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PubMed1992

Is CNS trauma a prerequisite for the elongation of CNS axons into denervated peripheral nerve?

The demonstration that some central nervous system (CNS) axons can regenerate when provided with a suitable environment raises the possibility of new treatments for CNS injury. However, at present the conditions for optimal regeneration are not well understood. For example, the methods used in previous studies have entailed CNS trauma as part of the research protocol (e.g. that resulting from the implantation of peripheral nerve grafts), and so the role of neuronal or axonal injury in the regrowth observed has been difficult to establish. To determine whether such injury is necessary for the central reinnervation of denervated peripheral nerve, the L5 dorsal root has been chronically denervated in rats by freeze-thawing its dorsal root ganglion (DRG), and the root has been left attached to either traumatized or non-traumatized spinal cord. The trauma induced was quite mild, and resulted from several vertical insertions of a fine needle. Two to 4 months later, retrogradely transported horseradish peroxidase (HRP) was used to label spinal neurons which sent axons into the denervated roots. HRP-labelled neurons were found in each of the spinal cords subjected to trauma, but no labelled neurons were observed in any of the non-traumatized cords. The number of HRP-labelled neurons in individual spinal cords was positively correlated with the degree of spinal cord trauma. We conclude first that the chronic and intimate presence of a denervated PNS tissue in continuity with the spinal cord is not, in itself, a sufficient stimulus to induce its reinnervation by CNS axons. Second, we conclude that under the conditions of this experiment CNS trauma is a prerequisite for the reinnervation of denervated peripheral nervous tissue by CNS axons.

Animals↗
PubMed1994

Denervation-induced dendritic alterations in CA1 pyramidal cells following kainic acid hippocampal lesions in rats.

Kainic acid (KA) lesions of the CA3 region of the hippocampus lead to denervation of ipsilateral CA1 neurons. To assess denervation-induced post-synaptic changes, intracellular physiological recordings were performed in the CA1 region in vitro, from both control and KA-treated tissue. The neurons were intracellularly stained with neurobiotin, reconstructed using a quantitative three-dimensional system and analyzed for morphometric and electrotonic parameters. Total dendritic length was slightly longer in the denervated CA1 cells and there was a selective and significant increase in both branches and terminals in the mid-stratum radiatum (300-550 microns from the soma using Sholl analysis) in the KA-treated rats compared to untreated controls, particularly for cells at 5 days post-lesion and later, which exhibited graded synaptically-evoked bursts. However, there was no significant difference in the basal dendritic arborization. Electrotonic modelling of the dendritic structure revealed specific membrane resistivity values of 33.4 k omega.cm2 for the normal CA1 cells and 29.8 K omega-cm2 for the KA-treated cells, assuming an internal resistivity of 200 omega.cm2, shrinkage correction of 1.57 and a spatial distribution of dendritic spines. The number of dendritic terminals of these denervated CA1 neurons at electrotonic distances between 0.5 lambda and 0.7 lambda also significantly increased in the cells from KA-treated animals. These findings indicate that there is a selective and specific increase in the number of apical terminals and dendritic branches following the unilateral kainic acid lesion. These apical branch changes may represent dendritic sprouting as a post-synaptic response to the denervation, which was particularly marked in neurons exhibiting graded synaptic bursting behavior.

Animals↗
PubMed1996

Surgical denervation increases protein tyrosine phosphatase activity in skeletal muscle.

Protein tyrosine phosphorylation, which plays an important role in synapse formation at the neuromuscular junction, appears to be regulated by presynaptic neurons. Innervation increases whereas denervation decreases the phosphotyrosine content at the neuromuscular junction. The innervation-dependent tyrosine phosphorylation may result from elevated activity of protein tyrosine kinases; alternatively innervation may down-regulate the protein tyrosine phosphatase activity in the skeletal muscle. To investigate the possible neuronal control of protein tyrosine phosphatase activity at the neuromuscular junction, we have characterized protein tyrosine phosphatase activity in rat skeletal muscle and studied the effects of surgical denervation on the phosphatase activity. Protein tyrosine phosphatase activity in the skeletal muscle, assayed using src [32P]-phosphorylated myelin basic protein as a substrate, was both time- and protein concentration-dependent and was inhibited by micromolar concentrations of vanadate and zinc ion, both of which are known to inhibit tyrosine phosphatases specifically. It was not affected, however, by chemicals known to inhibit acid and alkaline phosphatases or serine/threonine phosphatases. Surgical denervation caused an increase in protein tyrosine phosphatase activity in rat hindlimb muscles. The increase in phosphatase activity reached a maximum (2-fold above the normal) 4 days post-denervation and maintained a plateau for up to 24 days. The biochemical properties of the phosphatase activity in denervated muscle were similar to those of the phosphatase activity in the innervated muscles. These results demonstrate that protein tyrosine phosphatase activity in skeletal muscle is regulated by motoneurons.

