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PubMed1984

Supersensitivity of the rabbit iris sphincter muscle induced by trigeminal denervation: the role of substance P.

The rabbit left ophthalmic nerve (first branch of the left trigeminal nerve) was cut at the intracranial, peripheral side of the trigeminal ganglion and the effects of denervation were examined using iris sphincter muscle preparations isolated from the left and right eye, as denervated and control innervated preparations, respectively. Electrical transmural stimulation produced a substance P-operated contraction, in addition to a cholinergic one, in the preparation isolated from the right control eye. The former response was abolished in the preparation isolated from the left denervated eye, thereby indicating that the trigeminal, substance P nerve ipsilaterally innervates the iris sphincter muscle. Exogenously applied carbachol and substance P produced concentration-dependent contractions in preparations isolated from either eye. Supersensitivity characterized by a decrease in median effective concentration (EC50) values and an increase in maximal response was observed in the responses to both agents of the left denervated preparation. Such supersensitivity developed slowly after trigeminal denervation and 3 weeks was required for full development. Exogenously applied KCl produced substance P-operated and direct muscle contractions in the right control preparations. In the left denervated preparations, the substance P-operated contraction was either markedly attenuated or abolished, while the direct muscle-related contraction was enhanced after trigeminal denervation. The length of the left denervated preparation was longer than that of the right control preparation, and the resting tensions required to produce maximal carbachol contraction shifted to lower values. These physical changes of the iris sphincter muscle developed within 5 days after trigeminal denervation. In the non-denervated preparation treated with capsaicin in vitro, electrical transmural stimulation and KCl failed to produce the substance P-related contraction. However, supersensitivity to neither exogenously applied substance P, carbachol and KCl nor physical changes were observed in the capsaicin-treated preparation. These results suggest that trigeminal, substance P-related nerves tonically and ipsilaterally innervate the rabbit iris sphincter muscle and that the denervation results in non-specific supersensitivity. These findings are essentially the same as those observed in various types of smooth muscles after autonomic denervation.

Action Potentials↗
PubMed1984

Interaction of inactivity and nerve breakdown products in the origin of acute denervation changes in rat skeletal muscle.

The action of nerve breakdown products on innervated fibres of soleus and extensor digitorum longus muscles was investigated with the following procedures: partial denervation, sensory or sympathetic denervation, section of a previously transplanted foreign nerve. Each procedure was performed either in isolation or combined with chronic muscle inactivity obtained by blocking impulse conduction along the sciatic nerve. Silastic cuffs containing tetrodotoxin (TTX) and sodium chloride were utilized for the block. Partial denervation induced extrajunctional sensitivity to acetylcholine (ACh) and resistance to tetrodotoxin not only in the denervated but also in the innervated fibres. The effects in the innervated fibres were equal in magnitude to those in the denervated fibres, provided they were paralysed. The onset of the membrane changes was synchronous in the two classes of fibres and their amount correlated with the extent of partial denervation. If the innervated fibres were normally active, the membrane changes were still detectable, but considerably smaller than in the denervated fibres. Sensory denervation (removal of dorsal root ganglia L4 and L5) was followed by the development of moderate ACh supersensitivity and TTX resistance in chronically paralysed muscles. Furthermore, section of radicular nerves (total denervation, i.e. efferent plus afferent) induced larger membrane changes than those observed following section of ventral roots alone (efferent denervation). Sympathetic denervation was ineffective even when associated with chronic muscle paralysis. Section of a previously transplanted mixed nerve (superficial fibular) was ineffective if the soleus muscle was normally active, while it induced marked extrajunctional ACh sensitivity and TTX resistance when combined with chronic paralysis of the muscle. Section of a transplanted sensory nerve (sural) also induced extrajunctional membrane changes in paralysed soleus muscles, but their magnitude was much smaller than after section of mixed nerves. We conclude that products of nerve destruction, especially those of motor axons, induce membrane changes of striking magnitude when potentiated by muscle inactivity. Such an action may also explain the greater efficacy of denervation vs. pure inactivity, at least at early times after their onset.

