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PubMed1995

Up-regulation of ferritin heavy chain mRNA expression in the rat skeletal muscle after denervation: detected by means of differential display.

The differential display method was applied to identify gene expression, which is especially up-regulated in denervated skeletal muscle. Total RNA from normal and denervated rat facial muscles (muscles zygomaticus, levator nasolabialis and caninus) was isolated, amplified by polymerase chain reaction (PCR) using certain primers and separated by electrophoresis on a polyacrylamide gel. PCR products, the amounts of which were significantly higher in the operated side than in the control side, were cut out from the gel and sequenced. One of the cDNA fragments obtained in the present study showed 100% identity in nucleotide sequence to the rat ferritin heavy chain (FHC) mRNA. Northern blot analysis and in situ hybridization histochemistry confirmed that FHC mRNA expression was up-regulated after denervation and was distributed throughout whole muscle cell bodies. The biological damage attributed to superoxide and hydrogen peroxide is dependent on the presence of intracellular free iron. Intracellularly, most of the iron that is not metabolized is sequestered in ferritin as a crystalline core of ferric irons (Fe3+). These findings suggest that alterations in the ferritin subunit composition after denervation play an important role in iron metabolism in skeletal muscle cells, resulting in restriction of the biological tissue damage caused by reactive oxygen species.

Animals↗
PubMed1990

Increases in mRNA for cytoskeletal proteins in the denervated neuropil of the dentate gyrus: an in situ hybridization study using riboprobes for beta-actin and beta-tubulin.

Following destruction of entorhinal cortical (EC) input to the dentate gyrus there is an increase in protein synthesis within the denervated dendritic laminae. The present study utilized in situ hybridization to determine whether there were increases in the messenger RNAs (mRNAs) for beta-actin and beta-tubulin within the denervated neuropil of the dentate gyrus during the time of increased protein synthesis. Animals were prepared for in situ hybridization 2-21 days after a unilateral lesion of the EC. Brain sections were hybridized with either 3H or 35S-labeled riboprobes prepared from chick beta-actin and chick beta-tubulin mRNA. Analysis of light microscopic autoradiograms revealed increases in the mRNAs for beta-actin and beta-tubulin within the denervated neuropil between 6 and 8 days postlesion when compared to the intact dentate gyrus of the contralateral side. Labeling over the granule cell body layer was comparable on the two sides for both probes. Increases in both mRNAs were also observed in the scar tissue at the lesion site. These results suggest that local protein synthesis within the denervated neuropil of the dentate gyrus involves, in part, an increase in the production of actin and tubulin.

Actins↗
PubMedDate not supplied

Effect of chronic cholinergic denervation on the m1 muscarinic receptor mechanism.

The first three parts of the transduction mechanism for m1 muscarinic receptors (m1 receptors, receptor-G protein coupling, and the activation of phospholipase C) were studied in the rat hippocampus following unilateral or bilateral surgical lesions of the fimbria/fornix. One nM 3H-pirenzepine was used to label m1 receptors selectively. No changes in m1 receptor numbers were found between age 1.7 and 29 months old during normal aging or one year after cholinergic denervation. The interaction between m1 receptors and their associated G protein was examined by competition between 1 nM 3H-pirenzepine and oxotremorine-M in the presence and absence of a guanine nucleotide. The percentage of guanine nucleotide-sensitive high affinity binding sites for the agonist was similar in rats 1.7-29 months old and in rats 1 year after denervation. The ability of oxotremorine-M to activate phospholipase C, via m1, m3, and m5 receptors was also unchanged more than a year after cholinergic denervation of the hippocampus. We concluded that the initial steps in the m1 receptor transduction mechanism remain remarkably stable after denervation.

Acetylcholinesterase↗
PubMed1982

Changes in thromboxane B2 and 6-keto-PGF1 alpha after direct electrical stimulation of the denervated rat gastrocnemius1,2.

