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PubMed2004

mRNA expression of fibroblast growth factors and hepatocyte growth factor in rat plantaris muscle following denervation and compensatory overload.

We addressed the question of whether hypertrophy induced by compensatory overload differs according to innervation status, and how fibroblast growth factors (FGF) and hepatocyte growth factor (HGF) mRNAs are expressed in the rat plantaris muscle during overload (OL) and/or denervation. Male Wistar rats were divided into four groups (Normal-Cont, Normal-OL, Denervated-Cont, and Denervated-OL). according to the plantaris denervation and/or overload. Three weeks later, plantaris weight in Denervated-Cont and Denervated-OL was significantly lower than in the Normal-Cont. The muscle weights in the Normal-OL were higher than in the Normal-Cont. The muscle weights in the Denervated-OL were higher than in the Denervated-Cont. Three days after the treatment, FGF-2, FGF-6, FGF-7 and HGF mRNAs in the Normal-OL were significantly higher than those in the Normal-Cont. FGF-2, FGF-6, FGF-7 and HGF mRNAs in the Denervated-OL were also significantly higher after 3 days than those in the Denervated-Cont. After 7 days, FGF-2, FGF-5, FGF-6, FGF-7 and HGF mRNAs were significantly higher in the Normal-OL than those in the Normal-Cont. At 21 days, FGF-1, FGF-6 and HGF mRNA levels were significantly increased. In the Denervated-OL, FGF-2, FGF-7 and HGF mRNAs at 7 days, and FGF-2 mRNA at 21 days were significantly higher than those in the Denervated-Cont. FGF-2 and FGF-6 mRNA levels decreased significantly following denervation; however, FGF-1, FGF-5, FGF-7 and HGF mRNA levels increased and maintained this increase for the 21-days treatment period. Muscle hypertrophy was thus induced by compensatory overload irrespective of innervation status, possibly in association with certain FGFs and HGF. The differential mRNA expression patterns of FGFs and HGF observed following compensatory overload and/or denervation suggest distinct roles for individual FGFs and HGF in muscle hypertrophy and/or atrophy.

Animals↗
PubMed2022

Lipid hydroperoxides and oxylipins are mediators of denervation induced muscle atrophy.

Loss of innervation is a key driver of age associated muscle atrophy and weakness (sarcopenia). Our laboratory has previously shown that denervation induced atrophy is associated with the generation of mitochondrial hydroperoxides and lipid mediators produced downstream of cPLA2 and 12/15 lipoxygenase (12/15-LOX). To define the pathological impact of lipid hydroperoxides generated in denervation-induced atrophy in vivo, we treated mice with liproxstatin-1, a lipid hydroperoxide scavenger. We treated adult male mice with 5 mg/kg liproxstain-1 or vehicle one day prior to sciatic nerve transection and daily for 7 days post-denervation before tissue analysis. Liproxstatin-1 treatment protected gastrocnemius mass and fiber cross sectional area (∼40% less atrophy post-denervation in treated versus untreated mice). Mitochondrial hydroperoxide generation was reduced 80% in vitro and by over 65% in vivo by liproxstatin-1 treatment in denervated permeabilized muscle fibers and decreased the content of 4-HNE by ∼25% post-denervation. Lipidomic analysis revealed detectable levels of 25 oxylipins in denervated gastrocnemius muscle and significantly increased levels for eight oxylipins that are generated by metabolism of fatty acids through 12/15-LOX. Liproxstatin-1 treatment reduced the level of three of the eight denervation-induced oxylipins, specifically 15-HEPE, 13-HOTrE and 17-HDOHE. Denervation elevated protein degradation rates in muscle and treatment with liproxstatin-1 reduced rates of protein breakdown in denervated muscle. In contrast, protein synthesis rates were unchanged by denervation. Targeted proteomics revealed a number of proteins with altered expression after denervation but no effect of liproxstain-1. Transcriptomic analysis revealed 203 differentially expressed genes in denervated muscle from vehicle or liproxstatin-1 treated mice, including ER stress, nitric oxide signaling, Gαi signaling, glucocorticoid receptor signaling, and other pathways. Overall, these data suggest lipid hydroperoxides and oxylipins are key drivers of increased protein breakdown and muscle loss associated with denervation induced atrophy and a potential target for sarcopenia intervention.

Male↗
PubMed2006

PET measurement of cardiac and nigrostriatal denervation in Parkinsonian syndromes.