Acetylcholine↗
PubMed2002

Tetrodotoxin prevents motor unit enlargement after partial denervation in rat hindlimb muscles.

Findings that increased neuromuscular activity significantly reduced sprouting in partially denervated muscles prompted this present study to determine if the converse is true, namely that reduced activity promotes sprouting and motor unit (MU) enlargement. Partial denervation of rat hindlimb muscles by either the L4 or L5 spinal root avulsion resulted in extensive denervation (> 80 %) in tibialis anterior (TA) and medial gastrocnemius (MG) muscles, and moderate denervation (~50 %) in soleus (SOL) and plantaris (PL) muscles. The partially denervated muscles were then subjected to a 4 week programme of normal caged activity or TTX-induced neuromuscular inactivity. At 1 month, measurement of MU enlargement and quantification of sprouting were evaluated, respectively, by electrophysiological and histochemical means. Analysis of electrophysiological data showed that MU forces were significantly increased in both extensively and moderately denervated muscles 1 month after partial denervation and normal cage activity and that neuromuscular activity blockade by TTX completely abolished the MU enlargement in these partially denervated muscles. Histochemical analysis of sprouting revealed that the number of sprouts was significantly increased after partial denervation and normal cage activity, particularly after extensive denervation. TTX-induced neuromuscular inactivity dramatically reduced the number of sprouts and increased the number of free endplates in the extensively but not the moderately denervated muscles. These data demonstrate that a reduction in neuromuscular activity mediated by presynaptic blockade of neural action potentials reduces MU enlargement in partially denervated muscles by reducing axonal sprouting.

Anesthetics, Local↗
PubMed2005

Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle.

Apoptosis has been implicated in the regulation of denervation-induced muscle atrophy. However, the activation of apoptotic signal transduction during muscle denervation has not been fully elucidated. The present study examined the apoptotic responses to denervation in rat gastrocnemius muscle. Following 14 days of denervation, the extent of apoptotic DNA fragmentation as determined by a cytosolic nucleosome ELISA was increased by 100% in the gastrocnemius muscle. RT-PCR and immunoblot analyses indicated that Bax was dramatically upregulated while Bcl-2 was modestly increased; however, the Bax/Bcl-2 ratio was significantly increased in denervated muscles relative to control muscles. Analyses of ELISA and immunoblots from mitochondria-free cytosol extracts showed a significant increase in mitochondria-associated apoptotic factors, including cytochrome c, Smac/DIABLO and apoptosis-inducing factor (AIF). In addition to the upregulation of caspase-3 and -9 mRNA, pro-/cleaved caspase protein and proteolytic activity levels, the X-linked inhibitor of apoptosis (XIAP) protein level was downregulated. The cleaved product of poly(ADP-ribose) polymerase (PARP) was detected in muscle samples following denervation. Although we did not find a difference in the inhibitor of DNA binding/differentiation-2 (Id2) and c-Myc protein contents between the denervated and control muscles, the protein content of tumour suppressor p53 was significantly increased in both the nuclear and the cytosolic fractions with denervation. Moreover, denervation increased the protein content of HSP70, whereas the MnSOD (a mitochondrial isoform of superoxide dismutase) protein content was diminished, which indicated that denervation might have induced cellular and/or oxidative stress. Our data show that mitochondria-associated apoptotic signalling is upregulated during muscle denervation. We interpret these findings to indicate that apoptosis has a physiologically important role in regulating denervation-induced muscle atrophy.

Animals↗
PubMed1988

Responses to coronary artery occlusion in conscious dogs with selective cardiac denervation.

