Cell accumulation in the junctional region of denervated muscle.

Abstract

Abstract. If skeletal muscles are denervated, the number of mononucleated cells in the connective tissue between muscle fibers increases. Since interstitial cells might remodel extracellular matrix, and since extracellular matrix in nerve and muscle plays a direct role in reinnervation of the sites of the original neuromuscular junctions, we sought to determine whether interstitial cell accumulation differs between junctional and extrajunctional regions of denervated muscle. We found in muscles from frog and rat that the increase in interstitial cell number was severalfold (14-fold for frog, sevenfold for ra0 greater in the vicinity of junctional sites than in extrajunctional regions. Characteristics of the response at the junctional sites of frog muscles are as follows. During chronic denervation, the accumulation of interstitial cells begins within 1 wk and it is maximal by 3 wk. Reinnervation 1-2 wk after nerve damage prevents the maximal accumulation. Processes of the cells form a multilayered veil around muscle fibers but make little, if any, contact with the muscle cell or its basal lamina sheath. The results of additional experiments indicate that the accumulated cells do not originate from terminal Schwann cells or from muscle satellite cells. Most likely the cells are derived from fibroblasts that normally occupy the space between muscle fibers and are known to make and degrade extracellular matrix components. DNERVATION of skeletal muscles results in a marked increase in the number of mononucleated cells in the connective tissue between muscle fibers, particularly in cells that look much like fibroblasts (29,32,33,52). Since fibroblasts and other connective tissue cells make and degrade extracellular matrix constituents (6, 16), such changes raise the possibility that the cells that accumulate after denervation act to remodel the extracellular matrix of muscle. Indeed, several studies have shown that the concentrations of some extracellular matrix molecules are altered by denervation (4, 41,45). This is of particular interest since there is evidence that extracellular matrix components play a direct role in regeneration of the neuromuscular junction. For example, in vivo studies of damaged motor nerves have revealed that regenerating axons preferentially grow through tubes of Schwann cell basal lamina to reinnervate muscle fibers at the original synaptic sites on the myofibers' basal lamina sheaths (17,23,27,35), and in vitro studies have shown that neurites preferentially elongate on laminin, a major constituent of Schwann cell and muscle fiber basal lamina (10,21,26,37,43,46). Moreover, the myofiber basal lamina is known to contain molecules that direct the formation of synaptic apparatus in regenerating axon terminals and myofibers (3,7,12,30,44).In the study described here, we denervated frog and rat muscles and compared the change in number of mononucleated cells in junctional regions with that in extrajunctional regions. We report that for both species the increase in the number of mononucleated ...

Identity, developmental restriction and reactivity of extralaminar cells capping mammalian neuromuscular junctions

“…However, similar non-neural cells were identified in scanning electron micrographs by Desaki and Uehara (Desaki and Uehara, 1981), who described them as 'flattened stellate cells of unknown nature'. Other investigators recognised the association of fibroblast-like cells to NMJs (Murray and Robbins, 1982;Connor and McMahan, 1987;Connor, 1997;Caroni and Schneider, 1994) in their description of 'perisynaptic fibroblasts' (Covault and Sanes, 1985;Sanes et al, 1986;Connor and McMahan, 1987;Connor, 1997;Gatchalian et al, 1989;Weis et al, 1991). Perhaps perisynaptic fibroblasts and NMJ-capping cells are the same as the endothelial cells of Robertson (Robertson, 1956), but this remains unproven.…”

“…Peters et al, 1991) crop images of NMJs to exclude cells other than terminal Schwann cells, nerve terminals and muscle fibres. However, original published transmission electron micrographs of NMJs in frogs, lizards, chickens, mice, rats and humans frequently show slender cellular processes overlying the other principal cell types of the NMJ (Robertson, 1956;Desaki and Uehara, 1981;Connor and McMahan, 1987;Slater et al, 1992;Connor, 1997) (see also Fig. 4D).…”

Development of the Vertebrate Neuromuscular Junction

“…This situation differs greatly from that in developing muscle, in which axons lead Schwann cells to myotubes. Third, denervation induces selective proliferation of interstitial cells in perisynaptic areas, which leads to localized accumulation of the adhesive matrix molecules such as tenascin-C and fibronectin , Connor & McMahan 1987, Gatchalian et al 1989, Caroni & Schneider 1994. These molecules may promote or direct growth of regenerating axons as they approach their targets.…”

Scientific Discoveries: What Is Required for Lasting Impact

“…The identity of such products is unknown but would include products from degenerating axons and nerve terminals, denervated muscle fibers, or activated immune and tissue cells. Support for this idea comes from the observation that denervation elicits proliferation and accumulation of tissue cells, including macrophages, in affected muscles in both the frog and rat (84)(85)(86). The response is most pronounced in the junctional region but affects the entire length of the muscle.…”