Studies on the regenerative recovery of long-term denervated muscle in rats

Carlson, Bruce M.; Billington, Lynn; Faulkner, John A.

doi:10.3233/rnn-1996-10203

Cited by 39 publications

(54 citation statements)

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“…The satellite cell population increases dramatically during the first 2 months of denervation, but subsequently this is followed by a pronounced loss. These morphological findings correlate closely with the ability of the denervated EDL muscle to become restored after transplantation (Carlson et al, 1996), but whether or not the numerical data reported here are sufficient to explain the reduced restorative capacity of long-term denervated muscle remains to be determined.…”

Section: Discussionsupporting

confidence: 70%

“…The estimate of total satellite cells per EDL muscle at 7 months of denervation is only one-third of control values. Unfortunately, because of the extremely small size of many of the muscle fibers in muscles denervated from 12-18 months, it was not possible either to isolate individual muscle fibers for confocal microscopy or to make accurate counts of total muscle fibers, but, on the basis of mass and morphology of these muscles (Carlson et al, 1996;Lu et al, 1997) combined with the percentages reported in this paper, it is realistic to assume that the total satellite cell population per muscle fiber is reduced even further with increasing time of denervation.…”

Section: Discussionmentioning

confidence: 99%

“…An important practical issue is whether or not the quantitative data on satellite cell numbers shed any light upon the results of attempts to restore long-term denervated muscle. Both Gulati (1990) and Carlson et al (1996) found that grafts of 2 or 3 month denervated rat EDL muscles were restored to the same mass and contractile force as grafts of normal EDL muscles, but for longer periods of denervation restoration was less successful. The maximum tetanic force developed by grafts of 4 and 7 month denervated muscles declined in a straight line fashion from 2 month levels so that the recovery of force at 7 months was only 17% of that attained at 2 months.…”

Section: Discussionmentioning

confidence: 99%

“…Skeletal muscle is an end organ of the peripheral nervous system, and its differentiation, structural maintenance, and function are directly regulated by its motor nerve supply. After denervation, a muscle rapidly loses mass and contractile function, and the muscle fibers undergo atrophy, with an accompanying series of changes in structure, biochemistry, and physiology (Gutmann, 1962;Sunderland and Ray, 1950;Miledi and Slater, 1969;Schmalbruch et al, 1991;Carlson et al, 1996).…”

mentioning

confidence: 99%

“…In clinical practice, after several months of denervation, ranging from 6-18 months, human skeletal muscles are typically not restored to full function even if regenerating nerve fibers grow into them (Harrison, 1989;Sunderland, 1978). Attempts to restore denervated rat muscles by grafting them into an innervated site have shown that muscles denervated for 2 months or less become restored as well as grafts of control muscles, but for muscles denervated between 2 and 7 months the degree of restoration of mass and contractile force after grafting declines sharply and remains at less than 31 and 13%, respectively, of values for grafts of control muscles for denervation periods exceeding 7 months (Carlson and Faulkner, 1988;Gulati, 1990;Carlson et al, 1996).…”

mentioning

confidence: 99%

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Quantitative study of the effects of long-term denervation on the extensor digitorum longus muscle of the rat

et al. 1997

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Background In order to understand the cellular basis underlying the progressively poorer restorative capacity of long‐term denervated muscle, we determined the effects of long‐term denervation on the muscle fibers and satellite cell population of the rat extensor digitorum longus (EDL) muscle. Methods In 36 male rats, the right hind legs were denervated, and EDL muscles were removed 2, 4, 7, 12, and 18 months later. Muscles were either fixed for electron microscopic analysis or were dissociated into individual muscle fibers for direct fiber counting or for confocal microscopic analysis. Results The percentage of satellite cells rose from the 2.8% control value to 9.1% at 2 months of denervation; thereafter the percentage decreased to 1.1% at 18 months of denervation. The number of myonuclei per muscle fiber steadily declined from 410 in 4 month control muscle to 158 in 7 month denervated muscle. Up to 7 months of denervation, the total number of muscle fibers per muscle remained relatively constant at somewhat over 5,000. The calculated total satellite cell population in 4 month denervated EDL muscle was the same as that of controls at 65,000, but by 7 months of denervation it had declined to 21,000. With increasing time of denervation, the number of cross‐sectional profiles of muscle fibers not containing nuclei rose from 14% in control muscle to 49% in 12 month denervated muscle. This was correlated with a pronounced regular clumping of the nuclei, with pronounced nonnucleated segments between nuclear clumps. Conclusions Increasing times of denervation are accompanied by a pronounced decline in the number of myonuclei per muscle fiber and an initial rise and subsequent fall in satellite cell number. These changes are correlated with a decreasing restorative ability of these muscles over the same periods of denervation. Further work on the proliferative capacity of the remaining satellite cells is necessary before firm quantitative conclusions can be made. Anat. Rec. 248:346‐354 1997. © 1997 Wiley‐Liss, Inc.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Quantitative study of the effects of long-term denervation on the extensor digitorum longus muscle of the rat

et al. 1997

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Electron microscopic study of long-term denervated rat skeletal muscle

Huang²,

Carlson

1997

Anat. Rec.