UNLABELLED: Scintigraphic imaging with (123)I-metaiodobenzylguanidine ((123)I-MIBG) has demonstrated extensive losses of cardiac sympathetic neurons in idiopathic Parkinson's disease (IPD). In contrast, normal cardiac innervation has been observed in (123)I-MIBG studies of multiple-system atrophy (MSA) and progressive supranuclear palsy (PSP). Consequently, it has been hypothesized that cardiac denervation can be used to differentiate IPD from MSA and PSP. We sought to test this hypothesis by mapping the distribution of cardiac sympathetic neurons in patients with IPD, MSA, and PSP by using PET and (11)C-meta-hydroxyephedrine ((11)C-HED). Also, the relationship between cardiac denervation and nigrostriatal denervation was investigated by measuring striatal presynaptic monoaminergic nerve density with PET and (11)C-dihydrotetrabenazine ((11)C-DTBZ). METHODS: (11)C-HED and (11)C-DTBZ scans were obtained for patients with IPD (n = 9), MSA (n = 10), and PSP (n = 8) and for age-matched control subjects (n = 10). Global and regional measurements of (11)C-HED retention were obtained to assess the extent of cardiac sympathetic denervation. (11)C-DTBZ binding was measured in the caudate nucleus, anterior putamen, and posterior putamen. RESULTS: As expected, extensive cardiac denervation was observed in several of the patients with IPD. However, substantial cardiac denervation was also seen in some patients with MSA and PSP. (11)C-DTBZ studies demonstrated striatal denervation in all patients with IPD and in most patients with MSA and PSP. No correlation was found between cardiac (11)C-HED retention and striatal (11)C-DTBZ binding. CONCLUSION: Cardiac sympathetic denervation was found to occur not only in IPD but also in other movement disorders, such as MSA and PSP. This finding implies that scintigraphic detection of cardiac sympathetic denervation cannot be used independently to discriminate IPD from other movement disorders, such as MSA and PSP. Cardiac sympathetic denervation was not correlated with striatal denervation, suggesting that the pathophysiologic processes underlying cardiac denervation and striatal denervation occur independently in patients with parkinsonian syndromes. These findings provide novel information about central and peripheral denervation in patients with neurodegenerative disorders.

Adult↗
PubMed1997

Quantitative study of the effects of long-term denervation on the extensor digitorum longus muscle of the rat.

BACKGROUND: In order to understand the cellular basis underlying the progressively poorer restorative capacity of long-term denervated muscle, we determined the effects of long-term denervation on the muscle fibers and satellite cell population of the rat extensor digitorum longus (EDL) muscle. METHODS: In 36 male rats, the right hind legs were denervated, and EDL muscles were removed 2, 4, 7, 12, and 18 months later. Muscles were either fixed for electron microscopic analysis or were dissociated into individual muscle fibers for direct fiber counting or for confocal microscopic analysis. RESULTS: The percentage of satellite cells rose from the 2.8% control value to 9.1% at 2 months of denervation; thereafter the percentage decreased to 1.1% at 18 months of denervation. The number of myonuclei per muscle fiber steadily declined from 410 in 4 month control muscle to 158 in 7 month denervated muscle. Up to 7 months of denervation, the total number of muscle fibers per muscle remained relatively constant at somewhat over 5,000. The calculated total satellite cell population in 4 month denervated EDL muscle was the same as that of controls at 65,000, but by 7 months of denervation it had declined to 21,000. With increasing time of denervation, the number of cross-sectional profiles of muscle fibers not containing nuclei rose from 14% in control muscle to 49% in 12 month denervated muscle. This was correlated with a pronounced regular clumping of the nuclei, with pronounced nonnucleated segments between nuclear clumps. CONCLUSIONS: Increasing times of denervation are accompanied by a pronounced decline in the number of myonuclei per muscle fiber and an initial rise and subsequent fall in satellite cell number. These changes are correlated with a decreasing restorative ability of these muscles over the same periods of denervation. Further work on the proliferative capacity of the remaining satellite cells is necessary before firm quantitative conclusions can be made.

Animals↗
PubMed2000

Cell death in denervated skeletal muscle is distinct from classical apoptosis.