The extent to which cardiac denervation alters responses to myocardial ischemia remains controversial. This study compared responses to 24-h coronary artery occlusion (CAO) on measurements of wall thickness (ultrasonic crystals), regional myocardial blood flow (microspheres), and infarct size (triphenyltetrazolium chloride technique) in three groups of conscious dogs with 1) selective posterior left ventricular (LV) wall denervation, 2) selective ventricular denervation, or in 3) intact dogs. After CAO, hemodynamic changes were not different among the three groups. Wall thickening in the ischemic zone became akinetic or paradoxical early after CAO and did not recover in any group over the 24-h monitoring period. Blood flow in the area at risk fell similarly in all groups. Infarct size, as a percentage of the area at risk, was 45 +/- 7% in intact, 48 +/- 6% in posterior LV wall-denervated, and 48 +/- 8% in ventricular-denervated group. There was, however, a lower (P less than 0.05) frequency of arrhythmic beats per minute after 3 h of CAO in the ventricular-denervated group (3.2 +/- 1.4) compared with the intact (11.3 +/- 4.1) or posterior wall-denervated (12.6 +/- 3.2) group. An additional group of ventricular-denervated dogs was studied to determine the effects of sequential, brief 2-min CAO at 2, 4, and 8 wk after denervation. Responses of regional wall thickening to CAO were not affected significantly even after 8 wk following ventricular denervation. Thus, in conscious dogs, neither selective ventricular denervation nor selective denervation of the posterior LV wall improved collateral blood flow, affected regional function favorably, or reduced infarct size after CAO.

Animals↗
PubMed1975

Effects of acute unilateral renal denervation in the rat.

Studies were undertaken to characterize the renal responses to acute unilateral renal denervation and the mechanisms involved in these responses. Denervation was produced in anesthetized nondiuretic rats by application of phenol to the left renal artery. Studies were also performed in sham-denervated nondiuretic rats. Whole kidney and individual nephron studies were performed before and after denervation or sham denervation. Denervation increased urine volume from the left kidney to about twice its control value (P less than 0.001) and increased urinary sodium excretion from 332 neq min minus -1 to 1,887 neq min minus -1 (P less than 0.001). Glomerular filtration rate (GFR) and renal plasma flow (RPF) remained unchanged in both kidneys after the procedure. The innervated right kidney showed no changes in urine volume or in sodium excretion. After denervation, late proximal ratio of tubular fluid inulin concentration to that of plasma [(F/P)In] decreased from 2.23 to 1.50 (P less than 0.001) while single nephron GFR remained unchanged. Absolute reabsorption decreased from 16.5 to 9.9 n. min minus -1 (P less than 0.001). (F/P)In ratios were also decreased in early distal (from 6.21 to 3.18, P less 0.001) and late distal convolutions (from 16.41 to 8.33, P less than 0.001) during the experimental period. (F/P)Na ratios remained unchanged in the early distal convolutions, but increased from 0.18 to 0.38 (P less than 0.01) in late distal convolutions after denervation. Absolute Na reabsorption after denervation increased in the loop of Henle, distal convolution, and collecting ducts. Any changes in intrarenal hydrostatic pressures after denervation were always small. There were no changes in GFR, RPF, urine volume, urinary sodium excretion, or late proximal (F/P)In after sham denervation. We conclude that the diuresis and natriuresis seen after acute renal denervation were caused by a marked depression of sodium and water reabsorption in the proximal tubule with partial compensation in more distal nephron segments. These responses appeared to be unrelated to systemic or intrarenal hemodynamic changes. The results demonstrate an effect of the renal nerves on proximal tubular function.

Aminohippuric Acids↗
PubMed2004

Muscle-nerve-muscle neurotization for the reinnervation of denervated somatic muscle.

