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PubMed1992

Dextrans as markers for endocytosis in innervated and denervated skeletal muscle.

Fluorescence-labeled dextrans were evaluated as markers for endocytosis in skeletal muscle. Fluorescein isothiocyanate (FITC)-labeled dextrans (average molecular weight 3900 to 71200) showed a higher uptake in denervated than in innervated muscle both in vitro and in vivo. The in vitro uptake of FITC-dextran (35.600) increased linearly with time at 37 degrees C, and was almost completely inhibited by low temperature (4 degrees C). The uptake was not a pure bulk uptake, because a saturable component was evident from the concentration dependence and from competition experiments with unlabeled dextran. The uptake of FITC-labeled or rhodamine B isothiocyanate (RITC)-labeled dextrans in denervated muscle occurred mainly in small segments of the fibers centered around the denervated endplate region. However, not all denervated fibers showed such segments. Periodic acid Schiff's base staining for carbohydrates stained dextrans in denervated muscle fibers. Some staining, probably of lysosomes, was also observed in denervated muscle not exposed to dextran.

Animals↗
PubMed1993

Recovery of muscle after different periods of denervation and treatments.

Three aspects of reinnervation and recovery of skeletal muscle following various periods of denervation were investigated: (1) the effect of duration of denervation; (2) the effect of hyperthyroidism on recovery; and (3) whether the muscle or the nerve limits recovery. The rat medial gastrocnemius (MG) nerve was cut and then resutured after 0, 3, 7, 21, or 56 days. In a second group of animals, the MG muscle was denervated and, in addition, the animal received triiodothyronine (T3) supplementation during reinnervation. The third group of animals had the denervated MG muscle reinnervated by a larger number of newly transected foreign axons. The force produced by the reinnervated muscle depends on the period that the muscle was denervated. Recovery was impaired when the period of denervation exceeded 7 days. T3 treatment did not benefit the return of force production, nor did providing the muscle with a larger number of newly transected axons.

Animals↗
PubMed2003

Neuromuscular activity impairs axonal sprouting in partially denervated muscles by inhibiting bridge formation of perisynaptic Schwann cells.

Following partial denervation of rat hindlimb muscle, terminal Schwann cells extend processes from denervated endplates to induce and guide sprouting from the remaining intact axons. Increased neuromuscular activity significantly reduces motor unit enlargement and sprouting during the acute phase of sprouting. These findings led to the hypothesis that increased neuromuscular activity perturbs formation of Schwann cell bridges and thereby reduces sprouting. Adult rat tibialis anterior (TA) muscles were extensively denervated by avulsion of L4 spinal root and were immediately subjected to normal caged activity or running exercise (8 h daily) for 3, 7, 14, 21, and 28 days. Combined silver/cholinesterase histochemical staining revealed that the progressive reinnervation of denervated endplates by sprouts over a 1 month period in the extensively partially denervated TA muscles was completely abolished by increased neuromuscular activity. Immunohistochemical staining and triple immunofluorescence revealed that the increased neuromuscular activity did not perturb the production of Schwann cell processes, but prevented bridging between Schwann cell processes at innervated and denervated endplates. Our findings suggest that failure of Schwann cell processes to bridge between endplates accounts, at least in part, for the inhibitory effect of increased neuromuscular activity on sprouting.

Animals↗
PubMed1976

Chloride conductance of denervated gastrocnemius fibers from normal goats.

