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PubMed2001

Effects of extrinsic denervation with or without ischemia-reperfusion injury on constitutional mucosal characteristics in porcine jejunoileum.

We investigated the effects of jejunoileal denervation with or without ischemia-reperfusion on mucosal characteristics and small intestinal structure. Growing pigs underwent sham laparotomy, jejunal transection, or extrinsic jejunoileal denervation with or without in situ ischemia-reperfusion. Small intestinal morphology, crypt cell proliferation, enterocyte ultrastructure, and disaccharidase activities were analyzed from jejunum and ileum after eight weeks. Immunohistological analysis of the ileum showed no staining of catecholaminergic neurons after extrinsic denervation. Neural isolation of the jejunoileum with or without ischemia-reperfusion injury reduced weight gain and villous enterocyte density in the ileum, abolished the proximodistal gradient of sucrase activity, and increased mucosal thickness, villus height, and villus surface area in the ileum. However, gross jejunoileal morphology, crypt cell proliferation, and enterocyte ultrastructure remained unchanged. In conclusion, jejunoileal denervation in growing pigs selectively modulates constitutional mucosal characteristics in the ileum, presumably due to altered enterocyte turnover, without a decrease in small intestinal absorptive surface area. These changes are independent of short ischemia and subsequent reperfusion.

Animals↗
PubMed1998

Depletion of endogenous dopamine stores and shift in beta-adrenoceptor subtypes in cardiac tissue following five weeks of chronic denervation.

Surgical ablation of extrinsic cardiac nerve fibers results in a chronically denervated state of the left ventricle of the heart. The present study was performed to elucidate the effect of a period of 5 weeks of chronic denervation on cardiac catecholamine levels in general and dopamine in particular. Moreover, the possible effect on cardiac beta-adrenoceptor subtypes was investigated. Experiments were performed on adult dogs. In addition to adrenaline and noradrenaline the tissue levels of dopamine were found to be severely depressed. A significant shift from beta1- to beta2-adrenoceptor subtype was observed, while the total beta-adrenoceptor density remained unaffected. The present findings indicate that catecholamine synthesis in chronically denervated hearts is impaired upstream of dopamine and that a shift in beta-adrenoceptor subtype occurs already within a relatively short period of five weeks of denervation, and suggest that the lack of endogenous catecholamines influence the relative expression levels of the two subtypes of beta-adrenoceptors present in cardiac tissue.

Animals↗
PubMed2001

Myosin and SERCA isoform expression in denervated slow-twitch muscle of euthyroid and hyperthyroid rabbits.

Changes in the isoform patterns of myosin heavy chains (MHC) and Ca2+-ATPase (SERCA) were studied in long-term (72 days) denervated slow-twitch soleus muscles of euthyroid and hyperthyroid rabbits. MHC isoforms were separated electrophoretically. SERCA isoforms were assessed by electrophoretic separation of the trypsin-digested and phosphorylated fragments. Denervation led to pronounced slow-to-fast transitions with increases in the fast MHC and fast SERCA1a isoforms. Hyperthyroidism had no significant effect on the denervation-induced changes in SERCA isoforms, but led to slight increases in the relative concentrations of the fast MHC isoforms. A high correlation existed between the relative concentrations of slow myosin and SERCA2a in both innervated euthyroid and hyperthyroid soleus muscles. This correlation, however, seems to be less tight in denervated soleus muscles.

Animals↗
PubMed2003

Plasticity of the transverse tubules following denervation and subsequent reinnervation in rat slow and fast muscle fibres.

We have studied the effects of short term denervation followed by reinnervation on the ultrastructure of the membrane systems and on the content of and distribution of key proteins involved in calcium regulation of fast-twitch (FT) extensor digitorum longus (EDL) and slow-twitch (ST) soleus (SOL) muscle fibres. Ischiadic nerve freezing resulted in total lack of neuromuscular transmission for 3 days followed by a slow recovery, but no decline in twitch force elicited by direct stimulation. The latter measurements indicate no significant atrophy within this time frame. The membrane systems of skeletal muscle fibres were visualized using Ca92+)-K3Fe(CN)6-OsO4 techniques and observed using a high voltage electron microscope. [3H]nitrendipine binding was used to detect levels of dihydropyridine receptor (DHPR) expression. The Ca2+ pumping free sarcoplasmic reticulum domains were not affected by the denervation, but the Ca2+ release domains were dramatically increased, particularly in the FT-EDL muscle fibres. The increase is evidenced by a doubling up of the areas of contacts between SR and transverse (t-) tubules, so that in place of the normal triadic arrangement, pentadic and heptadic junctions, formed by multiple interacting layers of ST and t-tubules are seen. Frequency of pentads and heptads increases and declines in parallel to the denervation and reinnervation but with a delay. Immunofluorecence and electron microscopy observations show presence of DHPR and ryanodine receptor clusters at pentads and heptads junctions. A significant (P < 0.01) positive correlation between the level of [3H]nitrendipine binding component and the frequency pentads and heptads was observed in both the FT-EDL and ST-SOL muscle fibres indicating that overexpression of DHPRs accompanies the build up extra junctional contacts. The results indicate that denervation reversibly affects the domains of the membrane systems involved in excitation-contraction coupling.