Animals↗
PubMed1991

Experimental study on the influence of tension, immobilisation and denervation on muscle transplantation.

To observe the effects of tension and immobilisation on denervated muscle, rats' denervated soleus muscles were transplanted orthotopically at different tensions: high, neutral, moderate and low tension with immobilisation. Results were evaluated by measuring muscle mass, twitch and tetanic tension, and histologically by HE staining. The results showed better preservation of muscle weight in the high tension group. Atrophy and loss of function were rapid during the first 4 weeks and were greatest in the low tension group. Rate of atrophy was slowed and relatively stabilised at the eighth postoperative week. We conclude that increased tension with immobilisation produced slower initial atrophy and loss of function in denervated muscle flaps. Although slower, the atrophy continued during the prolonged immobilisation and there was no significant difference compared with neutral tension at a later period. Moreover, immobilisation produced atrophy and affected function regardless of the amount of tension. Increased tension decelerates and decreased tension accelerates denervation atrophy of muscle. Thus denervation, immobilisation and reduced tension are all detrimental in muscle transplantation.

Animals↗
PubMed1984

Rescue of blocked cells by reinnervation in denervated forelimb stumps of larval Ambystoma.

Cells of amputated, denervated larval Ambystoma forelimbs dedifferentiate and enter the cell cycle but do not subsequently proliferate sufficiently to form a blastema. The denervated limb stump resorbs slowly until reinnervation stimulates regeneration. We used this system to investigate the fate of cells in denervated limbs which undergo early but limited cycling in response to amputation. In Experiment 1, cells were labeled with [3H]thymidine (3H-T) on Day 4 postamputation (PA)/Day 3 postdenervation (PD). Labeled cells were still present on Day 7 PA, but were less frequently observed on Day 13 PA when the limbs were reinnervated and beginning to regenerate. In Experiment 2 we denervated 1 day preamputation to obtain earlier reinnervation and prevent loss of Day 4 PA labeled cells. Cells labeled with 3H-T on Day 4 PA/Day 5 PD were present throughout the denervation period and most were still present on Day 13 PA. Little or no mitotic activity was found among the labeled cells after the initial round of cycling. The apparent cell cycle block was released upon reinnervation on Days 12 and 13 PA when cycling resumed. Labeled mitotic figures were present on Day 13 PA, and the mitotic index of the labeled population increased as a result of reinnervation. These results demonstrate that blocked cells are rescued by nerves, re-enter the cell cycle, and thus contribute to the reinnervation blastema.

Ambystoma↗
PubMed1987

Expression of myosin heavy chain isoforms in regenerating myotubes of innervated and denervated chicken pectoral muscle.

Monoclonal antibodies were prepared to stage-specific chicken pectoral muscle myosin heavy chain isoforms. From comparison of serial sections reacted with these antibodies, the myosin heavy chain isoform composition of individual myofibers was determined in denervated pectoral muscle and in regenerating myotubes that developed following cold injury of normal and denervated muscle. It was found that the neonatal myosin heavy chain reappeared in most myofibers following denervation of the pectoral muscle. Regenerating myotubes in both innervated and denervated muscle expressed all of the myosin heavy chain isoforms which have thus far been characterized in developing pectoral muscle. However, the neonatal and adult myosin heavy chains appeared more rapidly in regenerating myotubes compared to myofibers in developing muscle. While the initial expression of these isoforms in the regenerating areas was similar in innervated and denervated muscles, the neonatal myosin heavy chain did not disappear from noninnervated regenerating fibers. These results indicate that innervation is not required for the appearance of fast myosin heavy chain isoforms, but that the nerve plays some role in the repression of the neonatal myosin heavy chain.

Animals↗
PubMed1976

The effect of denervation on the synchronization of contraction of the rat vas deferens.

