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PubMed1986

Decreased acetylcholine receptor content in denervated skeletal muscles infused with nerve extract.

The influence of a concentrated extract of soluble substances from the sciatic nerve upon the acetylcholine receptor (AChR) content in the soleus muscle of adult rats was examined by in vivo infusions. Internal and membrane-inserted AChR were quantitated by the specific binding of 125I-alpha-bungarotoxin (a-BuTX). Interestingly, the nerve extract had no apparent effect unless the soleus muscle was also denervated at the start of the infusion. Then, after 66 hr, substantially less (60-80%) binding of 125I-a-BuTX to AChR was observed compared to denervated solei that did not receive an infusion of nerve extract. However, the concentration of protein in the nerve extract had to exceed 5 mg/ml before this effect was evident. Infusions of phosphate-buffered saline, bovine serum albumin, rat liver extract, or human transferrin had no striking effect upon AChR. The prevention of the characteristic denervation-induced increase in non-junctional AChR by an active component in the nerve extract may be due to a trophic signal for decreased synthesis of AChR, but it is also possible that the degradation of AChR was increased.

Animals↗

PubMedDate not supplied

Treatment of denervated muscle by gangliosides.

Short-duration cooling of the nerve to the extensor digitorum longus muscle of the rat in vivo induced partially reversible denervation of the muscle and atrophy in the type 2 muscle fibers. Increases in cyclic adenosine monophosphate, cyclic guanosine monophosphate phosphodiesterase, adenylate cyclase, and guanylate cyclase were observed in the denervated muscle. Treatment with gangliosides of the bovine brain cortex seemed to improve the excitability of the surviving motor units and to encourage recovery of neuromuscular trophic control, but it did not affect the nerve conduction velocity or the contractile properties of the denervated muscle.

Animals↗

PubMedDate not supplied

A possible role for glucocorticoids in denervation atrophy.

Skeletal muscle atrophies after denervation. Glucocorticoids also cause skeletal muscle to atrophy. The data presented in this report demonstrate that after denervation there is a significant increase in the number of glucocorticoid receptors in the cytosol of skeletal muscle of rats. The results are consistent with the hypothesis that a skeletal muscle atrophies after denervation because it becomes hypersensitive to glucocorticoids.

Animals↗

PubMed1983

Effect of denervation on glycogen metabolism in fast and slow muscle of rat.

The postdenervation changes in glycogen metabolism were explored in fast (extensor digitorum longus, EDL), and slow (soleus, S) muscle of rat. During the first 12-14 hours after denervation, glycogen accumulates to a similar content in the two muscles, an effect reproduced by paralysis. Increase in the molecular weight of glycogen and decrease in the turnover rate of similar degree occur. During the ensuing 12-24 hours the glycogen concentration decreases in EDL (but not in S). This decrease is influenced by factors such as muscle type, longer or shorter nerve stump, age, and previous training of the animal. In both EDL and S, the rate of glucose incorporation into glycogen and the glycogen synthase [l/(l + D)] activity were depressed by denervation. The cAMP concentration increased 36 hours after denervation. This may have consequences on the muscle sensitivity to hormones. In fact, at this time, insulin did not increase glycogen synthase I activity or the glycogen content (with the exception of glycogen in S) and the effects of epinephrine on glycogen metabolism became more significant.

Animals↗

PubMed1985

Altered rat skeletal muscle carnitine with age and after denervation.

We investigated the effect of denervation on the concentration of total free, and acyl carnitine in the soleus (S), extensor digitorum longus (EDL), and anterior tibial (AT) muscles of the rat. Soon after denervation there was a marked decrease in total carnitine in all three muscles. Acyl carnitine levels decreased concomitantly with changes in total carnitine. In control but not in denervated muscle, the carnitine concentration was age-dependent during the period of rapid growth of the animals. The highest carnitine concentration was observed at 14 weeks of age. The results of this study suggest that normal innervation significantly influences carnitine-mediated lipid metabolism in skeletal muscle.

Age Factors↗

PubMed1985

Changes in intramuscular collagen and fibronectin in denervation atrophy.