Denervation of skeletal muscle is followed by the progressive loss of tissue mass and impairment of its functional properties. The purpose of the present study was to investigate the occurrence of cell death and its mechanism in rat skeletal muscle undergoing post-denervation atrophy. We studied the expression of specific markers of apoptosis and necrosis in experimentally denervated tibialis anterior, extensor digitorum longus and soleus muscles of adult rats. Fluorescent staining of nuclear DNA with propidium iodide revealed the presence of nuclei with hypercondensed chromatin and fragmented nuclei typical of apoptotic cells in the muscle tissue 2, 4 and to a lesser extent 7 months after denervation. This finding was supported by electron microscopy of the denervated muscle. We found clear morphological manifestations of muscle cell death, with ultrastructural characteristics very similar if not identical to those considered as nuclear and cytoplasmic markers of apoptosis. With increasing time of denervation, progressive destabilization of the differentiated phenotype of muscle cells was observed. It included disalignment and spatial disorganization of myofibrils as well as their resorption and formation of myofibril-free zones. These changes initially appeared in subsarcolemmal areas around myonuclei, and by 4 months following nerve transection they were spread throughout the sarcoplasm. Despite an increased number of residual bodies and secondary lysosomes in denervated muscle, we did not find any evidence of involvement of autophagocytosis in the resorption of the contractile system. Dead muscle fibers were usually surrounded by a folded intact basal lamina; they had an intact sarcolemma and highly condensed chromatin and sarcoplasm. Folds of the basal lamina around the dead cells resulted from significant shrinkage of cell volume. Macrophages were occasionally found in close proximity to dead myocytes. We detected no manifestations of inflammation in the denervated tissue. Single myocytes expressing traits of the necrotic phenotype were very rare. A search for another marker of apoptosis, nuclear DNA fragmentation, using terminal deoxyribonucleotidyl transferase mediated dUTP nick end labeling (the TUNEL method) in situ, revealed the presence of multiple DNA fragments in cell nuclei in only a very small number of cell nuclei in 2 and 4 month denervated muscle and to less extent in 7 month denervated muscle. Virtually no TUNEL reactivity was found in normal muscle. Double labeling of tissue denervated for 2 and 4 months for genome fragmentation with the TUNEL method and for total nuclear DNA with propidium iodide demonstrated co-localization of the TUNEL-positive fragmented DNA in some of the nuclei containing condensed chromatin and in fragmented nuclei. However, the numbers of nuclei of abnormal morphology containing condensed and/or irregular patterns of chromatin distribution, as revealed by DNA staining and electron microscopy, exceeded by 33-38 times the numbers of nuclei positive for the TUNEL reaction. Thus, we found a discrepancy between the frequences of expression of morphological markers of apoptosis and DNA fragmentation in denervated muscle. This provides evidence that fragmentation of the genomic DNA is not an obligatory event during atrophy and death of muscle cells, or, alternatively, it may occur only for a short period of time during this process. Unlike classical apoptosis described in mammalian thymocytes and lymphoid cells, non-inflammatory death of muscle fibers in denervated muscle occurs a long time after the removal of myotrophic influence of the nerve and is preceded by the progressive imbalance of the state of terminal differentiation. Our results indicate that apoptosis appears to be represented by a number of distinct isotypes in animals belonging to different taxonomic groups and in different cell lineages of the same organism.

Animals↗
PubMed1995

Regeneration in denervated toad (Bufo viridis) gastrocnemius muscle and the promotion of the process by low energy laser irradiation.

BACKGROUND: It is known that while denervated skeletal muscles have the ability to regenerate, maturation of regenerated myofibres does not take place under these conditions. Denervation also causes elevation of "invasive" and satellite cells, but the role of these cells in the regeneration process after injury to the denervated muscle is still unknown. Low energy lasers have recently been found to modulate and accelerate physiological processes in cells. The aim of the present study was to compare regeneration in denervated and innervated amphibian muscles and to investigate whether this process in denervated muscles can be stimulated by low energy laser irradiation prior to injury in these muscles. METHODS: Denervated gastrocnemius muscles of toads were irradiated with He-Ne laser (6.0 mW, 31.2 J/cm2) 7 days postdenervation (control muscle received red light irradiation at the same wavelength). Nine days after denervation cold injury was performed on the site of irradiation of both groups of muscles. At 14 days postinjury all muscles were removed and processed for histology and histomorphometric analysis of mononucleated cells, myotubes, and young myofibres in the regenerated zone. RESULTS: The volume fraction (percent of total injured zone) of the various histological structures in the injured zones 14 days after cold injury in the denervated (9 days prior to injury) muscles did not differ from innervated injured muscles at the same time interval postinjury. The mononucleated cells and myotubes in the laser irradiated muscles comprised 49 +/- 4% and 6 +/- 1% of the injured area, respectively, which was significantly lower than their volume fraction (67 +/- 2% and 11 +/- 2%, respectively) in the control muscles. The young myofibres populated 34 +/- 4% of the total injured area in the denervated and laser irradiated muscles which was significantly higher than their volume fraction (12 +/- 2%) in control denervated muscles. CONCLUSIONS: It is concluded that initial stages of regeneration can also take place in skeletal denervated and injured muscles of amphibians. The kinetics of the regeneration process are identical in denervated and innervated muscles. The process of regeneration in denervated muscles can be markedly enhanced if the muscle is irradiated by low energy laser prior to injury, probably by activation (stimulation of proliferation and/or differentiation) cells in the muscles that are "recruited" and participate in the process of regeneration.

Animals↗
PubMed2001

Effect of dopamine infusion on hemodynamics after hepatic denervation.

