Abortive myogenesis in denervated skeletal muscle: differentiative properties of satellite cells, their migration, and block of terminal differentiation

Abstract

Little is known about the biological properties of myogenic satellite cells during post-denervation muscle atrophy. The present study investigated the differentiative capacity of satellite cells and their involvement in the compensatory regenerative process in long-term denervated rat muscle. Electron microscopy and immunocytochemical labeling of muscle tissue 1-18 months following denervation demonstrated that despite activation of satellite cells, myogenesis in denervated muscle is abortive and does not lead to the formation of normal muscle fibers. Small sizes, poor development of the contractile system in newly formed denervated myotubes, and the absence of satellite cells on the surface indicate that their differentiation typically does not progress to terminal stages. Many immature myotubes degenerate, and others survive but are embedded in a collagen lattice near their parent fibers. Interestingly, newly formed myotubes located on the surface of parent muscle fibers beneath the basal lamina typically did not contain developed myofibrils. This suggests that the contacts of daughter and parent muscle fibers block myofibrillogenesis. Assembly of sarcomeres in most cases occurs following complete spatial separation of daughter and parent muscle fibers. Another manifestation of the involvement of myogenic precursors in abortive myogenesis is the formation of clusters of underdeveloped branching myotubes surrounded by a common basal lamina. We found that myoblasts can also fuse directly with differentiated muscle fibers. The presence of satellite cells near the openings in the basal lamina and in the interstitial space indicates that myogenic precursors can migrate through the basal lamina and form myotubes at a distance from parent fibers. Our data may explain why long-term denervated skeletal muscle has a poor capacity for regeneration and functional restoration.

Myogenesis in human denervated muscle biopsies

“…4,6 -8,15,23 It has been suggested that thin myofibers are derived from satellite cells detached from parent fibers after chronic denervation. 4,6 In a detailed electron microscopic investigation, Schultz provided compelling evidence for satellite cell detachment and myotube formation following denervation. 24 Within 1 week of denervation, basement membrane material was observed to partition-off the satellite cell, which was then found to be localized within the interstitial space.…”

“…4,6,23 These newly formed fibers, thoroughly characterized at the ultrastructural level, contain a poorly developed contractile system with many degenerated elements. 4 These incompletely differentiated fibers appear to arise from satellite cells that have detached from their parent myofibers, representing an "abortive" attempt at myogenesis. 4 Schmalbruch and colleagues described similar myofibers in rat muscle denervated for 6 -10 months.…”

“…4 These incompletely differentiated fibers appear to arise from satellite cells that have detached from their parent myofibers, representing an "abortive" attempt at myogenesis. 4 Schmalbruch and colleagues described similar myofibers in rat muscle denervated for 6 -10 months. 23 As small as 1 m in diameter, the majority of these muscle cells were so small that they could not be identified by routine light microscopy.…”

Regeneration of Reinnervated Rat Soleus Muscle Is Accompanied by Fiber Transition Toward a Faster Phenotype

“…In accordance with the literature (Ijkema-Paassen et al 2001), we found that the total fiber number significantly decreased in reinnervated soleus when compared with normal soleus, which suggests that at least one population of denervated fibers, delayed in reinnervation, has been eliminated. However, the question remains: do all denervated fibers undergo complete elimination (by apoptosis or other mechanisms); are they replaced by new myofibers originating from proliferating satellite cells to some extent; or alternatively, do they exist for a longer time in the denervated stage (Tews et al 1997;Borisov and Carlson 2000;Borisov et al 2001Borisov et al ,2005Tews 2002). In fact, Patterson et al (2006) did not find any decrease in fiber number after 50-day denervation of rat soleus muscle, or any sign of the presence of regenerating fibers.…”

The satellite cell as a companion in skeletal muscle plasticity:currency, conveyance, clue, connector and colander

“…Schultz et al, 1978;Schultz et al, 1985;Carlson, 1995;Hansen-Smith and Carlson, 1979;Tank et al, 1977;Grounds and McGeachie, 1987;Grounds and McGeachie, 1989; J. E. Anderson McGeachie et al, 1993;McGeachie and Grounds, 1987), which showed that satellite cells must proliferate in this repair process. Repair capacity in denervated or tenotomized muscle is retained to a lesser extent, and in the longer term, is constrained by accumulation of interstitial collagen and reduced fusion (Borisov et al, 2005a;Borisov et al, 2005b;Dedkov et al, 2001;Dedkov et al, 2002;Lu et al, 1997;McGeachie, 1985;McGeachie, 1989).Satellite cell proliferation is not seen as the limiting factor in muscle regeneration or growth, although that capacity may be exhausted in severe conditions such as muscular dystrophy (Original micrograph at ϫ140.) (E) A myotube (arrow) forming through addition of myogenic cells, identified (by in situ hybridization) by their expression of myogenin transcripts, a muscle-specific regulatory gene.…”