Membrane potentials, cable parameters, and component resting ionic conductances of gastrocnemius fibers from normal goats were measured in vitro at six to 32 days following denervation by section of the tibial nerve. Denervated fibers were depolarized an average of 11.6 +/- 1.5 mV (six preparations) from the control mean of 62.1 +/- 1.0 mV (124 fibers) over the period studied. Fibrillation, tetrodotoxin-resistant action potentials, and anode-break excitation were present in the denervated preparations after 13 days. The control cable parameters from 124 fibers (13 preparations) were membrane resistance, 1052 +/- 70 omega-cm2 and membrane capacitance, 6.2 muF/cm2. In denervated fibers membrane resistance increased two to three times in the 13 to 32 day period; membrane capacitance increased about 50% in normal solution at eight to nine, 27-28, and 32 days. Myoplasmic resistivity was assumed to be 112 omega-cm. Measurements were made at 38 degrees C. Component resting conductances were determined from the cable parameters in normal and chloride-free solution. Mean chloride conducantance GC1 and mean potassium conductance GK of control fibers were 776 +/- 49 mumhos/cm2 and 175 +/- 15 mumhos/cm2 (92 fibers), respectively. Following denervation GC1 increased slightly at six to nine days then fell to low values at 16 to 32 days that were close to or indistinguishable from zero. GK increased significantly to 372 +/- 40 mumhos/cm2 and 499 +/- 90 mumhos/cm2 at 16 to 20 and 32 days, respectively. It was concluded from these findings that GC1 and GK of mammalian skeletal muscle are controlled by factors from the nerve and/or muscle action potentials. Goat muscle is different from frog muscle in which GC1 does not change and GK decreases during denervation.

Action Potentials↗
PubMed1997

Transcriptional regulation of hexokinase II in denervated rat skeletal muscle.

Hexokinase II protein is augmented in denervated skeletal muscle; therefore, we determined if hexokinase II gene transcription rates and mRNA levels are increased with denervation. The right hindlimb skeletal muscles of male rats were denervated while the left hindlimbs were sham operated. Seventy-two h following surgery, rats were sacrificed and the gastrocnemius and soleus muscles were harvested for nuclear and RNA isolation. Nuclear run-on and ribonuclease protection analyses indicated that denervation increased hexokinase II transcription rates and mRNA levels 42% and 88%, respectively (p < 0.05). Total hexokinase activity rose 23% in denervated gastrocnemius muscle. In conclusion, the increase in hexokinase II gene transcription and mRNA may account for the increase in hexokinase II protein and the subsequent rise in total hexokinase activity in denervated rat skeletal muscle.

Animals↗
PubMed1997

The effects of denervation location on fiber type mix in self-reinnervated mouse soleus muscles.

Mouse soleus muscles were denervated by crushing the soleus nerve where it enters the muscle to determine if denervation followed by self-reinnervation can permanently alter the mix of fiber types in a muscle. Reinnervated and contralateral control muscles were sectioned at 2 and 7 months postdenervation and histochemically stained for myosin ATPase to determine the percentages of fast and slow twitch fibers in the muscles. It was found that, at both 2 and 7 months postdenervation, reinnervated muscles had a significantly higher percentage of slow twitch fibers than did contralateral control muscles (86.7 versus 67.8% at 2 months and 90.0 versus 69.3% at 7 months). Soleus muscles were also denervated by crushing the soleus nerve where it exists the gastrocnemius muscle (approximately 4 mm proximal to where the nerve enters the soleus muscle) to ascertain if the location of the nerve lesions plays a role in the ultimate outcome of the process of self-reinnervation. Reinnervated muscles and their contralateral muscles were sectioned at 2 months postdenervation and histochemically stained for myosin ATPase as before. It was found that, in contrast to muscles denervated at the point of nerve entry, muscles denervated 4 mm more proximal exhibited only a small increase in their percentage of slow twitch fibers which was not statistically significant (71.4 versus 68.4%). These results suggest that denervation followed by self-reinnervation can cause a permanent change in a muscle's fibers type mix and that the location of the nerve lesion strongly influences the final outcome of the reinnervation process.

Animals↗
PubMed1994

A comparison of the morphology of denervated with aneurally regenerated soleus muscle of rat.