Muscle-Nerve-Muscle (MNM) is the reinnervation of a denervated (recipient) muscle via a nerve graft inserted into the belly of an innervated (donor) muscle. MNM is studied for the reinnervation of intrinsic denervated somatic skeletal muscle by evaluating both restored muscle contractile ability and innervation state. In a rat model, muscle function is tested following MNM neurotization from an innervated (donor), extensor digitorum longus muscle to a denervated (recipient), peroneus digit quinti (PDQ) muscle. PDQ muscle cross-sections labeled for neural cell adhesion molecule protein (NCAM), a marker for fiber denervation. MNM neurotization results in the recovery of PDQ muscle force generating capacity (58% of Normal-control) and a significantly lower percentage of residual muscle fiber denervation (38% denervated) compared with the Denervated-control (79% denervated) group. MNM neurotization reinnervates 62% of the previously denervated muscle fibers in the PDQ muscle. No decrement in force capacity is observed in the donor EDL muscle. Nerve grafting for MNM neurotization may restore modest contractile function to denervated muscle and reinnervate relatively more denervated muscle fibers than the Denervated-control.

Anatomy, Cross-Sectional↗
PubMed1987

Glucose and amino acid uptake by exercising muscles in vivo: effect of insulin, fiber population, and denervation.

The first series of experiments was performed on control rats. The animals were injected iv with trace amounts of 2-deoxy-D-[1-14C]glucose [( 14C]DG) or alpha-[1-14C] aminoisobutyric acid with or without 0.1 U insulin/rat, and calf muscles of the right hindlimb were electrically stimulated to induce 1 contraction/sec. The exercise was discontinued 25 min after the injection, and cellular uptakes of DG or aminoisobutyric acid by soleus, plantaris, and gastrocnemius muscles in disintegrations per min/mg dry tissue weight were determined. The results of these experiments demonstrated that basal, insulin-induced, and exercise-induced uptakes of glucose and amino acids by muscles are dependent on muscle fiber population, and the stimulatory effects of exercise and insulin on soleus and plantaris muscles, but not gastrocnemius muscles, are synergistic rather than merely additive when both stimuli act together. The second series of experiments was performed in the same manner as the first series, except that the right hindlimb of each rat was denervated 3 days before the experiment. Cellular DG uptakes were determined in soleus, plantaris, and gastrocnemius muscles of the left (sham) hindlimb, which was always resting, and in corresponding muscles of the right (denervated) limb, which was either resting or exercising. In the resting state, the denervated soleus muscle had normal basal DG uptake, but, unlike sham soleus muscle, did not respond to insulin stimulation. Denervated plantaris and gastrocnemius muscles exhibited 264% and 150% elevations in basal glucose uptake, respectively, compared with corresponding sham muscles. The latter two denervated muscles did respond to insulin, but the hormone-induced increments in DG uptake were 68% and 45%, respectively, lower than in corresponding contralateral sham muscles. Under basal conditions, exercise had no effect on DG uptake by the denervated soleus muscle, but increased uptake by denervated plantaris and gastrocnemius muscles 207% and 778%, respectively. Stimulation of exercising denervated muscles with exogenous insulin did not increase DG uptake by any muscle above the level observed with exercise alone. The results show that manifestations of insulin resistance in denervated muscles depend on muscle fiber population; denervated muscles, which still retain some ability to respond to insulin, increase DG uptake during exercise, whereas such an increase is absent in denervated muscles completely unresponsive to insulin; and exercise does not improve or restore the ability of denervated muscles to respond to insulin.

Aminoisobutyric Acids↗
PubMed2001

Increased neuromuscular activity reduces sprouting in partially denervated muscles.