Denervation of the rat vas deferens results in both quantitative and qualtitative changes in the contraction of the isolated smooth muscle. The maximum contraction induced by norepinephrine, acetylcholine or serotonin is enhanced by denervation. The response of the tissue to 2 X 10(-4) M BaCl2 initiates a contraction which is more synchronized than the response of the control tissue. By use of 14C-sorbitol and Co-EDTA for estimating extracellular space and from fluorescence histochemical observations, it appears that facilitation of drug diffusion through the extracellular space plays an unimportant role in the altered response to drugs. In experiments which utilized a double-compartment tissue bath it was found that denervation enhanced the propagation of the contraction in the longitudinal direction. From measurements of the longitudinal tissue impedance it was determined that the resistance between smooth muscle cells was significantly decreased by denervation. These results suggest that denervation improves the propagation of excitation in this smooth muscle.

Animals↗
PubMed1982

Comparative study of supersensitivity to K+ after denervation and decentralization in rabbit ear artery.

The contractile response to potassium following denervation or decentralization of the central artery of the rabbit ear was studied in vitro. Denervation or decentralization for 8 weeks caused comparable supersensitivity to potassium: mean EC50 values obtained with isotonic high potassium solution were 21.3 mM in the denervated artery and 18.7 mM in the decentralized artery, and these values were significantly less than those (25-26 mM) of their respective contralateral control arteries (P less than 0.005, paired t-test). The maximum responses to potassium did not differ among the control, denervated and decentralized arteries. Phentolamine (3 X 10(-7) M) and propranolol (3 X 10(-7) M) had no significant effect on the response to potassium. Sensitivities to potassium with hypertonic high KCl solution and hypertonic high K2SO4 solution were virtually identical to those obtained with isotonic high potassium solution. The results suggest that denervation and decentralization produce identical postjunctional supersensitivity to potassium and that the lack of tonic activity of sympathetic nerves may be responsible for the phenomenon in the rabbit ear artery.

Animals↗
PubMed1985

Receptor-mediated uptake of horseradish peroxidase in innervated and denervated skeletal muscle.

The in vitro uptake of [3H]inulin and horseradish peroxidase (HRP) has been studied in innervated and 6 days denervated extensor digitorum longus muscle of the mouse. Both markers were taken up at a higher rate in denervated muscle. The increase in uptake after denervation was, however, larger for HRP than for [3H]inulin. After 2 h incubation at 37 degrees C, pH 7.3, in the presence of equimolar concentrations of HRP and [3H]inulin (approx. 2.1 microM), the uptake of HRP was approx. 8 times as great as the uptake of [3H]inulin in the same innervated muscles. In denervated muscle the HRP uptake was approx. 19 times as great as the [3H]inulin uptake in the same muscles. Various possible explanations of these differences in uptake have been considered and tested experimentally. [3H]Inulin uptake in skeletal muscle has previously been shown to obey bulk kinetics. The present investigation shows the HRP uptake to obey saturation kinetics. The HRP uptake shows dependency on divalent cations and is reduced if incubation is carried out at pH 6.4. The uptake of HRP, when used at a low, non-saturating concentration (10 micrograms/ml approx. 0.25 microM), is inhibited greater than or equal to 60% by yeast mannan (0.1 mg/ml), ribonuclease B (0.1 mg/ml, approx. 7.4 microM), mannose (30 mM), monodansylcadaverine (1 mM), chloroquine (100 microM), trifluoperazine (25 microM) or maleic acid (2 mM). It is concluded that HRP is taken up in innervated and denervated skeletal muscle by a process of receptor-mediated endocytosis and that this uptake is under neurotrophic control.

Animals↗
PubMed1983

Ca2+-activated protease in denervated rat skeletal muscle measured by an immunoassay.

Right hind leg muscles of adult male rats were denervated by transecting the sciatic nerve, while muscles of the left leg served as a control. On days 4, 9, and 18 after denervation, the rats were killed and the extensor digitorum longus and soleus muscles removed. Extracts were prepared which contained the Ca2+-activated protease. The molecular weight of the protease in the extracts, measured immunologically on Western blots of SDS-polyacrylamide gels, was identical to that of purified standard protease and was unaffected by denervation. The amount of protease in each extract was measured by a solid phase immunoassay using monospecific IgG labeled with 125I, and the results were expressed as units of protease activity per milligram noncollagen protein. There were increases of 40 to 80% in the mean values obtained for both denervated muscles compared with controls. Because the protease is probably localized on the cell membrane, these modest increases are likely to be a consequence of a generalized over-development of muscle membranes which follows denervation.

Animals↗
PubMed1984

Effect of nerve extract on number of acetylcholine receptors in denervated muscles of rats.