Soleus muscles of rats were denervated, treated with bupivacaine and autografted in order to induce aneural regeneration or only denervated. After 2-70 days, muscles were fixed and embedded in epoxy resin for light and electron microscopy. Regenerating muscles after 2 and 5 days consisted of a necrotic core and a rim of new fibres; the necrotic core had disappeared by day 10. The fibre size (mean cross-sectional area) was 139 microns2 after 10 days; it decreased to 22 microns2 after 70 days. Denervated muscle fibres measured 26 microns2 after 70 days. The sarcomere pattern was regular in 10-day regenerates but later degenerated. There were signs of fibre breakdown; immature regenerating fibres were still found after 70 days. Denervated muscles already contained a few new myotubes at 10 days; at 40 and 70 days fibre loss and regeneration were distinct. The percentage of satellite cells relative to myonuclei (normal 8%) doubled within the first 10 days after necrosis and then fell to less than one fourth of normal. Denervation for 70 days increased threefold the percentage of satellite cells in some muscles and in others caused a decrease to half of normal. The number of fibre cross-sections in regenerated muscles was about 3000 after 10-70 days; this was roughly the same number as in normal soleus muscles. The true number of fibres, however, may have been smaller because regenerated fibres tend to branch. It is concluded that aneurally regenerating muscle fibres reach a high degree of structural differentiation, but then atrophy, degenerate and vanish; they are replaced by new fibres, which do not reach the size of the first fibres, presumably because the satellite cell pool without innervation eventually becomes exhausted. The slow and non-synchronized breakdown of denervated soleus muscle fibres induces proliferation of satellite cells as in necrotized muscles; those muscles which had fewer satellite cells than normal after 70 days might already be showing exhaustion.

Animals↗
PubMed1994

Contractile properties of aneurally regenerated compared with denervated muscles of rat.

The time course of aneural regeneration in slow-twitch soleus muscles of young adult rats was studied and compared with the changes following denervation in soleus and fast extensor digitorum longus muscles. Regeneration was induced by auto-grafting after treatment with bupivacaine; isometric contractions were recorded from 5 to 70 days later. Force was detected at 5 days; at 12 days force was maximal (at least 20% of original) and thereafter fell exponentially. Force varied normally with total fibre area, except at 5 and 71 days when force generating capacity was low. Contraction and relaxation in the twitch were longer than normal (maximally at 5 days), and were closer to denervated soleus than EDL; in contrast, the maximal rate of rise of force was as high as that of denervated EDL and much higher than in denervated soleus. It is suggested that the muscle was fundamentally fast contracting, but the twitches were probably slow because of greater than normal activation following a single stimulus--a hypothesis supported by twitch:tetanus ratios that were higher than in denervated muscles. Tetanic force was much more sensitive than normal to changes of muscle length from optimum, despite the fact that the lengths of regenerated muscles were similar to those of contralateral muscles. The properties of denervated soleus gradually approached those of regenerated soleus, probably because of replacement of original fibres by regenerated ones.

Animals↗
PubMed1993

Differential effects of neonatal denervation on intrafusal muscle fibers in the rat.

The response of developing muscle spindles to denervation was studied by sectioning the nerve to the medial gastrocnemius muscle of rats at birth. The denervated spindles were examined daily throughout the first postnatal week for changes in ultrastructure and expression of several isoforms of myosin heavy chain (MHC). Each of the three different types of intrafusal muscle fiber exhibited a different response to denervation. Within 5 days after the nerve section nuclear bag2 fibers degenerated completely; nuclear bag1 fibers persisted, but ceased to express the 'spindle-specific' slow-tonic MHC isoform and thereby could not be differentiated from extrafusal fibers; nuclear chain fibers did not form. The capsules of spindles disassembled, hence spindles or their remnants could no longer be identified 1 week after denervation. Neonatal deefferentation has little effect on these features of developing spindles, so removal of afferent innervation is presumably the factor that induces the loss of spindles in denervated muscles. Degeneration of the bag2 fiber, but not bag1 or extrafusal fibers, reflects a greater dependence of the bag2 fiber than the bag1 fiber on afferent innervation for maintenance of its structural integrity. This difference in response of the two types of immature bag fiber to denervation might reflect an origin of the bag2 fibers from a lineage of myogenic cells distinct from that giving rise to bag1 or extrafusal fibers, or a difference in the length of contact with afferents between the two types of bag fiber prior to nerve section.

