins, with muscle agrin potentially interacting with both types of protein to enable signal transmission. Although numerous studies have been carried out on skeletal muscle diseases, such as Duchenne muscular dystrophy, recessive autosomal muscular dystrophies and other skeletal myopathies, insufficient data exist on the relationship between costameres and the pathology of the second motor nerve and between costameric proteins and muscle agrin in other conditions in which skeletal muscle atrophy occurs. Previously, we carried out a preliminary study on skeletal muscle from patients with sensitive-motor polyneuropathy, in which we analysed the distribution of sarcoglycans, integrins and agrin by immunostaining only. In the present study, we have examined the skeletal muscle fibres of ten patients with sensitive-motor polyneuropathy. We used immunofluorescence and reverse transcriptase PCR to examine the distribution of vinculin, talin and dystrophin, in addition to that of those proteins previously studied. Our aim was to characterize in greater detail the distribution and expression of costameric proteins and muscle agrin during this disease. In addition, we used transmission electron microscopy to evaluate the structural damage of the muscle fibres. The results showed that immunostaining of α 7B-integrin, β 1D-integrin and muscle agrin appeared to be severely reduced, or almost absent, in the muscle fibres of the diseased patients, whereas staining of α 7A-integrin appeared normal, or slightly increased, compared with that in normal skeletal muscle fibres. We also observed a lower level of α 7B-and β 1D-integrin mRNA and a normal, or slightly higher than normal, level of α 7A-integrin mRNA in the skeletal muscle fibres of the patients with sensitive-motor polyneuropathy, compared with those in the skeletal muscle of normal patients. Additionally, transmission electron microscopy of transverse sections of skeletal muscle fibres indicated that the normal muscle fibre architecture was disrupted, with no myosin present inside the actin hexagons. Based on our results, we hypothesize that skeletal muscle inactivity, such as that found after denervation, could result in a reorganization of the costameres, with α 7B-integrin being replaced by α 7A-integrin. In this way, the viability of the skeletal muscle fibre is maintained. It will be interesting to clarify, by future experimentation, the mechanisms that lead to the down-regulation of integrins and agrin in muscular dystrophies.

Expression of muscle-specific integrins in masseter muscle fibers during malocclusion disease

“…Previously, a similar behavior of the integrin network was demonstrated analyzing human gastrocnemius muscle of subjects affected by sensitive-motor polyneuropathy (26,58). During this muscular inactivity it is possible to hypothesize that a reorganization of the transmembrane occurred, maintaining the viability of the skeletal muscle fibers (58).…”

“…During this muscular inactivity it is possible to hypothesize that a reorganization of the transmembrane occurred, maintaining the viability of the skeletal muscle fibers (58).…”

Immunohistochemial evaluation of sarcoglycans and integrins in gingival epithelium of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw

“…The extracellular matrix molecule laminin is a large heterodimeric glycoprotein and it is required for basement membrane architecture, providing mechanical support to adjacent cells (11,12). The vinculin-talin-integrin system constitutes a well known protein machinery which in skeletal muscle fibers forms the costameres (13)(14)(15)(16)(17). Vinculin head is known to bind to ·-actin and talin, whereas vinculin tail is known to bind to paxillin, F-actin and phosphatidylinositol 4,5 bisphosphate (18).…”

Myopathic changes in murine skeletal muscle lacking synemin

“…Costameres are structures at the sarcolemma of striated muscle fibers that align circumferentially around the Z disks and the M bands of the nearest myofibrils, and longitudinally, to form a rectilinear sarcolemmal network comprised of integral membrane proteins (such as dystroglycan, the sarcoglycans, and Na-K-ATPase), proteins of the extracellular matrix (such as laminin and collagen IV), and proteins of the membraneassociated cytoskeleton (such as dystrophin, syntrophins, spectrin, ankyrin, and vinculin) (12,23,26,41,48,66,71,76,82,87,93,95). Many muscular dystrophies are attributable to mutations in costameric proteins, especially to mutations of proteins of the dystrophin-glycoprotein complex (2,6,10,12,15,27,42,63,74,95).Costameres are linked to the superficial myofibrils of the contractile apparatus by microfilaments, comprised at least in part of ␥-actin (26,43,82), and by IFs, including desmin and several forms of keratin (4,5,7,10,49,54,68,73,88,92). Elimination of these proteins by homologous recombination leads to myopathies.…”