The effects of increasing neural activity on sprouting remain unclear and controversial. In a rat model of partial denervation of skeletal muscles, we investigated the effect of neuromuscular activity on sprouting. Rat hindlimb muscles were partially denervated by avulsion of either L4 or L5 spinal root. Immediately after partial denervation, the rats were divided into three groups: (1) normal caged activity, (2) running exercise on wheels, 8 hr daily, and (3) functional electrical stimulation (FES) of sciatic nerves, 20 Hz for 8 hr daily. At 1 month, muscle unit (MU) enlargement was quantitated electrophysiologically and histochemically. MU twitch force was increased by four- to fivefold by partial denervation in extensively denervated tibialis anterior (TA) and medial gastrocnemius (MG) and by approximately twofold in moderately denervated plantaris (PL) and soleus (SOL). For the extensively denervated TA and MG muscles, MU enlargement, measured electrophysiologically, declined significantly after an average of 1757 +/- 310 m/d running exercise and daily FES for 1 month. The detrimental effects on MU enlargement were much less but significant in the moderately denervated PL and did not reach statistical significance in the moderately denervated SOL muscle. Histochemical evaluation of sprouting showed a reduction in the number of sprouts in the extensively denervated TA muscle, but not the moderately denervated PL and SOL muscles, by increased neuromuscular activity. Thus, increased neuromuscular activity is detrimental primarily in muscles that are extensively denervated, and the MUs are smaller than under conditions in which the muscles experience normal physiological levels of activation.

Animals↗
PubMed1986

Overwork effect on partially denervated rat soleus muscle.

The purpose of this study was to assess the effect of overwork induced by synergistic tenotomy on the muscle weight (MW) and isometric tetanic tension (Po) of the partially denervated rat soleus muscle. Forty-nine young adult male Sprague-Dawley rats were divided into six groups (n = 5 to 9): normal control (N), normal synergistically tenotomized (N-ST), L4 denervated control (L4), L4 denervated synergistically tenotomized (L4-ST), L5 denervated control (L5), and L5 denervated synergistically tenotomized (L5-ST). Bilateral L4 or L5 root transections produced partial denervation. To yield soleus muscle overwork the gastrocnemius and plantaris muscles were bilaterally tenotomized in all ST groups at the time of denervation. The soleus MW and Po were examined seven days following denervation and tenotomy. Compared to their respective controls, there was increased MW in the N-ST (43.5%, p less than 0.01) and the L4-ST (38.6% p less than 0.01) groups. The L5-ST group showed no significant change in MW compared to the L5 group. Tetanic tension was increased only in the N-ST group. The L4-ST and L5-ST groups did not show any change in Po compared to their respective controls. Despite marked denervation, the L5 group did not show any atrophy as compared to the N group, suggesting passive stretch of the denervated muscle fibers, hypertrophy of the innervated muscle fibers and peripheral sprouting prevented the loss of MW due to denervation. Overwork in this markedly denervated group could not produce any increase in the MW or Po.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Denervation-induced formation of adrenergic synapses in the superior cervical sympathetic ganglion of the rat and the enhancement of this effect by postganglionic axotomy.

A study has been made at the ultrastructural level of the effects of denervation and axotomy on the synapse population of the rat superior cervical ganglion. Superior cervical ganglia were subjected unilaterally to acute (survival, 48 h) or chronic preganglionic denervation (survival, 41-189 days) by cutting the cervical sympathetic trunk; in chronic denervation experiments regeneration of preganglionic nerve fibres into the ganglion was prevented by suturing the proximal (caudal) stump of the trunk into the sternomastoid muscle. In some chronic experiments the preganglionic denervation was combined with simultaneous crush axotomy of the major postganglionic branches of the ganglion, the internal and external carotid nerves (axotomized-denervated ganglia). Control observations were made in contralateral ganglia and in ganglia from normal rats. After excision and before fixation, ganglia were incubated briefly in the presence of 5-hydroxydopamine to label adrenergic vesicles. Chronic denervation caused a statistically significant 12% decrease from control values in the cytoplasmic minor axes of the principal ganglionic neurones; axotomy combined with chronic denervation led to a 6% increase in this dimension, which was not statistically significant. The minor axes of the neuronal nuclei did not differ significantly from control values in either type of experiment. Axotomy combined with denervation led however to a 36% decrease in the incidence of nucleated neuronal profiles per unit area of ganglion. Counts of synapses were made in the various classes of ganglia and their incidence was expressed per nucleated neuronal profile, to permit comparison within and between experiments. Normal and control ganglia showed a high incidence of synapses of preganglionic cholinergic type. Nerve terminal profiles and synapses containing small dense-cored vesicles, as distinct from the efferent synapses of small granule-containing cells, were not found to be present on the principal neurones or their dendrites in these ganglia, despite strong 5-hydroxydopamine labelling of small dense-cored vesicles within cell bodies and dendrites. After acute denervation extremely few residual synapses were found in the ganglion, in areas remote from small granule-containing cells, and these residual synapses were of the cholinergic type. Acute denervation led to the appearance of vacated or isolated postsynaptic densities; such densities were also found, but were fewer in number, in chronically denervated and axotomized-denervated ganglia.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Effects of surgical sympathetic denervation on myo-inositol trisphosphate production and contraction in the dilator and sphincter smooth muscles of the rabbit iris: evidence for interaction between the cyclic AMP and calcium signaling systems.