The distribution of collagen types I, III, and V and fibronectin was investigated by means of immunofluorescent techniques in denervated and normal rat skeletal muscle. During a period of 28 days, a distinct atrophy developed in the denervated gastrocnemius muscle and was accompanied by an increase in types I and III collagen in the endomysium and perimysium. The amount of type V collagen showed little change, whereas fibronectin increase closely parallelled types I and III collagen. The results indicate that denervation atrophy in muscles is accompanied by striking fibrotic changes due to mesenchymal types I and III collagen.

Animals↗

PubMed1987

The effect of isometric short-term electrical stimulation on denervated muscle.

Electrical stimulation was applied daily for 20 minutes to denervated rabbit extensor digitorum longus muscle. One group was stimulated with short tetani, another with 1-Hz frequency, using isometric contractions for both. Tetanic stimulation induced severe fibrosis and is harmful to denervated muscle. One Hertz stimulation retarded denervation-induced fatigue and atrophy, as well as slowing of contraction time.

Animals↗

PubMed1987

Glucocorticoid excess induces preferential depletion of myosin in denervated skeletal muscle fibers.

The combined effects of dexamethasone treatment (1 mg/Kg/day) plus denervation (DEX-DEN), were studied at 7, 13, and 28 days by microscopic, biochemical, and physiological techniques in plantaris and soleus muscles of adult rats. The results were compared with corresponding dexamethasone-treated (DEX) and denervated (DEN) muscles and appropriate controls. There was a significantly more marked atrophy of all fiber types in the DEX-DEN plantares at 7 and 13 days than in either DEX or DEN muscles. The degree of atrophy was greatest in type 2B fibers in DEX-DEN plantares. Electron microscopy revealed a severe preferential depletion of thick myofilaments in DEX-DEN plantares and solei but not in DEX or DEN muscles. The thick myofilament depletion in DEX-DEN muscles occurred in addition to a severe overall reduction of myofibrillar caliber. Gel electrophoresis showed a marked preferential decrease of myosin heavy chain in DEX-DEN plantares and solei, but not in either DEX or DEN muscles. Myosin light chains were also markedly reduced in DEX-DEN plantares and solei. In vitro physiological studies showed a marked reduction of the denervation-induced twitch potentiation in DEX-DEN solei. Maximal tetanic tension (20 Hz stimulation) per gram weight of muscle as well as the twitch-tetanus ratio was significantly reduced only in DEX-DEN solei in relation to controls. Myosin depletion in DEX-DEN muscles may be due to a severe preferential inhibition of its synthesis coupled with an accelerated catabolism.

Actins↗

PubMed1990

Effect of clenbuterol on normal and denervated muscle growth and contractility.

The reported anabolic action of some beta 2 agonists may have clinical applications in certain muscle wasting states. Administration of clenbuterol (2 mg/kg diet for 14 days) to rats resulted in a limited degree of hypertrophy of normal muscles; the effect was more pronounced on fast-twitch muscles than on slow-twitch muscles. The anabolic effect was greatest in denervated muscles, where it was significantly more effective on the slow-twitch type. Clenbuterol significantly improved the contractile properties of denervated slow-twitch muscle, reverting them toward normal, but had little effect on contractile properties of denervated fast-twitch muscle. Such differential effects of clenbuterol must be taken into consideration in the evaluation of any future human intervention study.

Animals↗

PubMed1990

Effects of intermittent high frequency electrical stimulation on denervated EDL muscle of rabbit.

This study was performed to determine whether electrical stimulation can retard denervation-induced changes. The denervated extensor digitorum longus of the rabbit, a fast-twitch muscle, was stimulated at a rate mimicking its motoneuron firing pattern. The 100-Hz stimulation given intermittently subjected the muscle to a low mean total daily frequency of 1.6 Hz. Four weeks of stimulation resulted in no effect upon the denervated stimulated muscle. This stimulation protocol, therefore, is unable to substitute for the lost neuronal influence of the nerve. The muscle contralateral to the stimulated side showed physiological changes making it unsuitable to serve as a control.

Animals↗

PubMed1991

Real-time sonography of acute and chronic muscle denervation.