Animals↗
PubMed1972

Early biochemical consequences of denervation in fast and slow skeletal muscles and their relationship to neural control over muscle differentiation.

1. One week after denervation several biochemical characteristics of the fast extensor digitorum longus and slow soleus muscles from adult rats were investigated and compared with the characteristics of the corresponding unoperated contralateral muscles. 2. After these short periods of denervation-induced atrophy, the isolated myosins showed unchanged ATPase (adenosine triphosphatase) activities, but there was the expected difference between fast and slow muscle. 3. The specific activities of several soluble enzymes and their characteristic patterns were found to be only slightly modified in both the extensor and soleus muscles after denervation, as were most of the activities measured in the isolated mitochondria. 4. The most significant modifications were in the isolated sarcoplasmic reticulum, and appeared to be specific to either slow or fast muscle. 5. Denervation of slow muscle led to a marked increase of Ca(2+)-transport rates, and of the specific activity of the Mg(2+)-activated K(+)-modulated Ca(2+)-stimulated ATPase, together with changes in the polyacrylamide-electrophoretic profiles of the microsomal membrane protein. Transformation of these several properties of slow muscle sarcoplasmic reticulum to those of fast muscle sarcoplasmic reticulum was further substantiated by electron-microscopic analysis after negative staining. Control experiments with tenotomized soleus muscle gave negative results. 6. The isolated sarcoplasmic reticulum from fast muscle showed a slight diminution of ATPase-linked Ca(2+)-transport activity and a selective increase of rotenone-insensitive NADH-cytochrome c reductase activity, in addition to a greater emphasis on slow-type electrophoretic components of the structural membrane protein. 7. The significance of these results in relation to specific differentiating influences from motor nerves is discussed.

Adenosine Triphosphatases↗
PubMed1981

Increased muscle calcium. A possible cause of mitochondrial dysfunction and cellular necrosis in denervated rat skeletal muscle.

Mitochondrial preparations derived from denervated rat skeletal muscle and paired controls were characterized with respect to their ability to take up externally added Ca2+. The denervated and control muscle homogenates and mitochondrial [Ca2+] were also determined. Our data indicate that the denervated mitochondria are able to take up less Ca2+ than the controls before uncoupling occurs. This defect is associated with elevated [Ca2+] in homogenate and mitochondrial fractions in the denervated state. The causal relationship between Ca2+ overload, mitochondrial functional damage and cell necrosis is discussed.

Animals↗
PubMed1988

Induction of carbonic anhydrase III mRNA and protein by denervation of rat muscle.

Carbonic anhydrase III (CAIII) protein and mRNA amounts in fast- and slow-twitch rat muscles were examined after resection of the sciatic nerve. Striking changes occur in the fast-twitch anterior tibialis (AT) and extensor digitorum longus (EDL) muscles, where CAIII protein and mRNA are increased several-fold 16 days after denervation. The data suggest that these changes are regulated in part by changes in gene transcription and that they perhaps signal a fast-to-slow fibre type transition in these denervated muscles. AT and EDL show some differences in the effects of denervation, which are suggestive of variation in the timing of denervation-induced responses and/or the CAIII protein/mRNA turnover rates in the two muscles.

Actins↗
PubMed1990

Effect of denervation on the expression of glycogen phosphorylase in mouse skeletal muscle.

After sciatectomy of the left hind-limb of C57BL/J mice, a denervation-induced muscular atrophy ensued and was accompanied by a decrease in the specific activity of glycogen phosphorylase to approx. 25% of control values. The cofactor of phosphorylase, pyridoxal 5'-phosphate, was used as a specific label in the determination of the degradation rate of the enzyme following nerve section. After a delay of 3-4 days, phosphorylase was degraded approx, twice as rapidly in the denervated gastrocnemius (0.20 day-1) as in the control muscle (0.12 day-1). The effect of denervation on phosphorylase mRNA was measured by quantitative Northern-blot analysis using a rat skeletal-muscle phosphorylase cDNA probe. After an initial rapid decline, phosphorylase mRNA levels stabilized in denervated muscle at 50% of the value measured in the contralateral control muscle.