The effects of norepinephrine (NE), carbachol (CCh), NaF, 3-isobutyl-1-methylxanthine (IBMX), and high K+ concentration (80 mM) depolarization on inositol trisphosphate (IP3) accumulation, cyclic AMP (cAMP) formation, and contraction were investigated in the dilator and sphincter smooth muscles of the sympathetically denervated as well as the normal rabbit eye. (a) In the denervated dilator muscle, NE-stimulated IP3 production and contraction are enhanced. (b) In the sphincter muscle of rabbits that have undergone sympathetic denervation. CCh-stimulated IP3 production and contraction are attenuated. (c) The increase in tension by a maximal effective dose of NaF (209 mM) in the dilator was 12.5 and 18 mg of tension/mg wet weight in normal and denervated tissue, respectively, and in the sphincter was 33.8 and 15.2 mg of tension/mg wet weight in normal and denervated tissue, respectively. NaF had no effect on cAMP formation. (d) Addition of NE had no effect on cAMP formation in both the normal and denervated dilator, whereas basal and IBMX-induced cAMP formation increased. in the denervated sphincter over that of the normal tissue by 15 and 60%, respectively. (e) Isoproterenol (5 microM) increased cAMP formation in the normal and denervated sphincter by 47 and 91%, respectively. (f) Whereas CCh inhibits cAMP formation in the normal sphincter, it lost its inhibitory effect in the sphincter with denervation. (g) IBMX (0.1 mM) attenuated the CCh-stimulated IP3 production and contraction of the sphincter by approximately 30% of their respective controls. (h) High K+ concentration depolarization attenuated contraction in both dilator and sphincter muscles with denervation. These observations suggest that an increase in the level of cAMP in the iris sphincter due to sympathetic denervation could lead to inhibition of phospholipase C (or other target sites, such as phosphorylation of the muscarinic receptor, Gp protein itself, myosin light chain kinase, or the IP3 receptor), IP3 production, and contraction. In conclusion, we suggest that the supersensitivity and subsensitivity observed after surgical sympathetic denervation of the iris dilator and sphincter muscles, respectively, are caused by alterations in the efficiency of coupling, probably through the Gp proteins, between their respective receptors and the breakdown of polyphosphoinositides by phospholipase C. In addition, we propose that the sympathetic nervous system can regulate, through alterations in cAMP levels, the muscarinic stimulation of IP3 accumulation and contraction in the iris sphincter. These findings add further support to the hypothesis that there are reciprocal interactions between the cAMP and IP3-Ca2+ signaling systems and the contractile response in the iris smooth muscle.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Electron microscopic study of long-term denervated rat skeletal muscle.

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.

Animals↗
PubMed2002

A specific force deficit exists in skeletal muscle after partial denervation.