Animals↗
PubMed1978

Cell proliferation in skeletal muscle following denervation or tenotomy. A series of autoradiographic studies.

Autoradiographic experiments using 3H-thymidine were designed to analyse cell proliferation which occurs in skeletal muscle after denervation and after tenotomy. In mouse tibialis anterior and tongue muscles during the first 24 h after denervation or tenotomy labelling levels were low and did not differ significantly from sham operated control muscles. By 48 h after denervation and tenotomy of tibialis anterior muscles, increased levels of labelling occurred in both muscle and connective tissue nuclei. Daily pulse labelling for 7 days after denervation produced a labelling level which was 8 times that of sham operated controls, 25--30% of the total nuclear population being labelled. Denervated muscles had twice the level of labelling compared to tenotomised muscles. These results provide conclusive evidence that both denervation and tenotomy stimulate cell proliferation in skeletal muscle and it is suggested that the increased numbers of labelled muscle nuclei are likely to be the result of mitotic activity in muscle satellite cells.

Animals↗
PubMed1984

The effect of long-term denervation on the ultrastructure of Pacinian corpuscles in the cat.

The ultrastructure of Pacinian corpuscles of the cat located in the crural region and innervated by the interosseous nerve was studied 1 to 14 months after denervation. Both the Pacinian inner core and capsule remained well preserved one month after denervation. However, the denervated inner cores underwent progressive atrophy and wasting, which resulted in a gradual reduction of the amount of inner-core cells and lamellae, widening of interlamellar clefts, formation of empty spaces in the axial region and a considerable increase in the number of collagen fibrils. In spite of the wasting, the inner core still survived 14 months after denervation, but at least half of its volume became occupied by collagen fibrils which surrounded the remaining inner-core cells and lamellae. Collagen fibrils assembled in the denervated core were markedly thinner than those found in the capsule, as is also the case in normal Pacinian corpuscles. In the capsule, discrete focal degeneration, occasional pyknosis of the innermost capsular cells and macrophage infiltration were observed from the first month after nerve section onward, but the number of capsular layers remained within the normal range (30-40) up to 14 months after denervation.

Animals↗
PubMed1985

Can cells extruded from denervated skeletal muscle become circulating potential myoblasts? Implications of 3H-thymidine reutilization in regenerating muscle.

The hypothesis that satellite cells which leave denervated skeletal muscle might become circulating potential myoblasts which could participate in myogenesis in distant sites in the body has been tested. Sixteen mice had one hindlimb denervated and were given 7 daily injections of 3H-thymidine (3H-Tdr). One day later extensor digitorum longus muscle isografts from unlabelled mice were inserted into each hindlimb. As controls, the procedure was repeated in 6 non-denervated labelled mice. Fourteen days after their insertion, isografts in denervated mice contained many labelled myotubes with a labelling index of 55 +/- 4% (mean +/- SEM). In the control isografts in non-denervated ice, 38 +/- 4% of myotube nuclei were labelled. The results show that either labelled cells, or 3H-Tdr, had transferred from the host to isografts in both cases. The probability of 3H-Tdr reutilization was demonstrated in regenerating livers of 8 similarly labelled mice, where 34 +/- 3% hepatocytes adjacent to crush lesions were labelled after 14 days. This conclusion was reached because only 2-3% of normal hepatocytes incorporate 3H-Tdr under these conditions and this population is inadequate to provide sufficient labelled precursor cells for the large numbers of labelled regenerated hepatocytes. Therefore, it was concluded that 3H-Tdr reutilization is the most likely explanation for labelled myotube nuclei in the muscle isografts (rather than movement of labelled precursor cells), and that additional label for reutilization had been derived from breakdown of labelled cells in denervated muscle. The data do not support the hypothesis of a circulating precursor for skeletal muscle cells.

Animals↗
PubMed1996

Denervation and outlet obstruction induce a net synthesis of contractile and cytoskeletal proteins in the urinary bladder of the male rat.