We have shown elsewhere that injection of an extract of peripheral nerves reduces the atrophy of denervated muscle fibers in vivo. Denervated muscle fibers exhibit supersensitivity to acetylcholine owing to the production of extrajunctional acetylcholine receptors. We sought to determine whether or not injection of nerve extract can influence the numbers of acetylcholine receptors in normal, immobilized, or denervated extensor digitorum longus muscles of rats. The receptors were assayed by measuring the binding of 125I-alpha-bungarotoxin. Normally innervated muscles injected with nerve extract exhibited slightly increased binding of the toxin, but this was due to the injections per se. Immobilization caused a small, transient increase in binding of alpha-bungarotoxin, whereas denervated muscles bound considerably more toxin than innervated controls. The nerve extract did not reduce or prevent the increase in acetylcholine receptors caused by denervation but instead caused an even greater increase. We concluded that the neurotrophic factor extracted from peripheral nerve that is responsible for the maintenance of the sizes of the fibers probably does not down-regulate extrajunctional acetylcholine receptors. The limitation of acetylcholine receptors to the end-plate regions is probably effected by a different mechanism which has yet to be elucidated.

Acetylcholine↗
PubMed1984

Effects of stretch and denervation on protease activities of normal and dystrophic chicken muscle.

Changes of protease activities that follow passive stretch, denervation, and denervation plus stretch were followed in the patagialis muscle of normal and dystrophic chicks between 6 and 7 weeks of age. The baseline activities of cathepsin C, cathepsin D, and leucine aminopeptidase in dystrophic muscle were 2 to 3.5 times higher than in normal muscle. Passive stretch and denervation induced increases in protease activities by 40 to 120% in normal muscle, whereas the same treatments did not significantly affect the activities of the enzymes in dystrophic muscle. We conclude that the level of protease activity in dystrophic chicken muscle at 6 weeks of age had already attained a maximum limit and could not be increased even by denervation. In spite of protease activities, which were not different from control dystrophic muscle, denervated dystrophic muscles lost muscle weight rapidly whether they were stretched or not. They weighed 60% less than the innervated control muscle after 7 days. Inherently high protease activities in dystrophic muscle do not vary at this age regardless of whether or not the muscle is gaining or losing weight.

Animals↗
PubMed1986

Effect of denervation on sarcolemmal proteins and glycoproteins of fast and slow mammalian skeletal muscle.

We compared the protein and glycoprotein composition of a sarcolemmal membrane fraction isolated from normal and denervated rat extensor digitorum longus (EDL) and soleus muscles. Membranes from EDL and soleus muscles showed significantly different protein compositions. A relatively small number of glycoproteins, which were all minor proteins, accounted for the majority of concanavalin A (ConA) and Ricinus communis agglutinin (RCA120) binding. These glycoproteins appear to be common to EDL and soleus but bound different relative amounts of lectin in the two muscles. A large proportion of the ConA binding sites in EDL, but not soleus, were cryptic (not accessible by ConA unless the membrane structure was disrupted). Denervation had a differential effect on sarcolemma from the two muscles with EDL exhibiting large changes and soleus changing little if at all. Several major proteins changed their relative concentrations after denervation and the relative amount of RCA120 bound to the major glycoproteins also changed. The major ConA-binding glycoproteins did not change in either membrane but denervation resulted in the exposure of most of the cryptic ConA-binding sites in EDL membranes. Endogenous sialyl- and galactosyl-transferase activities in the membrane fractions significantly increased in EDL, but did not change in soleus, suggesting that the turnover of the glycoproteins is increased in EDL after denervation.

Animals↗
PubMed1987

Effect of denervation on adenine nucleotides in skeletal muscle from normal and dystrophic mice.

The effect of denervation on the adenine nucleotide content of fast- and slow-twitch skeletal muscle of the C57BL mouse was studied by high-performance liquid chromatography. From the adenine nucleotide content the energy charge, a measure of high-energy phosphate available to the cell, was calculated. The energy charge of the extensor digitorum longus muscle was significantly higher than that of the same muscle from dystrophic mice (C57BL/6J dy2j/dy2j) and on denervation decreased to the values found in the innervated muscle from dystrophic animals. Denervation of the muscle in dystrophic mice did not change the energy charge of that muscle. The energy charge of the soleus muscle from both normal and dystrophic mice was similar and did not change on denervation. It is proposed that in the dystrophic process a functional denervation of skeletal muscle occurs which preferentially affects fast-twitch muscle, leading to a reduction in the energy charge.