Skeletal muscle demonstrates a specific force deficit after repair of injured peripheral nerves, microneurovascular muscle transfer, and normal aging. Because atrophy cannot account for deficits in specific force, other, unknown, mechanisms are responsible for the resulting muscle contractile dysfunction under these circumstances. We tested the hypothesis that a subpopulation of denervated fibers is partially or completely responsible for the specific force deficit after partial denervation of the rat extensor digitorum longus muscle (EDL). Adult Fisher rats underwent either sham exposure or partial transection of 80% of the cross-sectional area of the left deep peroneal nerve. After a 2-week recovery period, maximum isometric force (F(0)) was measured in situ and maximum specific force (sF(0)) was calculated for EDL from both control (n = 8) and partial denervation (n = 7) groups. Innervated fiber cross-sectional area (CSA(inn)) was measured directly from whole EDL cross sections after immunohistochemical labeling for neural cell adhesion molecule (NCAM), a marker of muscle fiber denervation. A corrected specific force value (sF(0-inn)) was calculated by normalizing F(0) to CSA(inn). Partial skeletal muscle denervation resulted in significant reductions in muscle mass, F(0), and sF(0). The percentage of muscle fibers expressing NCAM in the extrajunctional sarcolemma increased from 1.0 +/- 0.8% in control to 49 +/- 15% in partially denervated EDL muscles. A 62.7% deficit in EDL specific force was observed after partial denervation. Denervated muscle fibers accounted for 59.3% of this deficit, but sF(0-inn) still differed significantly between control and partially denervated muscles, with a 25.5% difference between groups. In partially denervated muscles, the specific force deficit is partially but not fully explained by a subpopulation of noncontractile, denervated fibers.

Animals↗
PubMed1999

A regenerative change during muscle adaptation to denervation in rats.

The purpose of this study is to examine the cellular and molecular events coincident with muscle denervation, especially the regenerative changes seen following muscle denervation, the role of satellite cells in this process, and the possibility of apoptotic degeneration of myonuclei as a mechanism of myonuclei loss during muscle denervation atrophy. Myosin heavy chain (MHC) isoform expression during muscle denervation was examined using pyrophosphate acrylamide gel electrophoresis and immunohistochemistry. DNA fragmentation (apoptosis) in myonuclei of denervated fibers was investigated using agarose gel electrophoresis, the TUNEL technique and ELISA for cytoplasmic histone-associated DNA fragmentation. Immunohistochemistry for MyoD and BrdU was also performed. Following muscle denervation, embryonic MHC, which is not expressed in adult healthy muscles, was expressed in some denervated fibers as well as in small activated satellite cells; maximal expression was observed 2 to 3 weeks after denervation. Activation and proliferation of satellite cells were observed, while few typical regenerating fibers were identified. It is speculated that most activated satellite cells fused to the denervated maternal fibers in order to repair them instead of fusing to each other to form new fibers as a mechanism that compensates for the atrophic changes after denervation. Although DNA ladder formation was not observed with agarose gel electrophoresis, DNA fragmentation was detected by the TUNEL technique and ELISA, suggesting that apoptotic degeneration contributes to the loss of myonuclei associated with denervation atrophy.

Animals↗
PubMed1994

Experimental study of the pathogenesis of acute acalculous cholecystitis: role of autonomic denervation.

This study was undertaken to elucidate the role of autonomic denervation in the pathogenesis of acute acalculous cholecystitis. In Experiment I, the gallbladder was denervated by performing either celiac neurotomy (sympathetic denervation) or truncal vagotomy (parasympathetic denervation), or both, in dogs. In Experiment II, 45-min ischemia and 90-min reperfusion of the gallbladder with or without autonomic denervation were performed by simultaneously occluding the middle hepatic artery and superior mesenteric vein. Celiac neurotomy, and truncal vagotomy, or both, did not cause cholecystitis. Sympathetic denervation, however, decreased the amount of mucin in the gallbladder mucosa and parasympathetic denervation caused reduction of the tissue blood flow, as well as the accumulation of lipid peroxide and xanthine oxidase in the gallbladder mucosa. These changes were most remarkable 1-2 weeks after denervation and were alleviated 4 weeks after denervation. Ischemia-reperfusion 2 weeks after denervation caused more severe cholecystitis than ischemia-reperfusion alone. The most severe inflammation developed in animals that received both celiac neurotomy and truncal vagotomy. These results suggest that autonomic denervation alone does not induce acute cholecystitis, but that it plays an important role in the progression of the inflammatory process in ischemia-reperfusion injury.