Radio-immunoassay was used to measure the amounts of Thromboxane B2 (TXB2) and 6-keto-PGF1 alpha produced in the gastrocnemius muscles of rats after denervation and direct electrical stimulation (2-4 mA intensity and 4 msec duration pulses given at 10 Hz continuously, 8 hours each day for 14 days). Compared to the normal control side, the normal-stimulated, the denervated control and the denervated-stimulated muscles, all indicated increases in the content (ng/g muscle) of TXB2 (120-155%, P less than 0.01) and 6-keto-PGF1 alpha (90-10 7%). This study suggests that electrical stimulation as well as denervation may lead to an elevation of these prostanoids.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

The study of energy metabolism in denervated skeletal muscle with 31P-NMR.

1. The denervated frog sartorius muscle showed a decrease in the energy store more than that in the control. 2. In the caffeine contractures, both the denervated and the innervated muscles showed similar sequential changes in the relative concentration of phosphocreatine (PCr) to beta-adenosine triphosphate (beta-ATP) and inorganic phosphate (Pi) to beta-ATP. Instead, the intracellular pH value of the denervated muscle was lower than that of the control. 3. It is suggested that phosphate metabolism of the denervated muscle during contracture shows little difference from that of the control, nevertheless, the buffering capacity is decreased in the early stage of atrophy.

Animals↗
PubMed1984

Differential effects of succinylcholine and acetylcholine on endplate and extrajunctional membranes of normal and denervated mouse skeletal muscle fibres.

Depolarization provoked by 10(-7)-10(-4) succinylcholine (SCh) and acetylcholine (ACh) was measured in thin bundles dissected from normal and 1-15 days denervated mouse muscles using the microelectrode technique. The muscles were superfused by Cl- -free solutions containing 30 mM K+ to prevent contracture responses. In endplate areas of normal muscles, sensitivity to SCh was roughly 10 times higher than the sensitivity to ACh. By contrast, the extrajunctional membrane of chronically denervated muscles was less sensitive to SCh than to ACh by about the same factor. The extrajunctional membrane of non-denervated soleus muscles was also more sensitive to ACh than to SCh but, unlike the response of the denervated membrane, the depolarization was transient.

Acetylcholine↗
PubMed1991

In vitro denervation of frog skeletal muscle: expression of several conductance classes of nicotinic receptors.

The question arose as to whether the altered kinetic properties of the nicotinic acetylcholine receptor-ion channel complex (AChR) observed after muscle denervation could be due to post-translational modifications. Single AChR properties of in vitro denervated skeletal muscle were studied using the cell-attached patch-clamp technique. Patch-clamp recordings from junctional regions of fibers daily treated with cycloheximide, a protein synthesis inhibitor, and phenylmethylsulfonyl fluoride, a protease inhibitor, revealed single conductance class of acetylcholine (ACh)-activated currents after acute dissociation and several conductance classes 3-14 days after muscle denervation. alpha-Bungarotoxin blocked all conductance states induced by ACh. Biochemical assays carried out on the same experimental conditions disclosed that chronic treatment of the fibers with cycloheximide inhibited the incorporation of [3H]leucine into precipitable protein. The present findings provided evidence that the altered functional properties of nicotinic receptors after muscle denervation may occur without new transcription.

Acetylcholine↗
PubMed1981

Cyclic nucleotides in the denervated rat diaphragm and the effect of cyclic AMP on ornithine and adenosylmethionine decarboxylases.

The concentrations of cyclic AMP and cyclic GMP were measured in the denervated rat diaphragm at various times following unilateral phrenicectomy. Cyclic AMP concentration was raised by the second day after operation, reached a peak by the third day, followed by another increase at around 10 days. By contrast, cyclic GMP concentration was decreased within a day after denervation and remained below control levels at all subsequent times studied. Epinephrine in vitro produced a comparable increase in the concentration of cyclic AMP in both normal and denervated tissue. The concentration of adenosine appeared unchanged in the denervated diaphragm by comparison with its innervated control. Activity of ornithine decarboxylase was elevated in the diaphragms of rats treated with dibutyryl cyclic AMP, but this effect could also be achieved with sodium butyrate alone. Adenosylmethionine decarboxylase activity, was unaffected after treatment with either compound. These observations and others discussed are taken to indicate a lack of direct relationship between cyclic AMP concentrations and the activity of the rate-limiting enzymes of polyamine biosynthesis in the rat diaphragm.

Adenosylmethionine Decarboxylase↗
PubMed1988

Role of polyamines and intracellular pH change in the hypertrophy of the denervated rat hemidiaphragm.