Animals↗
PubMed1995

Increase in ubiquitin-protein conjugates concomitant with the increase in proteolysis in rat skeletal muscle during starvation and atrophy denervation.

The rapid loss of skeletal-muscle protein during starvation and after denervation occurs primarily through increased rates of protein breakdown and activation of a non-lysosomal ATP-dependent proteolytic process. To investigate whether protein flux through the ubiquitin (Ub)-proteasome pathway is enhanced, as was suggested by related studies, we measured, using specific polyclonal antibodies, the levels of Ub-conjugated proteins in normal and atrophying muscles. The content of these critical intermediates had increased 50-250% after food deprivation in the extensor digitorum longus and soleus muscles 2 days after denervation. Like rates of proteolysis, the amount of Ub-protein conjugates and the fraction of Ub conjugated to proteins increased progressively during food deprivation and returned to normal within 1 day of refeeding. During starvation, muscles of adrenalectomized rats failed to increase protein breakdown, and they showed 50% lower levels of Ub-protein conjugates than those of starved control animals. The changes in the pools of Ub-conjugated proteins (the substrates for the 26S proteasome) thus coincided with and can account for the alterations in overall proteolysis. In this pathway, large multiubiquitinated proteins are preferentially degraded, and the Ub-protein conjugates that accumulated in atrophying muscles were of high molecular mass (> 100 kDa). When innervated and denervated gastrocnemius muscles were fractionated, a significant increase in ubiquitinated proteins was found in the myofibrillar fraction, the proteins of which are preferentially degraded on denervation, but not in the soluble fraction. Thus activation of this proteolytic pathway in atrophying muscles probably occurs initially by increasing Ub conjugation to cell proteins. The resulting accumulation of Ub-protein conjugates suggests that their degradation by the 26S proteasome complex subsequently becomes rate-limiting in these catabolic states.

Adenosine Triphosphate↗
PubMed1996

Effects of acute and chronic unilateral renal denervation on the tubuloglomerular feedback mechanism.

We recently observed a time-dependent resetting of the tubuloglomerular feedback (TGF) sensitivity to a subnormal level after acute unilateral renal denervation (aDNX). The present investigation compares the effects of aDNX with those of chronic unilateral renal denervation (cDNX), i.e one week after aDNX. All experiments were performed in anaesthetized rats prepared for micropuncture. cDNX led to increases in urine, sodium and potassium excretion in denervated kidneys, while contralateral kidneys showed reduced excretion of these parameters. GFR was increased in denervated kidneys, but unchanged on the contralateral side. TGF activity was determined by measuring the maximal stop-flow pressure response (delta Psf) and the tubular flow rate at which 50% of the maximal response occurred (turning point; TP). cDNX decreased TGF sensitivity, as indicated by an increased TP from 19.1 nL/min in sham-DNX to 26.1 nL/min. Concomitantly, TP in contralateral kidneys was significantly decreased to 15.9 nL/min, aDNX led to a greater sensitivity reduction: TP increased from 19.8 to 34.0 nL/min and contralaterally TP decreased to 14.0 nL/min. delta Psf in cDNX increased by 63% compared to sham-DNX, while on the contralateral side this was unchanged. No difference in delta Psf was found between control, DNX and contralateral kidneys in the aDNX group. In summary, these experiments show that the previously reported decrease in TGF sensitivity in aDNX kidneys still persists after one week, although less pronounced. As a result of the decreased TGF sensitivity, GFR is kept on a high level in cDNX kidneys. Contralateral kidneys show reversed resetting.

Animals↗
PubMed1999

Interferon-gamma and interleukin-12 genes are preferentially expressed during early experimental African trypanosomiasis and suppressed by denervation of the spleen.