Acute Disease↗
PubMed1986

Difference in the ability of neonatal and adult denervated muscle to accumulate acetylcholinesterase at the old sites of innervation.

In adult rat sternocleidomastoid muscle, AChE is concentrated in the region rich in motor end-plates (MEP). All major AChE forms, "16 S," "10 S," and "4 S," are accumulated at high levels, and not only "16 S" AChE. After denervation, muscle AChE decreases; 2 weeks after denervation, low levels (20-40% of control) are reached for all forms. During the following weeks, a slow but steady increase in "10 S" and "16 S" AChE occurs in the denervated muscle. At this stage, all forms are again observed to be highly concentrated in the region containing the old sites of innervation. Thus, in adult rat muscle the structures able to accumulate "16 S," "10 S," and "4 S" AChE in the MEP-rich regions remain several months after denervation. In normal young rat sternocleidomastoid muscle at birth, all AChE forms are already accumulated in the MEP-rich region. After denervation at birth, the denervated muscle loses its ability to keep a high concentration of "4 S," "10 S," and "16 S" AChE in the old MEP-rich region. All AChE forms are still present 1 month after denervation, but they are decreased and diffusedly distributed over the whole length of the muscle. In particular, "16 S" AChE is detected in the same proportion (10-15%) all along the denervated muscle. Thus, the diffuse distribution of AChE, and especially "16 S" AChE, after neonatal denervation, contrasts with the maintained accumulation observed in adult denervated muscle. It seems that denervation of young muscle results in a specific loss of the muscle ability to concentrate high levels of all AChE forms at the old sites of innervation.

Acetylcholinesterase↗
PubMed1983

Systemic and regional haemodynamic effects of renal denervation in spontaneously hypertensive rats.

Systemic and regional haemodynamic effects of renal denervation were evaluated in adult (six-month-old) male spontaneously hypertensive rats (SHR) using the Fick procedure and electromagnetic flowmetry technique. Renal denervation (bilateral, 10% phenol in ethanol), performed five to eight days before the experiment, resulted in a significant decrease (-12%) in arterial pressure in conscious SHR (denervated = 182 +/- 4 versus sham = 207 +/- 8 mmHg, P less than 0.05) that was associated with a reduction in total peripheral resistance (TPR: denervated = 1.83 +/- 0.19 versus sham = 2.78 +/- 0.29 mmHg/ml/min, P less than 0.05) and an increase in cardiac output (denervated = 106 +/- 10 versus sham = 80 +/- 9 ml/min, P less than 0.05). Heart rate was not different between the two groups. Renal, hindquarter and superior mesenteric blood flows, determined under pentobarbital anaesthesia, of denervated SHR were not significantly different from sham values. Renal vascular resistance (mmHg/ml/min) was substantially reduced (-39%) in the denervated SHR (denervated = 25.1 +/- 1.86 versus sham = 41.1 +/- 3.48, P less than 0.01), but vascular resistances in the hindquarter and superior mesenteric beds were not reduced significantly. In this preparation TPR was reduced 32% in denervated SHR. The data demonstrate that renal denervation in adult SHR proves an antihypertensive vasodilator-like effect related to a decrease in TPR with increased cardiac output. The reduction in renal vascular resistance in denervated SHR may produce a major contribution to decreased TPR. Other beds may also contribute to the decrease in TPR, although to a lesser extent, since the decrease in TPR cannot be fully accounted for by decreased renal vascular resistance.

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