BACKGROUND: . The effects of dopamine (DA) on systemic hemodynamics are better understood than its effects on hepatic hemodynamics, especially after liver denervation occurring during liver transplantation. Therefore, a porcine model was used to study DA's effects on hemodynamics after hepatic denervation. MATERIALS AND METHODS: Fifteen pigs underwent laparotomy for catheter and flow probe placement. The experimental group (n = 7) also underwent hepatic denervation. After 1 week, all pigs underwent DA infusion at increasing doses (3-30 mcg/kg/min) while measuring hepatic parameters [portal vein flow (PVF), hepatic artery flow (HAF), total hepatic blood flow (THBF = HAF + PVF), portal and hepatic vein pressures] and systemic parameters [heart rate (HR), mean arterial pressure (MAP)]. RESULTS: There was a significant increase in HAF from baseline to the 30 mcg/kg/min DA infusion rate (within-subjects P < 0.01), but the differences between the two groups were not significant. PVF and THBF showed large effects (increases) with denervation, but the increase in flow with DA infusion was not present after denervation. Perihepatic pressures were unchanged by denervation or DA. Heart rate differed significantly between the control and denervated animals at baseline, 3, 6, 12 (all P < 0.05), and 30 mcg/kg/min DA (P = 0.10). Control vs denervation MAP at baseline was 100 +/- 4 vs 98 +/- 4 Torr and at 30 mcg/kg/min it was 110 +/- 3 vs 101 +/- 5 mm Hg. CONCLUSIONS: Hepatic flows tended to be higher after denervation. HAF showed similar increases with DA in both control and denervation groups. Increases in PVF and THBF with DA infusion were not present after denervation. HR was significantly decreased and MAP tended to be lower after denervation. The HR and MAP response to DA was similar in both groups. Therefore, both denervation and DA infusion have an effect on systemic and hepatic hemodynamics.

Animals↗
PubMed1997

Effects of long-term phasic electrical stimulation on denervated soleus muscle: guinea-pig contrasted with rat.

Guinea-pig soleus muscles were denervated and electrically stimulated for periods of 43 to 66 days. Stimuli were in 1 s bursts of 40 Hz pulses, repeated every 5 min. Other guinea-pigs were denervated for 82 days without stimulation and, in a third group, the soleus muscle was necrotized and allowed to regenerate without reinnervation for 13-15 days. Isometric and isotonic recordings were made in vivo. Denervated guinea-pig muscles were embedded in epoxy resin for light and electron microscopy. Chronic stimulation of denervated guinea-pig soleus had no effects on the prolonged twitch or on reduced maximal shortening velocity, maximal rate of rise of tension and tetanic force. This contrasts with the slow-to-fast conversion produced by denervation and denervation-stimulation of rat soleus. Loss of force was much greater in rat than guinea-pig after denervation, and chronic stimulation increased force in rat to the same level as in guinea-pig after denervation (with or without stimulation). Eighty-day denervated guinea-pig soleus did not reveal those morphological signs of fibre breakdown and regeneration which are prominent in denervated rat soleus muscles. Those changes in rat resembled aneurally regenerated muscles in several aspects, especially the increased incidence of fibres with internal myo-nuclei which did not appear in guinea-pig soleus after denervation. Aneurally regenerated guinea-pig soleus became fast like aneurally regenerated rat muscle. Our data are compatible with the hypothesis that slow-to-fast transformation of denervated rat soleus is not directly brought about by chronic stimulation but by de-novo formation of fast-contracting regenerated fibres. The persistence of fibrillation in guinea-pig but not rat after denervation may account for the species difference.

Animals↗
PubMed1976

The adrenergic innervation and adrenergic receptor activity of the feline urinary bladder and urethra in the normal state and after hypogastric and/or parasympathetic denervation.