The transient hypertrophy of the denervated rat hemidiaphragm is associated with a rise in concentrations of putrescine and spermidine. Hypertrophy still occurs following denervation in rats injected with difluoromethylornithine which reduces the increase in spermidine and particularly putrescine levels. Administration of isobutylmethylxanthine tended to raise putrescine concentrations in the denervated but not innervated tissue. No evidence could be found that the enhanced protein synthesis rate in the denervated tissue is associated with an increase in intracellular pH.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Effects of denervation on the responses of the rat tail artery to alpha beta-methylene ATP.

1. One microM alpha beta-methylene ATP (alpha beta meATP) caused transient contraction and depolarization of the smooth muscle of the rat tail artery. 2. The peak contraction was greater in denervated arteries; the peak depolarization was the same in normal and denervated arteries. 3. This suggests that alpha beta meATP receptors do not increase following denervation. 4. In denervated arteries electrical stimulation produced depolarizing responses that were not due to neurotransmitter release but which were blocked by alpha beta meATP. 5. It is suggested that alpha beta meATP may be a blocker of cation channels.

Adenosine Triphosphate↗
PubMed1983

Increases in protein-precursor incorporation in the denervated neuropil of the dentate gyrus during reinnervation.

Cellular metabolic events accompanying postlesion synaptogenesis in the hippocampus were studied by analyzing incorporation of protein precursor ([3H]leucine) in the dentate gyrus. Adult rats were injected intravenously with [3H]leucine at periods from 2 to 60 days following unilateral destruction of the entorhinal cortex, and were killed 30 min later. Precursor incorporation was quantified autoradiographically by counting silver grains over the cell bodies and dendrites of dentate granule cells ipsi- and contralateral to the lesion. The relative grain density was increased over the denervated portion of the neuropil at 6-12 days postlesion, corresponding to the early phase of terminal proliferation and reactive synaptogenesis. Whereas incorporation was increased over the denervated neuropil, the availability of [3H]leucine was decreased relative to the contralateral side in autoradiographic preparations designed to reveal the concentration of the unincorporated 3H-labeled precursor and its diffusible degradation products. Silver grains were not selectively associated with glial cells bodies or vascular elements, but rather were distributed diffusely throughout the neuropil. Increases in grain density over the denervated zone were observed when animals were killed 8 min after the leucine injection, suggesting that the increases were not due solely to rapid transport from granule cell bodies to dendrites. We propose that an increased incorporation of protein precursor occurs primarily within the denervated dendrites of granule cells during the early phase of reinnervation, and that protein synthetic activity in these cells might be involved in the process of reinnervation.

Animals↗
PubMed1985

The fate of proliferating cells in skeletal muscle after denervation or tenotomy: an autoradiographic study.

During the first 7 days after denervation or tenotomy of skeletal muscle there is increased cell proliferation, as measured autoradiographically by [3H]thymidine incorporation. By 21 days most of the labelled cells have disappeared. The present experiment was designed to measure residual levels of labelling in skeletal muscles at 21 days after denervation or tenotomy, when [3H]thymidine had been available for the first 7 days. This was to determine the fate of cells labelled at 7 days and to detect whether continued cell proliferation had occurred during the intervening period, as evidenced by the dilution of nuclear label. Tibialis anterior muscles of 16 mice were denervated, tenotomized or sham-operated, and the animals injected with a single daily pulse of [3H]thymidine for the first 7 days only. In denervated muscle the 11% of muscle nuclei and 41% of connective tissue nuclei labelled at 7 days had decreased to 2 and 13%, respectively, by 21 days. These values were still significantly higher than in 21 day controls (0.2 and 1.9%, respectively). In muscle nuclei (myonuclei and satellite cell nuclei) there was a significant decrease in the amount of label per nucleus. This was interpreted as evidence of continued cell proliferation. However, this did not produce an increase in numbers of muscle nuclei. It was concluded that: there was turnover of satellite cells and possibly myonuclei, the latter probably through continued division and incorporation of satellite cells; and the extra satellite cells and myonuclei produced were probably extruded from the fibre to the extracellular space.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The effect of muscle activity on motor unit size in partially denervated rat soleus muscles.

