Remodeling of the vascular bed and progressive loss of capillaries in denervated skeletal muscle

Abstract

Very little is known regarding structural and functional responses of the vascular bed of skeletal muscle to denervation and about the role of microcirculatory changes in the pathogenesis of post-denervation muscle atrophy. The purpose of the present study was to investigate the changes of the anatomical pattern of vascularization of the extensor digitorum longus muscle in WI/HicksCar rats 1, 2, 4, 7, 12, and 18 months following denervation of the limb. We found that the number of capillaries related to the number of muscle fibers, i.e. the capillary-to-fiber ratio (CFR), decreased by 88%, from 1.55 +/- 0.35 to 0.19 +/- 0.04, during the first 7 months after denervation and then slightly declined at a much lower rate during the next 11 months of observation to 10% of the CFR in normal muscle. Between months 2 and 4 after denervation, the CRF decreased by 2.4 times, from 58% to 24% of the control value. The loss of capillaries during the first 4 months following nerve transection was nearly linear and progressed with an average decrement of 4.16% per week. Electron microscopy demonstrated progressive degeneration of capillaries following nerve transection. In muscle cells close to degenerating capillaries, the loss of subsarcolemmal and intermyofibrillar mitochondria, local disassembly of myofibrils and other manifestations of progressive atrophy were frequently observed. The levels of devascularization and the degree of degenerative changes varied greatly within different topographical areas, resulting in significant heterogeneity of intercapillary distances and local capillary densities within each sample of denervated muscle. Perivascular and interstitial fibrosis that rapidly developed after denervation resulted in the spatial separation of blood vessels from muscle cells and their embedment in a dense lattice of collagen. As a result of this process, diffusion distances between capillaries and the surfaces of muscle fibers increased 10-400 times. Eighteen months after denervation most of the capillaries were heavily cushioned with collagen, and on the average 40% of the muscle cells were completely avascular. Devascularization of the tissue was accompanied by degeneration and death of muscle cells that had become embedded in a dense lattice of collagen. Immunofluorescent staining for the vascular isoform of alpha-actin revealed preservation of major blood vessels and a greater variability in thickness of their medial layer. Hyperplastic growth of the medial layer in some blood vessels resulted in narrowing of their lumens. By the end of month 7 after denervation, large deposits of collagen around arterioles often exceeded their diameters. Identification of oxidative muscle fibers after immunostaining for slow-twitch myosin, as well as using ultrastructural criteria, has shown that after 2 months of denervation oxidative muscle fibers were less susceptible to atrophy than glycolytic fibers. The lower rate of atrophy of type I muscle fibers at early stages of denervation may be explained by their initially bette...

Differentiation of activated satellite cells in denervated muscle following single fusions in situ and in cell culture

“…The myogenic response is activated early following denervation and its initiation does not require severe atrophic changes or death of muscle fibers (for discussion see Borisov et al 2001). There are indications that satellite cells in denervated muscle are involved in several structural types of regenerative reactions and that degeneration of muscle cells and capillaries in this experimental model occurs only at advanced stages of post-denervation atrophy (Borisov et al 2000Borisov and Carlson 2000). Interestingly enough, we found direct ultrastructural evidence of fusions of satellite cells with mature muscle fibers in long-term denervated muscle of adult rats (Borisov et al 2005).…”

Skeletal muscle atrophy increases cell proliferation in mice gastrocnemius during the first week of hindlimb suspension

“…The subsequent increase in connective tissue surrounding the intramuscular capillaries may disturb the blood supply to muscle Wbres, likely resulting in a vicious cycle of events that enhance the atrophic process (Appell 1990;Jarvinen et al 2002). Furthermore, the interstitial Wbrosis may lead to a kind of ischemic condition in muscle contributing to the progressive loss of muscle mass (Borisov et al 2000). All the other cell types presented a consistent decline in BrdU-labelled numbers per Wbre.…”

“…The structural adjustment of capillaries to a straight conWguration is an important morphological consequence of hindlimb unloading because it may decrease the ability of oxygen delivery (Fujino et al 2005). In this sense, it is likely that endothelial apoptosis can be a major factor in the remodelling of the capillary network during weightlessness (Borisov et al 2000;Fujino et al 2005). However, little is known about the coupling between the microvasculature and decreased functional demands, as probably occurring during muscle atrophy.…”

Adaptation of muscle fibre types and capillary network to acute denervation and shortlasting reinnervation

“…Experiments have involved mechanical and chemical denervation, and muscles have been excised at various time intervals after denervation (cf. Mrazkova and Puzanova 1971;Chernukh and Alexeeva 1975;Carpenter and Karpati 1982;Large and Tyler 1985;Ziada et al 1989;Tyml et al 1999;Borisov et al 2000;Dedkov et al 2002;Wagatsuma et al 2005). The capillary network has only been studied in two-dimensional muscle sections.…”