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Background This study describes the ultrastructure of long‐term denervated rat extensor digitorum longus and tibialis anterior muscles, with particular emphasis on understanding the cellular basis for the reduced restorative capacity of long‐term denervated muscle. Methods In 30 male WI/HicksCar rats, the right hindleg was denervated for periods of 1, 2, 4, 5.5, 6, 7, 12, 14, and 18 months before tissues were prepared for electron microscopy. Results Atrophy of muscle fibers was prominent by the second month post‐denervation. At this time, type II fibers showed greater atrophy than type I fibers. At further periods of denervation, atrophy of all fibers was seen; and with increasing times of denervation the muscle fibers became surrounded by dense mats of collagen fibers. Muscle spindles persisted for the duration of this study. At two and four months, satellite cells showed signs of activation, such as elongated cytoplasmic processes and an increased concentration of cytoplasmic organelles. As denervation progressed, activated satellite cells became more widely separated from their associated muscle fibers, and basal lamina material was deposited between the satellite cells and muscle fibers. Some satellite cells broke free from their muscle fibers, and others acted as bridges between two muscle fibers. Evidence was seen of both muscle fiber degeneration and the regeneration of new muscle fibers, often more than one regenerating fiber beneath a single basal lamina. Loose folds of basal lamina were often present around atrophic muscle fibers. As denervation progressed, the morphology of individual muscle fibers varied. Some contained well‐ordered lattice arrays of myofilaments, whereas in others considerable sarcomeric disorganization was evident. Mitochondria became smaller and rounded; elements of the sarcoplasmic reticulum proliferated and became more disorganized; lipid droplets, glycogen deposits, and autophagic vesicles were all present in the cytoplasm of atrophic muscle fibers. Conclusions In addition to muscle fiber atrophy, long‐term denervated muscles show evidence of myofiber and capillary death, as well as the deposition of massive amounts of interstitial collagen. These changes, all of which would appear to reduce the restorative capacity of the denervated muscle, take place concurrently with the morphological activation of satellite cells. The latter indicates that even in the denervated condition, restorative processes occur concurrently with regressive processes. Anat. Rec. 248:355–365, 1997. © 1997 Wiley‐Liss, Inc.

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Reparative myogenesis in long‐term denervated skeletal muscles of adult rats results in a reduction of the satellite cell population

et al. 2001

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This study, conducted on 25-month denervated rat hindlimb muscles, was directed toward elucidating the basis for the poor regeneration that is observed in long-term denervated muscles. Despite a ϳ97.6% loss in mean cross-sectional area of muscle fibers, the muscles retained their fascicular arrangement, with the fascicles containing ϳ1.5 times more fibers than age-matched control muscles. At least three distinct types of muscle fibers were observed: degenerating, persisting (original), and newly formed (regenerated) fibers. A majority of newly formed fibers did not appear to undergo complete maturation, and morphologically they resembled myotubes. Sites of former motor end-plates remained identifiable in persisting muscle fibers. Nuclear death was seen in all types of muscle fibers, especially in degenerating fibers. Nevertheless, the severely atrophic skeletal muscles continued to express developmentally and functionally important proteins, such as MyoD, myogenin, adult and embryonic subunits of the nicotinic acetylcholine receptor, and neural-cell adhesion molecule. Despite the prolonged period of denervation, slow and fast types of myosin were found in surviving muscle fibers. The number of satellite cells was significantly reduced in long-term denervated muscles, as compared with age-matched control muscles. In 25-month denervated muscle, satellite cells were only attached to persisting muscle fibers, but were never seen on newly formed fibers. Our data suggest that the absence of satellite cells in a population of immature newly formed muscle fibers that has arisen as a result of continuous reparative myogenesis may be a crucial, although not necessarily the only, factor underlying the poor regenerative ability of long-term denervated muscle. Anat Rec 263: 139 -154, 2001.

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Studies on the regenerative recovery of long-term denervated muscle in rats

Cited by 39 publications

References 0 publications

Quantitative study of the effects of long-term denervation on the extensor digitorum longus muscle of the rat

Quantitative study of the effects of long-term denervation on the extensor digitorum longus muscle of the rat

Electron microscopic study of long-term denervated rat skeletal muscle

Reparative myogenesis in long‐term denervated skeletal muscles of adult rats results in a reduction of the satellite cell population

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