After long-term parasymphatetic denervation, detrusor muscle hypertrophy was found regardless of whether the hypogastric nerves had been sectioned simultaneously or not. After hypogastric denervation only, there was no difference in gross appearance from normal bladders. Adrenergic innervation was studied by means of a histochemical fluorescence technique. After hypogastric denervation, there was usually a slight increase in the detrusor innervation, and a clear decrease in the trigone and urethral adrenergic innervation. After parasympathetic denervation, the detrusor showed an increase in adrenergic innervation, while the innervation of the trigone and the urethra was unchanged. After simultaneous parasympathetic and hypogastric denervation, the adrenergic innervation of the detrusor was similar to that of the bladders subjected to parasympathetic denervation only. The adrenergic innervation of the trigone and urethra was similar to that found after hypogastric denervation only. Adrenergic receptor functions were studied by a method in which changes in the isometric tension of muscle strips were recorded following different pharmacological treatments. In the normal state, noradrenalin and phenylephrine caused contraction and isoprenaline relaxation of the trigone-urethra. In the detrusor, noradrenalin caused relaxation of strips contracted by carbacholine. Relaxed detrusor muscle strips were usually not contracted by noradenalin. In 2 out of 8 normal cats, however, a contraction was observed after very large doses of noradrenalin. After hypogastric denervation, the adrenoreceptor functions were consistent with those of the normal state. After parasympathetic denervation, the trigone-urethral receptor functions were unchanged compared with the normal receptor functions. In the detrusor, isoprenaline caused relaxation and noradrenalin and phenylephrine contraction. After simultaneous parasympathetic and hypogastric denervation, the results were consistent with those obtained after parasympathetic denervation only. Thus, the present study showed an increased adrenergic detrusor innervation and alpha-receptor activity after parasympathetic denervation regardless of whether the hypogastric nerves had been sectioned simultaneously or not. Although alpha-receptors might exist in the normal detrusor, beta-receptors dominate strongly. After parasympathetic denervation, there seems to be a change in the relation between alpha- and beta-receptors in favour of alpha-receptors.

Animals↗
PubMed1999

Satellite cells on isolated myofibers from normal and denervated adult rat muscle.

Satellite cells (SCs) in normal adult muscle are quiescent. They can enter the mitotic program when stimulated with growth factors such as basic FGF. Short-term denervation stimulates SC to enter the mitotic cycle in vivo, whereas long-term denervation depletes the SC pool. The molecular basis for the neural influence on SCs has not been established. We studied the phenotype and the proliferative capacity of SCs from muscle that had been denervated before being cultured in vitro. The expression of PCNA, myogenin, and muscle (M)-cadherin in SCs of normal and denervated muscle fibers was examined at the single-cell level by immunolabeling in a culture system of isolated rat muscle fibers with attached SCs. Immediately after plating (Day 0), neither PCNA nor myogenin was present on normal muscle fibers, but we detected an average of 0.5 M-cadherin(+) SCs per muscle fiber. The number of these M-cadherin(+) cells (which are negative for PCNA and myogenin) increased over the time course examined. A larger fraction of cells negative for M-cadherin underwent mitosis and expressed PCNA, followed by myogenin. The kinetics of SCs from muscle fibers denervated for 4 days before culturing were similar to those of normal controls. Denervation from 1 to 32 weeks before plating, however, suppressed PCNA and myogenin expression almost completely. The fraction of M-cadherin(+) (PCNA(-)/myogenin(-)) SCs was decreased after 1 week of denervation, increased above normal after denervation for 4 or 8 weeks, and decreased again after denervation for 16 or 32 weeks. We suggest that the M-cadherin(+) cells are nondividing SCs because they co-express neither PCNA or myogenin, whereas the cells positive for PCNA or myogenin (and negative for M-cadherin) have entered the mitotic cycle. SCs from denervated muscle were different from normal controls when denervated for 1 week or longer. The effect of denervation on the phenotypic modulation of SCs includes resistance to recruitment into the mitotic cycle under the conditions studied here and a robust extension of the nonproliferative compartment. These characteristics of SCs deprived of neural influence may account for the failure of denervated muscle to fully regenerate. (J Histochem Cytochem 47:1375-1383, 1999)

Animals↗
PubMed2001

Interrelations of myogenic response, progressive atrophy of muscle fibers, and cell death in denervated skeletal muscle.