The concentrations of the contractile proteins actin and myosin and the cytoskeletal protein desmin were determined in urinary bladders from normal rats, and from rats with bladder outlet obstruction or denervation. Ten days of obstruction or total denervation by bilateral removal of the pelvic ganglia resulted in an almost fourfold increase in bladder weight. Actin and myosin concentrations did not change significantly. The total amount of actin was 1624 +/- 235 micrograms in the control bladder. In the obstructed and denervated bladders it increased significantly to 6277 +/-648 micrograms and 7671 +/- 835 micrograms, respectively. The desmin/actin ratio was 0.237 +/- 0.012 in the control bladders, and increased significantly to 0.369 +/- 0.015 in the obstructed and 0.343 +/- 0.022 in the denervated bladders. Partial denervation by removal of the pelvic ganglion on one side only increased bladder weight by 52%, but did not increase the desmin/actin ratio. The content of actin in such bladders increased by 82%. Both obstruction (which increases the functional load of the detrusor muscle cells) and denervation (which produces bladder paralysis) are known to induce hypertrophy of the detrusor smooth muscle cells. The study shows that the desmin/actin ratio and the total amount of contractile proteins increase in response to the hypertrophy as such, and not to the work performed by the smooth muscle cells, and that the nerves have no trophic influence on the growth response. Also, even a limited lesion of the bladder innervation is associated with growth and a net increase in the amount of contractile proteins.

Actins↗
PubMed1992

Slow-to-fast transformation of denervated soleus muscle of the rat, in the presence of an antifibrillatory drug.

The myofibrillar changes of rat denervated soleus muscle were studied in the presence and in the absence of an antifibrillatory drug. After bilateral sciaticotomy, a concentrated solution of procainamide hydrochloride was steadily released, by way of a miniosmotic pump, in the space between the soleus and the gastrocnemius muscles of one leg. Fibrillation activity of soleus muscles was checked electromyografically at 3- to 5-day intervals. On the 21st day following denervation the muscles were excised, stained for adenosine triphosphatase activity and analysed for myosin heavy chain (MHC) isoforms. In the denervated-procainamide-treated muscles fibrillation was consistently (-75% on average) depressed in comparison to the contralateral denervated muscles. Type 1 (slow) fibres and MHC isoform were also significantly reduced, to the advantage of type 2A (fast) fibres and MHC isoform. The results support the view that denervation inactivity, like other kinds of muscle inactivity, favours the expression of fast type myofibrillar isoforms, and that this effect is counteracted, at least partially, by the spontaneous activity of the denervated muscle.

Animals↗
PubMed1990

Increase in electrically-stimulated Ca2+ release and suppression of caffeine response in diaphragm muscle of alloxan-diabetic mice compared with the denervation effect.

Changes in intracellular Ca2+ release in the diaphragm muscle of alloxan-diabetic mice were compared with changes in normal muscles and non-diabetic denervated muscles. We measured Ca2+ transient aequorin luminescence by direct electrical stimulation of these muscles. External Ca2(+)-free solution readily decreased the Ca2+ transient in normal muscles but had less of an effect in diabetic muscles. Only when the muscles were pre-injected with EGTA (reducing intracellular levels of free Ca2+) did the Ca2+ transients decrease significantly in diabetic muscles, however, there was no effect in denervated muscles. The caffeine-induced increase in Ca2+ transients, however, was delayed in both diabetic muscles and non-diabetic denervated muscles. The caffeine response was observed in normal muscles under the external Ca2(+)-free conditions even after EGTA-pretreatment, whereas it was suppressed, after a brief increase, in both diabetic and non-diabetic denervated muscles. These results demonstrate (1) the insensitivity of intracellular Ca2+ mobilization to external Ca2+ levels and the ready accumulation of intracellular Ca2+ in the cytosol in the diabetic state, (2) increased permeability to Ca2+ in the denervated state and (3) impairment of the Ca2+ pool which responds to caffeine in both diabetes and the non-diabetic denervated state. Diabetic neuromyopathy thus appears to be a state of abnormal Ca2(+)-mobilization caused secondarily by high levels of blood glucose.