It has been shown previously that after section of L5 ventral ramus at 5 days the intact axons of L4 ventral ramus retain their large neonatal peripheral field in the rat soleus muscles. Soleus muscles of 5-day-old rats were partially denervated by section of their major neural input, L5 ventral ramus, and in addition paralysed with alpha-bungarotoxin for 3-5 days. The motor unit size was examined 2 months later. The tension developed by individual motor units from muscles that were partially denervated and in addition temporarily paralysed was much less than that after partial denervation alone. This reduced tension output was not due to muscle atrophy but to a smaller number of muscle fibres supplied by individual axons. Thus, unlike after partial denervation only, motoneurons were unable to maintain their large neonatal territory when the muscle was temporarily paralysed and they were unable to reoccupy this territory after the muscles recovered from the paralysis. The possibility that arrested muscle maturation due to paralysis has a permanent effect on motor unit size is discussed.

Animals↗
PubMed1990

Reinnervation and recovery of mouse soleus muscle after long-term denervation.

Reinnervation and recovery of the mouse soleus muscle were studied 2-10 months after denervation periods of about 7 months. To maintain denervation the right sciatic nerve was frozen 14 times at 2-week intervals. Though initially intermittent muscle reinnervation occurred, contractile force of denervated muscles was reduced to less than 10% of the contralateral muscles by the fifth nerve freezing and further declined thereafter. Following reinnervation, recovery of soleus muscle force proceeded slowly to reach plateau values after 5-6 months. Tetanic muscle force reached on average 72% (range 58-86%, n = 12) of contralateral muscles after 5-10 months, (P less than 0.01, t-test for absolute values) and 87% of unoperated animals after 10 months (P less than 0.05, n = 5). Muscle fibre diameters were significantly reduced in reinnervated muscles, but frequency distributions were normal and similarly shaped in reinnervated and control muscles, suggesting complete muscle reinnervation and the absence of denervated fibres even at 2 months of reinnervation. Total numbers of muscle fibres were similar in reinnervated (842 +/- 73 S.D., n = 15), contralateral (854 +/- 104 S.D., n = 15) and control soleus muscles (853 +/- 77 S.D., n = 5). The number of myelinated axons in regenerating soleus nerves reached control values by 3 months after the last freezing, continued to increase till 6 months (150% of control), and declined thereafter (125% at 9-10 months). In the contralateral soleus nerves the number of myelinated axons remained constant during this period. Nerve fibre diameters remained abnormally small; even after 10 months of reinnervation fibre diameters were unimodally distributed with a mean diameter of 3.3 microns in contrast to the bimodal distribution in intact nerves (mean values 3.9 and 9.0 microns, respectively). Total fibre cross-section area per nerve increased with time but reached only 54% +/- 6 S.D., (n = 3) of contralateral nerves by 10 months. The relative thickness of the myelin sheath (g-ratio) returned to normal after 9-10 months. Anatomically, muscle reinnervation appeared to be complete by 7-8 weeks since unusually small muscle fibre profiles were absent.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1991

Chronic eticlopride and dopamine denervation induce equal nonadditive increases in striatal D2 receptor density: autoradiographic evidence against the dual mechanism hypothesis.

In an attempt to resolve experimental discrepancies regarding the mode of action of D2 receptor regulation following denervation or chronic receptor blockade, rats with extensive unilateral destruction of the mesotelencephalic dopaminergic projections induced by intracerebral 6-hydroxydopamine were injected daily for 21 days with either saline or the potent, selective D2 antagonist eticlopride (0.5 mg/kg, i.p.). Four days after the last injection of eticlopride or saline, rats were killed, and brain sections through the caudate-putamen and nucleus accumbens septi were incubated with [3H]spiroperidol or (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5- phenyl-1H-3-benzazepin-7-ol ([3H]SCH 23390) to assay D2 and D1 receptors, respectively. Autoradiographic analysis revealed that chronic eticlopride treatment increased the density of D2 sites in the intact hemisphere for all regions examined without further augmenting the already increased density of D2 receptors seen in the dopamine-denervated hemisphere. D2 receptor density was independent of functional sensitivity as evidenced by the fact that rats treated chronically with eticlopride rotated contralateral to the 6-hydroxydopamine lesion following systemic administration of the selective D2 agonist quinpirole during the neuroleptic wash-out period, despite the fact that D2 receptor binding was not significantly different in the left and right hemispheres of these subjects. D1 receptor density was not affected by eticlopride treatment but was significantly reduced reduced in the dopamine-denervated hemisphere. [3H]Mazindol labeling of high-affinity DA uptake sites indicated that the extent of dopamine denervation was greater than 97% in both saline- and eticlopride-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

Delayed response to denervation in muscles of C57BL/Ola mice.