Little is known concerning the time-course and structural dynamics of reactivation of compensatory myogenesis in denervated muscle, its initiating cellular mechanisms, and the relationship between this process and the progression of postdenervation atrophy. The purpose of this study was to investigate the interrelations between temporal and spatial patterns of the myogenic response in denervated muscle and progressive atrophy of muscle fibers. Another objective was to study whether reactivation of myogenesis correlates with destabilization of the differentiated state and death of denervated muscle cells. It has remained unclear whether muscle fiber atrophy was the primary factor activating the myogenic response, what levels of cellular atrophy were associated with its activation, and whether the initiation and intensity of myogenesis depended on the local and individual heterogeneity of atrophic changes among fibers. For this reason, our objective was also to identify the levels of atrophic and degenerative changes in denervated muscle fibers that are correlated with activation of the myogenic response. We found that the reactivation of myogenesis in the tibialis anterior and extensor digitorum longus muscles of the rat starts between days 10-21 following nerve transection, before atrophy has attained advanced level, long before dead cells are found in the tissue. Formation of new muscle fibers reaches its maximum between 2 and 4 months following denervation and gradually decreases with progressive postdenervation atrophy. The myogenic response is biphasic and includes two distinct processes. The first process resembles the formation of secondary and tertiary generations of myotubes during normal muscle development and dominates during the first 2 months of denervation. During this period, activated satellite cells form new myotubes on live differentiated muscle fibers. Most of the daughter myotubes in 1- and 2-month denervated muscle develop on the surface of fast type parent muscle fibers, and some of the newly formed muscle fibers express slow myosin. Some fast type parent fibers are weakly or, more rarely, moderately immunopositive for embryonic isomyosin. This indicates that reactivation of myogenesis may also depend on the fiber type. The level of atrophy, destabilization of the differentiated myofiber phenotype, and degenerative changes of individual fibers in denervated muscle are very heterogeneous. The myogenic response of the first type is associated predominantly with fibers of average and higher than average levels of atrophy. Muscle cells that undergo a lesser degree of atrophy also form daughter fibers, although with a lower incidence. We did not find any correlation between the size of newly formed fibers and the level of atrophy of parent fibers. The topographical distribution of new myotubes both in the peripheral and central areas of the mid-belly equatorial sections at the early stages following nerve transection indicates that myogenesis of the first type represents a systemic reaction of muscle to the loss of neural control. These data indicate that activation of the myogenic response does not depend on cell death and degenerative processes per se. The second type of myogenesis is a typical regenerative reaction that occurs mainly within the spaces surrounded by the basal laminae of dead muscle fibers. Myocytes of different sizes are susceptible to degeneration and death, which indicates that cell death in denervated muscle does not correlate with levels of muscle cell atrophy. The regenerative process frequently results in development of abnormal muscle cells that branch or form small clusters. Replacement of lost fibers becomes activated between 2 and 4 months following nerve transection, i.e., mainly at advanced stages of postdenervation atrophy, when cell death becomes a contributing factor of the atrophic process. In long-term denervated muscle, the first and second types of myogenesisoccur concurrently, and the topographical distribution of the myogenic response becomes more heterogeneous than during the first weeks following denervation. Thus, our data demonstrate differential temporal and spatial expression of two patterns of myogenesis in denervated muscle that appear to be controlled by different regulatory mechanisms during the postdenervation period. (c) 2001 Wiley-Liss, Inc.

Animals↗
PubMed2006

Deficiency of the Bax gene attenuates denervation-induced apoptosis.

Apoptosis has been implicated in mediating denervation-induced muscle wasting. In this study we determined the effect of interference of apoptosis on muscle wasting during denervation by using mice genetically deficient in pro-apoptotic Bax. After denervation, muscle wasting was evident in both wild-type and Bax(-/-) muscles but reduction of muscle weight was attenuated in Bax(-/-) mice. Apoptotic DNA fragmentation increased in wild-type denervated muscles whereas there was no statistical increase in DNA fragmentation in denervated muscles from Bax(-/-) mice. Mitochondrial AIF and Smac/DIABLO releases and Bcl-2, p53 and HSP27 increased whereas XIAP and MnSOD decreased to a similar extent in muscles from wild-type and Bax(-/-) mice following denervation. Mitochondrial cytochrome c release was elevated in denervated muscles from wild-type mice but the increase was suppressed in muscles from Bax(-/-) mice. Increases in caspase-3 and -9 activities and oxidative stress markers H(2)O(2), MDA/4-HAE and nitrotyrosine were all evident in denervated muscles from wild-type mice but these changes were absent in muscles from Bax(-/-) mice. Moreover, ARC increased exclusively in denervated Bax(-/-) muscle. Our data indicate that under conditions of denervation, pro-apoptotic signalling is suppressed and muscle wasting is attenuated when the Bax gene is lacking. These findings suggest that interventions targeting apoptosis may be valuable in ameliorating denervation-associated pathologic muscle wasting in certain neuromuscular disorders that involve partial or full denervation.

Animals↗
PubMed1989

Changes in the properties of synaptic channels opened by acetylcholine in denervated frog muscle.