Adenine Nucleotides↗
PubMed1987

Effect of denervation and injected nerve extract on soluble proteins of extensor digitorum longus muscles of rats.

Right extensor digitorum longus muscles of rats were denervated. After 7 days the soluble proteins were extracted from denervated and contralateral control muscles and fractionated into 32 bands by electrophoresis on polyacrylamide gels. The distribution of protein among the bands was calculated for each muscle. In denervated muscles the proportion of the total protein was increased in 11 bands and decreased in 6, relative to control muscles. Daily injection of denervated muscles with nerve extract, previously shown to offset postdenervation loss of muscle protein and shrinkage of muscle fibers, prevented the increased level of one protein and exaggerated the change in two others. Two bands, not affected by denervation, were decreased by the extract.

Animals↗
PubMed1988

Alterations in contractile properties of extensor digitorum longus muscle from C57BL/6J mice following denervation at 1 day of age.

Changes in contractile properties of developing fast-twitch skeletal muscle of the C57/BL6J mouse were studied following neonatal denervation. A sciatic neurectomy was performed at 1 day of age and then denervated and control muscles were examined at 7, 14, and 21 days postdenervation. In addition, normal muscles were studied at 1 day of age. The denervated muscles exhibited prolongation of time-to-peak twitch tension and half-relaxation time, a slowing of the maximum velocity of shortening, and a marked increase in resistance to fatigue compared with controls. Isometric tetanus tension was reduced compared to the control muscle both in absolute terms and when expressed relative to body weight at all ages studied. The absolute isometric twitch tension was reduced at 7 and 14 days, but was reduced only at 21 days when expressed as a fraction of the muscle weight. Post-tetanic twitch potentiation failed to appear in the denervated muscle. It would appear that neonatal denervation results in an uncoupling of the developmental pattern of skeletal muscle.

Animals↗
PubMed1988

Total denervation stabilizes the infarcted canine myocardium.

The effect of total cardiac denervation upon the electrophysiology of infarcted canine myocardium was studied at both organ and cellular levels. Fifteen dogs underwent coronary ligation to produce an infarct at the apex of the left ventricle (Group 1, n = 15). A second group of dogs (Group 2, n = 14) underwent total intrapericardial denervation with subsequent infarct 15.0 +/- 0.3 (mean +/- SEM) days later. All animals had bipolar epicardial pacing electrodes placed on the right ventricle and the infarct border zone of the left ventricle. Strength-interval curves were performed one or two times per week in conscious animals to assess cardiac excitability. Animals were sacrificed 18.1 +/- 0.5 days following infarct and histologic studies were performed to determine infarct size. Standard microelectrode techniques were also utilized to determine cellular parameters. Denervation was found to lengthen the absolute refractory period and prevent increases in the relative refractory period which were observed in innervated animals following infarct. Isolated tissue data including measurements of maximal rate of depolarization, mean diastolic potential, action potential amplitude, action potential duration at 50% repolarization, and effective refractory period indicated that denervation protects against cellular deterioration and improves electrophysiologic cellular characteristics. These studies suggest that under conditions of myocardial ischemia, denervation produces an electrically more stable myocardium which is less excitable and probably less vulnerable to lethal arrhythmias.

Action Potentials↗
PubMed1985

ConA and WGA receptors in rat skeletal muscles. Changes in density, distribution and composition following denervation.

The differential binding of fluorescein-labeled ConA, WGA and UEA to cryostatic sections of control and of 8 days denervated muscles is described. Receptor sites for ConA and WGA appear to be very abundant in skeletal muscles and their abundance seems to increase following denervation. In contrast, concentration of receptor sites for UEA is below the sensitivity of the method. Differences in the distribution of the binding sites for ConA and WGA, apparent in untreated sections, were further analysed following predigestions by collagenase, hyaluronidase or neuraminidase. The most important difference among lectins appeared to be the preferential binding of ConA to the surface of muscle fibres and of WGA to connective tissue. By comparing results in control and denervated muscles a clear change of the effects of neuraminidase on WGA binding was evident following denervation. The binding of fluorescein-labeled ConA and WGA to untreated and to predigested cryostatic sections of skeletal muscle is a sensitive and simple histochemical method which can disclose precocious changes in composition of glycoconjugates following denervation and, what might be useful, in other experimental or pathological conditions.

Animals↗