The cross talk between the central nervous system (CNS) and the immune system includes among others, the modulation of immune responses by the autonomic nervous system. Here, we investigated the effects of a splenic denervation on cytokine induction in early experimental African trypanosomiasis. Profiles of the cytokine mRNA expression for interleukin (IL)-4, interleukin (IL)-6, interleukin (IL)-10, interleukin (IL)-12, tumour necrosis factor (TNF)-alpha, tumour necrosis factor (TNF)-beta, transforming growth factor (TGF)-beta and interferon (IFN)-gamma were examined at 4 h, 8 h and 12 h postinfection (p.i.), and in noninfected controls. Only IFN-gamma and IL-12 were significantly expressed over noninfected controls. Already at 4 h p.i. both cytokines were expressed and showed more increased levels at 12 h. Sympathetic denervation of the spleen markedly reduced the mRNA expression for both IFN-gamma and IL-12. Con A was used as a positive control and showed an enhanced mRNA expression, which was also suppressed by a splenic denervation. To demonstrate that the mRNA expression had resulted in a cytokine production, we looked for the protein level of IFN-gamma at 4 h p.i. by immunohistochemistry and found increased levels of IFN-gamma, which was also inhibited by the denervation. Sham-operated animals exhibited similar responses as the nondenervated controls. Our data present for the first time very early kinetics for a cytokine gene expression during an experimental African trypanosomiasis. Furthermore, the data suggest a regulatory role for the autonomic nervous system on cytokine responses at both the mRNA and the protein levels.

Animals↗
PubMed1999

Expression of functional alpha7 nicotinic acetylcholine receptor during mammalian muscle development and denervation.

We have studied, on the transcriptional, protein and functional level, the expression of alpha7 nicotinic acetylcholine receptors (nAChR) in the course of rat muscle development, denervation and renervation. At foetal day 13, alpha7 nAChR expression was observed in somites and developing muscles of the back, but not yet in migrating myoblasts. Two days later, concomitant with myoblast aggregation, the alpha7 isoform began to be expressed in isolated myoblasts, with the highest level of expression in the frontal zone of the migrating wave. On foetal day 18, a time when the myoblasts in the upper hindleg have fused, alpha7 nAChR expression was most prominent in the outer layer of muscle tissue. The highest level of expression was observed in the first postnatal week, when practically all muscle cells stained positively for alpha7 protein. During the following weeks, alpha7 nAChR expression slowly decreased and practically disappeared in adult hindleg muscle. Following chronic denervation of adult Soleus muscle fibres, expression of alpha7 nAChR returned within 2-4 weeks. Electrophysiological measurements showed that the alpha7 nAChR of chronically denervated soleus muscle fibres were functional and, in particular, that they could be activated by choline. The presence of the alpha7 nAChR in developing and denervated muscle suggests a role for this nicotinic receptor in neuronal pathfinding and/or endplate stabilization.

Animals↗
PubMed1996

Denervation, but not decentralization, reduces nerve growth factor content of the mesenteric artery.

In the present study we applied an improved nerve growth factor (NGF) extraction method to examine the effects of denervation and sympathetic decentralization on NGF levels in vascular tissue. Adult male Wistar Kyoto rats underwent mesenteric arterial denervation or splanchnic nerve transection. Four days after operation, animals were killed, and the mesenteric artery and coeliac-superior mesenteric ganglia were removed. The arterial adventitia was stripped from the media to measure NGF levels in nerve and smooth muscle separately. A high concentration of NGF was detected in the normal artery, 90% of which was in the adventitial layer. Surgical denervation significantly reduced the NGF levels in the artery and ganglia by 78 and 71%, respectively. However, within the artery the level of NGF was reduced in the adventitia but not in the media. Thus, the large reduction of NGF content resulted from the loss of nerve plexus from the artery. In contrast, decentralization did not alter the NGF content in the artery, in either the adventitia or media. Our results are in marked contrast to previous studies reporting elevated levels of NGF following denervation. This discrepancy is explained by the ability of our new procedure to extract much greater amounts of NGF from the tissue.

Animals↗
PubMed2000

GluR1 glutamate receptor subunit is regulated differentially in the primate basal ganglia following nigrostriatal dopamine denervation.

Nigrostriatal dopaminergic denervation is associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. The excitatory neurotransmitter glutamate mediates neural signaling at crucial points of this circuitry, and glutamate receptors are differentially distributed in the basal ganglia. Available evidence suggests that the glutamatergic corticostriatal and subthalamofugal pathways become overactive after nigrostriatal dopamine depletion. In this study, we have analyzed the regulation of the GluR1 subunit of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in the basal ganglia of primates following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine denervation. The dopamine denervation resulted in distinct alterations in GluR1 distribution: (1) GluR1 protein expression was markedly increased in caudate and putamen, and this was most pronounced in the striosomes; (2) GluR1 protein was altered minimally in subthalamic nucleus; (3) expression of GluR1 was down-regulated in the globus pallidus by 63% and in the substantia nigra by 57%. The down-regulation of GluR1 expression in the output nuclei of the basal ganglia, the internal segment of the globus pallidus and the substantia nigra pars reticulata, may be a compensation for the overactive glutamatergic input from subthalamic nucleus, which arises after striatal dopamine denervation. Our results indicate that the glutamatergic system undergoes regulatory changes in response to altered basal ganglia activity in a primate model of Parkinson's disease. Targeted manipulation of the glutamatergic system may be a viable approach to the symptomatic treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Efficacy of the "baby-sitter" procedure after prolonged denervation.