Acetylcholine (ACh)-activated channels in end-plates of frog sartorius muscle were studied at various times after denervation. Mean open times of the synaptic membrane channels were derived from the time constant of decay of miniature end-plate currents (tau MEPC) evoked by ACh quanta released from Schwann cells, which replace the motor nerve terminals after these degenerate. Membrane current noise, elicited by iontophoretic application of ACh to voltage-clamped end-plates, was also used to determine mean open time (tau noise) and conductance of the ion channels. About 1 week after denervation, soon after Schwann cell MEPCs appeared, they had a tau similar to that of the neural MEPC in innervated end-plates. However, 5-6 weeks after denervation tau MEPC was increased by a factor of about 5. Circa 4 weeks after denervation, cholinesterase activity of the denervated muscle decreased to 76% of that in the contralateral, innervated muscle, and even 4 months after the operation it was still 64%. Thus, it is unlikely that a change in acetylcholinesterase activity is the main factor responsible for the increase in tau of Schwann cell MEPC. About 1 week after denervation tau noise was close to that in innervated end-plates (about 2 ms). Twelve to 24 days after denervation the average channel open time was 4.5 +/- 1.0 ms, with some end-plates still showing normal 'fast' channels. However, in muscles denervated for 47-113 days the open time was 12.9 +/- 1.9 ms. In the early and intermediate periods, ACh-induced noise spectra with two components were obtained from many end-plates, indicating the simultaneous activation of two different types of channels. At some end-plates during the early and intermediate periods after denervation, but not after about 5 weeks, neostigmine caused the appearance of a component, which was as fast as that of normal end-plate channels. In other experiments small doses of alpha-bungarotoxin were applied in order to predominantly block extra-junctional receptors. In the early period of denervation, when two components were present in the noise spectra, alpha-bungarotoxin eliminated the slow component leaving channels as fast as in innervated end-plates. After prolonged denervation, a component with tau of about 5.5 ms was occasionally disclosed by application of alpha-bungarotoxin. tau noise and tau MEPC from the same end-plate closely agreed. Our results indicate that at frog end-plates the open time of the majority of the synaptic channels opened by ACh becomes longer with increasing time after denervation.

Acetylcholine↗
PubMed1988

Resistance of protein and glucose metabolism to insulin in denervated rat muscle.

Denervated (1-10 days) rat epitrochlearis muscles were isolated, and basal and insulin-stimulated protein and glucose metabolism were studied. Although basal rates of glycolysis and glucose transport were increased in 1-10-day-denervated muscles, basal glycogen-synthesis rates were unaltered and glycogen concentrations were decreased. Basal rates of protein degradation and synthesis were increased in 1-10-day-denervated muscles. The increase in degradation was greater than that in synthesis, resulting in muscle atrophy. Increased rates of proteolysis and glycolysis were accompanied by elevated release rates of leucine, alanine, glutamate, pyruvate and lactate from 3-10-day-denervated muscles. ATP and phosphocreatine were decreased in 3-10-day-denervated muscles. Insulin resistance of glycogen synthesis occurred in 1-10-day denervated muscles. Insulin-stimulated glycolysis and glucose transport were inhibited by day 3 of denervation, and recovered by day 10. Inhibition of insulin-stimulated protein synthesis was observed only in 3-day-denervated muscles, whereas regulation by insulin of net proteolysis was unaffected in 1-10-day-denervated muscles. Thus the results demonstrate enhanced glycolysis, proteolysis and protein synthesis, and decreased energy stores, in denervated muscle. They further suggest a defect in insulin's action on protein synthesis in denervated muscles as well as on glucose metabolism. However, the lack of concurrent changes in all insulin-sensitive pathways and the absence of insulin-resistance for proteolysis suggest multiple and specific cellular defects in insulin's action in denervated muscle.

Adenosine Triphosphate↗
PubMed2006

[Long-term results following denervation of the wrist in patients with stages II and III SLAC-/SNAC-wrist].

INTRODUCTION: Mid-carpal arthrodesis, proximal row carpectomy and wrist arthrodesis are commonly cited in the literature as successful methods for pain reduction in patients with advanced carpal collapse (SLAC-/SNAC-wrist stages II and III). However, studies of isolated wrist denervation in patients who still possess good wrist mobility appear to be an underrepresented topic, especially in the German literature. PURPOSE: Based on follow-up results, it was possible to establish to what extent patients benefit long-term from isolated wrist denervation, whilst retaining wrist mobility. PATIENTS AND METHOD: 46 patients (6 female, 40 male) with a diagnosis of SLAC-wrist (n = 10) or SNAC-wrist (n = 36) stages II and III underwent wrist denervation of points 1 - 4, 6, 9 and 10 according to Wilhelm, between 1990 and 2001, following a positive denervation test. No previous reconstructive wrist surgery had been performed on any of the patients, whose average age at the time of denervation was 47 years. In 29 cases the dominant hand was affected, and in 22 cases the symptoms could be classified as post-traumatic. Post-operative follow-up was possible in 32 out of 46 cases (70 %), and occurred on average 6.3 years post-denervation (range 2.3 to 14 years). RESULTS: Twelve out of 32 patients (32 %) reported to be pain-free at follow-up, with a post-operative period ranging from 2.3 to 11.4 years (average 6.2 years). Six patients (18.75 %) continued to experience pain when load-bearing, which remained unchanged over a period of several years. Three patients (9 %) reported pain after stress, five patients (15.6 %) the recurrence of severe pain, which developed on average 3.8 years post-operatively. Two patients (6.25 %) experienced no analgesic benefits following wrist denervation, and four patients underwent wrist arthrodesis on average 13.5 months post-denervation, due to remaining or additional symptoms. Nineteen out of 32 patients subjectively reported a significant improvement following wrist denervation. Reassessment of range of movement post-denervation showed a reduction of 8.1 % in wrist extension/flexion, and 20 % in radio/ulna-abduction. Compared to the unaffected side, this represented an average loss of 28 % wrist extension/flexion, and 33.5 % radio/ulna-abduction. An average 51 % increase in hand strength could be shown at follow-up, leaving an average 30 % deficit compared to the unaffected hand. Evaluation of these results using the Krimmer score showed a good - very good outcome in 20 of the 32 patients (62.5 %); six patients were found to have a satisfactory outcome, and six patients a poor outcome. Subjective measures of pain (obtained using visual analogue scales) showed a reduction from 68.13 pre-operatively to 25.63 post-operatively. The DASH assessment (parts A and B) attained an average post-operative value of 17.1. CONCLUSION: Denervation of the wrist in patients with SLAC-/SNAC-wrist stages II and III can achieve a long-term elimination or reduction of pain, whilst improving hand strength, and having only a minimal impact on wrist range of movement. Wrist denervation should therefore be given preference over wrist arthrodesis, midcarpal arthrodesis or proximal row carpectomy in patients with good wrist mobility.