Aequorin↗
PubMed1986

Modifications in the histochemical and biochemical changes in tenotomized rat soleus by denervation.

Response of tenotomized rat soleus muscle to denervation performed at different time intervals, has been investigated. Tenotomized muscles showed typical central core lesions seven days post-operatively. These were not observed in m-ATPase stained sections of simultaneously denervated and tenotomized muscles, and muscles denervated 24 h after tenotomy. Central core lesions were not prevented in muscles denervated 28 h after tenotomy, indicating that tenotomy effects responsible for central lesions are completed by this time. Myosin light chain pattern of muscles denervated 28 h after tenotomy, and tenotomized only were similar showing increased LC3/LC1 ratio. Simultaneously denervated and tenotomized muscle however showed all the three light chains relatively equal in quantity. The results suggest that elimination of neural activation within 28 h prevents myofibrillar loss and minimized other changes which occur due to tenotomy.

Animals↗
PubMed1982

Water and sodium excretion in unilaterally denervated normal and sodium depleted anesthetized rats before and after plasma volume repletion.

The possible role of a reduction in plasma volume (PV) by surgery as well as the importance of dietary Na supply in denervation natriuresis have been investigated on Inactin-anesthetized male rats subjected to acute unilateral renal sympathectomy. Four groups were studied: I. Normal Na diet (n = 14); II. Low Na diet (boiled rice for 2 weeks) -- isotonic glucose infusion (n = 10); III. Low Na diet -- isotonic saline infusion (n = 5); IV. Normal and low Na diet rats served as conscious control (n = 10). Surgery caused a 9-11% increase in hematocrit and a 15-18% decrease in PV in groups I-III. Plasma volume repletion (PVR) reverted these changes. In group I sodium excretion from both kidneys was only a fraction of that in conscious animals kept on the same diet (group IV) and marked denervation natriuresis was observed. After PVR sodium output of innervated (I) kidneys was not different from that of conscious rats but denervated (D) kidneys excreted twice that amount. In group II Na excretion was increased compared to conscious Na depleted controls, and PVR augmented further this difference. Surprisingly, the difference in urinary sodium excretion (UNaV) between I and D kidneys was absent after surgery and was minimal after PVR in this group. In group III physiological saline infusion reverted the effect of Na depletion and denervation natriuresis was present both before and after PVR. It is concluded that PV reduction does not play a major role in denervation phenomenon. In Na depleted anesthetized rats denervation natriuresis is absent or minimal.

Anesthesia↗
PubMed1986

Contractile responses of rat plantaris muscles following partial denervation, and the influence of daily exercise.

The study was designed to determine the influence of increased daily neuromuscular activity on the sprouting response of motoneurones following partial denervation. Female Sprague-Dawley rats had one hindlimb partially denervated by transecting lumbar radicular nerve L4, and were subsequently subjected to a daily programme of increased activity, including grid climbing and voluntary wheel exercise, for 9 days. Functional sprouting was estimated on day 10 by comparing the L5-evoked plantaris muscle forces, measured in situ, with those of the contralateral L5. Comparisons were made between responses from exercised and non-exercised rats. Tetanic (200 Hz) contribution of L5 axons to plantaris muscle force doubled during the period following partial denervation, but did not attain the equivalent of whole muscle tetanic tension of normal controls. Twitch: tetanic ratios were elevated, and tetanic contractions "fatigued" to a greater extent in partially denervated muscles, signifying limitations on the part of each sprouting motoneurone to tetanically activate its enlarged complement of muscle fibres. No influence of daily exercise following the lesion on any of these functional indices of motoneurone sprouting was evident. Increased daily neuromuscular activity, performed within the restrictions imposed by the neuromuscular deficit, does not influence motoneurone sprouting responses. This is in contrast to the enhancement of sprouting previously reported for motoneurones of rats subjected to intense, prolonged, daily exercise preceding the partial denervation, and when neurones remaining following partial denervation are electrically stimulated for relatively short periods of time (1 h), the day of the lesion.

Animals↗