Muscle fibre areas and numbers, tetanic force, resident macrophage numbers and acetylcholine sensitivity were measured in normal and denervated soleus muscles of C57BL/Ola mice for comparison with data from outbred and other inbred strains. Serum creatine kinase levels were also measured. The muscles of normal C57BL/Ola mice had more fibres, generated more tension, had fewer resident macrophages and had a lower acetylcholine sensitivity than muscles of other strains. The normal level of serum creatine kinase was lower in C57BL/Ola mice than in Balb/c mice. Following denervation, the mean cross-sectional area of muscle fibres in Balb/c mice started to fall from day 1 but a fall was not seen in muscles from C57BL/Ola mice until day 5. The development of increased acetylcholine sensitivity was slower in the C57BL/Ola mice although the values in all mouse strains had converged by five days. The levels of serum creatine kinase also rose more slowly following denervation in C57BL/Ola mice. The differences between the data from C57BL/Ola mice and others are ascribed to the slow rate of Wallerian degeneration in that strain. The results support the view that the effects of denervation on muscle are due to both inactivity and an inflammatory effect contributed by nerve degeneration. The mutation that causes slow nerve degeneration may, however, also affect muscle directly, making it more resistant to catabolism.

Acetylcholine↗
PubMed1992

Response of developing rat fast muscles to partial denervation.

The changes of motor unit size following partial denervation of the extensor digitorum longus muscles in rat neonates (at five to six days) and later in development (at 18-20 days) were studied. Extensor digitorum longus muscle is innervated mainly by axons from L4 ventral ramus and to a lesser extent by axons from L5 ventral ramus. In neonates the motor units in extensor digitorum longus are large, and they become restricted to their adult size during the first two weeks of life. Six to 10 weeks after removing the major input to extensor digitorum longus, i.e. L4 ventral ramus at five to six days, the motor unit sizes of axons in the remaining L5 ventral ramus decrease from their expanded neonatal territory to their adult smaller size. In spite of partial denervation the motor units remain small throughout the animal's life and the denervated muscle fibres do not become "occupied" by sprouts from the remaining axons of L5 ventral ramus motor nerves. Partial denervation of extensor digitorum longus muscles at 18-20 days by section of the L4 ventral ramus leads to the expected two- to three-fold increase in the size of motor units of L5 ventral ramus. These results are taken to show that fast motor units of neonatal rats are unable to maintain their enlarged peripheral field, while later in development their axons can sprout and occupy an expanded peripheral field.

Aging↗
PubMed1993

Morphological correlates of physiological responses in partially denervated mouse muscle during aging.

To evaluate the effect of partial denervation on age changes, morphological and physiological parameters were studied in young versus old extensor digitorum longus (EDL) muscles. The aims of this study were to elucidate synaptic maintenance in general and specifically to assess the adaptability of motor neurons from young and old animals to an enlarged field of innervation. Partial denervation was carried out in two groups of 30-40 g mice, aged within 6 or 24 months, by sectioning of the nerve supplying EDL muscle under methoxyfluorane anaesthesia. Sham operations were carried out on additional animals which served as controls. Five weeks' post-surgery, the safety factor of synaptic transmission was estimated by dividing the nerve-evoked twitch tension generated in 1 mM Ca2+ Krebs by that generated in 2.5 mM Ca2+ Krebs. Low Ca2+ Krebs caused a more pronounced decline in twitch tension in young control EDL muscles than old control. After partial denervation, young EDL twitch tensions were not significantly different while old were 20% of those in normal Krebs. Zinc Iodide Osmium (ZIO) stained nerve terminal parameters were significantly increased with aging. After partial denervation, nerve terminal areas were 46 and 39% larger in young and old mice, respectively, compared to their corresponding controls. Present data suggest that motor neurons of old mice are unable to develop and maintain an enlarged field of innervation.

Aging↗