This study was undertaken to evaluate whether 40 percent of the hypoglossal nerve, which showed optimal efficacy in restoring orbicularis oculi muscle (OOM) function after different percentages of partial neurectomy in a previous study would be effective after prolonged denervation time. Twenty Sprague-Dawley rats were divided into four groups. In first-stage surgery the left facial nerve of all animals was transected at the level of the stylomastoid foramen and main zygomatic branch. Group A (controls) consisted of animals with only left facial nerves transected (no repair). In Groups B, C, and D the facial nerve was transected and the facial musculature was denervated for a period of 4, 8, and 12 weeks respectively. During a second-stage procedure, a 40 percent neurectomy was performed on the hypoglossal nerve. Subsequently, a nerve transfer was performed by coaptations of a saphenous nerve graft to the neurectomized hypoglossal nerve and the main zygomatic branch of the facial nerve that innervated the OOM. Behavioral analysis of blink reflex, electrophysiology, and axon and motor end-plate counts in Groups B, C, and D showed superior results compared to Group A. There was no statistically significant difference observed among Groups B, C, and D (p > 0.05). Despite the diminished number of axons in the zygomatic branch and motor end-plates in the orbicularis oculi muscle after 12 weeks of denervation, there was still sufficient muscle target recovery to effect some eye closure in all groups except the controls. This study demonstrated in this model that the 40 percent partial neurectomy of the XII to VII component of the "baby-sitter" procedure was effective even after prolonged denervation.

Animals↗
PubMed1996

[Ultrasound follow-up after experimental muscle denervation].

AIM: To describe sonographical results following acute, experimental muscle denervation. METHOD: Denervation of the supraspinatus and infraspinatus muscles was performed in 28 New Zealand white rabbits by segmental resection of the suprascapular nerve. The changes in the sonographic image of the muscles were follow up and documented at short intervals over 2 months. RESULTS: The sonographically detectable changes following denervation follow a definite pattern. In addition to the reduction in muscle diameter, sonographical signs of denervation include an increase of echodensity and an inhomogeneity of echotexture that appeared on day 14 after injury and became more prominent at larger intervals. CONCLUSION: Sonography may play a supportive role in the diagnosis and follow-up of neurogenic muscle atrophy.

Animals↗
PubMed1975

Synthesis of acetylcholine receptor by denervated rat diaphragm muscle.

Acetylcholine receptor was purified by affinity chromatography from denervated rat hemidiaphragms that had been incubated in organ culture for 24 hr in medium containing [35-S] methionine. Radioactive acetylcholine receptor was identified in purified preparations by zone sedimentation in a sucrose gradient, by isoelectric focusing, and by precipitation with an antiserum to the acetylcholine receptor from electric eel. When innervated and denervated hemidiaphragms were incubated with [35-S] methionine in organ culture, and the acetylcholine receptors from each were purified separately, only the preparation from denervated muscles contained radioactive receptor as determined by zone sedimentation. We conclude that newly synthesized receptor is accumulated as a result of muscle denervation.

Acetylcholine↗
PubMed1980

Denervation increases turnover rate of junctional acetylcholine receptors.

The turnover rates of junctional acetylcholine receptors were measured in innervated and denervated mouse sternomastoid neuromuscular junctions by 125I-labeled alpha-bungarotoxin binding. First, we determined that the density of labeled toxin initially bound to the neuromuscular junction was essentially unchanged up to 16 days after denervation. Innervated muscles and muscles that had been denervated 8 days previously were then saturated with labeled toxin, and the specific label at the endplate regions was compared by gamma counting 7 days later. At that time, the residual junctional label seen in innervated muscle was 3.2 times greater than in denervated muscle. Electron microscope autoradiography further showed that, after saturation with unlabeled toxin, new binding sites appeared rapidly at the specialized receptive region of the postsynaptic membrane with an apparent half-time of turnover of 2-3 days. At innervated junctions, the half-time of turnover was about 10 days. These data show that the mechanisms that control receptor turnover rates are different from those that control high-density receptor clustering. The slow turnover rate of junctional receptors appears to be more directly dependent on the presence of the nerve than is the clustering of junctional receptors.

Acetylcholine↗