Presented are real-time ultrasound findings in partially and completely denervated muscles of 30 patients with focal neuropathy and various other disorders of the second motor neuron. Sonographic scans of affected muscles are analyzed in conjunction with unaffected muscles of the same individual, under identical examination conditions. Initial pathological ultrasound changes could be detected as soon as 2 weeks after an acute neurogenic lesion. In denervation, the echodensity of the muscle was high and the normal intramuscular pattern was decomposed. Findings were more intense in severe and longstanding denervation. Ultrasound-indicated pathology correlated highly (chi-square: P less than 0.001) with pathological spontaneous activity detected by electromyography. Focal and systemic neuropathies showed no differences in ultrasound pathology. Six cases with central motor palsy had normal sonograms. Poor spatial resolution of real-time ultrasonography--as compared with CT and MRI--is compensated by its bedside availability, frequent repeatability without patient risk and discomfort, and its in vivo correlation of muscle morphology with muscle function.

Adult↗

PubMed1992

Denervation increases clenbuterol sensitivity in muscle from young rats.

Clenbuterol has been shown to ameliorate denervation-induced atrophy and, therefore, clearly has therapeutic potential in the treatment of muscle wasting conditions in man. Previous studies have used dosages in rats which would be unacceptable in clinical practice, but the present results show that denervated muscle has a greater sensitivity to the drug than innervated or cardiac muscle. Fiber hypertrophy and an increase in protein and RNA content could be observed in denervated muscles but not in innervated muscles at a dose of 10 micrograms/kg body weight. When considered on a metabolic body weight basis, the effective dose in rats and the "safe" dose in man are surprisingly comparable. The observations imply that there is good reason to suppose that clenbuterol could be effective in ameliorating similar wasting conditions in man.

Animals↗

PubMed1992

Scanning electron microscopic study of denervated and reinnervated intrafusal muscle fibers in rats.

Isolated muscle spindles from lower lumbrical muscles of rats were used to study the 3-dimensional organization of intrafusal structures by scanning electron microscopy following (a) complete denervation, (b) reinnervation after a single crush lesion of the sciatic nerve, or (c) reinnervation after transection and immediate suture of this nerve. One week after complete denervation, previous sites of intrafusal motor endplates were transformed into sarcolemmal ovoid bulges. These bulges persisted in denervated muscle spindles up to 12 weeks. Regenerated motor nerve endings were detected on intrafusal muscle fibers 1 month, and thereafter following sciatic nerve crush injuries, and 3 months and later following transection and suture of the nerve. Furthermore, 3 different types of subsynaptic areas of motor nerve terminals were observed. The scanning electron microscopic technique also allowed visualization of splitting and fusion of intrafusal muscle fibers. The findings are discussed in view of their possible functional implications.

Animals↗

PubMed1992

Transient neonatal denervation alters the proliferative capacity of myosatellite cells in dystrophic (129ReJdy/dy) muscle.

It has been previously shown that transiently denervated, neonatal dystrophic muscle fails to undergo the degeneration-regeneration cycle characteristic of murine dystrophy (Moschella and Ontell, 1987). Thus, the myosatellite cells (myogenic stem cells) in these muscles have been spared the mitotic challenge to which dystrophic myosatellite cells are normally subjected early in the time course of the disease. By in vitro evaluation of the proliferative capacity of myosatellite cells derived from extensor digitorum longus (EDL) muscles of 100-day-old genetically normal (+/+) and genetically dystrophic [dy/dy (129ReJdy/dy)] mice and from muscles of age-matched mice that had been neonatally denervated (by sciaticotomy) and allowed to reinnervate, it has been possible to directly determine whether the cessation of spontaneous regeneration in older dy/dy muscles in vivo, is due to an innate defect in the proliferative capacity of the myosatellite cells or exhaustion of the myosatellite cells' mitotic activity during the regenerative phase of the disease. This study demonstrates that transient neonatal denervation of dystrophic muscle (Den.dy/dy) increases the number of muscle colony-forming cells (MCFs) per milligram of wet weight muscle tissue, increases the plating efficiency, and significantly increases the in vitro mitotic activity of dystrophic myosatellite cells toward normal values. The increased mitotic capability of myosatellite cells derived from Den.dy/dy muscle as compared to unoperated dy/dy muscle suggests that there is no innate defect in the proliferative capacity of the myosatellite cells of dy/dy muscles and that the cessation of spontaneous regeneration in the dy/dy muscles is related to the exhaustion of their myosatellite cells' mitotic capability.

Animals↗

PubMed1992

Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1997

Dihydropyridine receptor and ryanodine receptor gene expression in long-term denervated rat muscles.

Following disruption of the nerve supply, extensor digitorum longus (EDL) and soleus (SOL) muscles in rats are known to exhibit alterations in excitation-contraction coupling. After total RNA isolation from the denervated and the contralateral control muscles performed at 25 and 50 days following denervation, RNase protection assays were carried out with four cDNA probes specific for the skeletal and cardiac isoforms of both the DHPR alpha 1-subunit and the RyR. Longterm denervation increased the expression of the mRNA for skeletal DHPR and skeletal RyR in SOL muscle, but it also significantly increased the expression of the mRNA for the cardiac isoform of the DHPR alpha 1 subunit in EDL muscle.

Animals↗

PubMed1995

Agrin gene expression in ciliary ganglion neurons following preganglionic denervation and postganglionic axotomy.

Agrin is an extracellular matrix protein that has been implicated as a synaptogenic agent in the peripheral and central nervous systems. Both the level of expression and pattern of alternative splicing of agrin mRNA are developmentally regulated. As a step toward identifying signals important in regulating agrin gene expression in neurons, we examined the effects of postganglionic axotomy or preganglionic denervation on agrin mRNA levels and alternative splicing in ciliary ganglia of posthatch chicks. In comparison to unoperated age-matched controls, in situ hybridization with a pan-specific agrin cRNA probe demonstrated a significant decrease in neuronal agrin mRNA expression as a result of axotomy. Reverse transcription-polymerase chain reaction analysis demonstrated that axotomy also resulted in changes in the pattern of alternative splicing of agrin mRNA. Underlying these changes are decreases in the molar amounts of transcripts encoding the neuron-specific isoforms agrin8 and agrin19, homologous to rat agrin proteins that have high AChR aggregating activity. Similar, but less dramatic changes in agrin expression following axotomy were also observed in unoperated neurons on the contralateral side. In contrast, the only significant change in agrin gene expression following ganglionic denervation was a small decline in the relative abundance of agrin 8 mRNA in operated versus unoperated age-matched control ganglia. Major changes in agrin gene expression following axotomy but not denervation are consistant with the notion that agrin synthesized by ganglionic neurons exerts its effects in the periphery rather than at synapses formed between ciliary ganglion neurons and their preganglionic input. These data suggest that the pattern of alternative splicing and the absolute amount of agrin mRNA in ciliary ganglion neurons may be regulated by target tissue interactions.

Agrin↗

PubMed1995

Changes in responsiveness to extracellular ATP in chick skeletal muscle during development and upon denervation.

Skeletal muscles in developing chick embryos were tested for responsiveness to adenosine 5'-triphosphate (ATP), a substance known to depolarize chick skeletal muscle in culture. The sensitivity to extracellular ATP was tested at various stages of development in five different muscles; pectoralis superficia, anterior latissimus dorsi, posterior latissimus dorsi, sartorious, and gastrocnemius. At the earliest time that muscles were tested (Embryonic Day 6, stage 30 of Hamburger and Hamilton, 1951) application of ATP(50-100 microM) elicited vigorous contractions in all five muscles, but within a few days (Embryonic Day 17, stage 43) none of the muscles contracted in response to ATP. Sensitivity declined at approximately the same time in all five of these muscles. Intracellular recordings made from muscle fibers near the time of hatching (Embryonic Days 18-21 or Postnatal Days 1-2) indicated that the loss of the ability to contract in response to ATP was due to the total loss of responsiveness to ATP. Surgical denervation of the anterior latissimus dorsi and posterior latissimus dorsi was performed in a series of chicks 1-2 days after hatching, and the ability of these muscles to contract in response to ATP was tested 3-10 days after the surgery. Contractions in response to ATP were present in many of the muscles. Thus denervation of muscles in newly hatched chicks led to the reappearance of sensitivity to ATP. The disappearance of ATP responsiveness shortly after muscles become innervated and the reappearance of ATP responsiveness following denervation suggest that the expression of ATP responsiveness is regulated by motor neurons.

Adenosine Triphosphate↗