Adult↗
PubMed1995

Adaptation of nicotinic acetylcholine receptor, myogenin, and MRF4 gene expression to long-term muscle denervation.

Muscle activity alters the expression of functionally distinct nicotinic acetylcholine receptors (nAChR) via regulation of subunit gene expression. Denervation increases the expression of all subunit genes and promotes the expression of embryonic-type (alpha 2 beta delta gamma) nAChRs, while electrical stimulation of denervated muscle prevents this induction. We have discovered that the denervation-induced increases in alpha, beta, gamma, and delta subunit gene expression do not persist in muscles that have been denervated for periods extending beyond a couple of months. However, expression of RNA encoding the epsilon-subunit remains elevated suggesting a return to expression of predominantly adult-type (alpha 2 beta delta epsilon) nAChR in long-term denervated muscles; a finding confirmed by single channel patch-clamp analysis. Since the nAChR subunit genes are regulated by the MyoD family of muscle regulatory factors, and the genes encoding these factors are also induced following short-term muscle denervation, we determined their level of expression in long-term denervated muscle. Although MyoD and myf-5 RNA levels remained elevated, myogenin and MRF4 RNAs were induced only transiently by muscle denervation. Surprisingly, Id-1, a negative regulator of transcription, was gradually induced in denervated muscle with RNA levels peaking about two months after denervation. It is likely that this maintained level of increased Id expression, in conjunction with the returning levels of myogenin and MRF4 expression, account for the reduced level of embryonic receptors in long-term denervated muscle. These changing patterns of gene expression may have important consequences for the ability of muscle to recover function after denervation.

Adaptation, Physiological↗
PubMed2002

Skeletal muscle denervation increases satellite cell susceptibility to apoptosis.

Peripheral motor nerve trauma severely compromises skeletal muscle contractile function. Satellite cells respond to denervation by dividing multiple times, ultimately fusing with other satellite cells or myocytes to form new muscle fibers. After chronic denervation, satellite cell numbers decline dramatically, impairing the ability to regenerate and repair myofibers. This satellite cell depletion may contribute to the mechanical deficit observed in denervated or reinnervated muscle. Apoptosis, an evolutionarily conserved form of cell suicide, is a potential mechanism for satellite cell depletion in denervated skeletal muscle. This work tested the hypothesis that skeletal muscle denervation increases satellite cell susceptibility to apoptotic cell death. Adult rats underwent sciatic nerve transection to denervate the distal hindlimb musculature; rats of similar age without the operation served as controls. Two, 6, 10, or 20 weeks after denervation (n = 6 each group), the gastrocnemius and soleus were excised, enzymatically digested, and plated for satellite cell culture. After reaching 95 percent confluence, satellite cells were treated for 24 hours with tumor necrosis factor-alpha (20 ng/ml) and actinomycin D (250 ng/ml), known pro-apoptotic agents. Immunostaining for activated caspases, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and hematoxylin and eosin staining were performed to identify apoptotic satellite cells. Percentages of apoptotic cells were quantified histomorphometrically. In addition, the presence or absence of bcl-2 and bax was determined by Western blot analysis of control, 6 weeks of denervation, and 10 weeks of denervation specimens. At 6 and 10 weeks after nerve transection, TUNEL and caspase activity were increased more than two-fold in satellite cells isolated from denervated muscle compared with those isolated from control muscle (p < 0.05). In all experimental groups, retention of adherence to the collagen-coated substrate was strongly associated with satellite cell survival. Western blot analysis revealed that adherent satellite cells from all groups expressed both bcl-2 and bax. These data support the authors' hypothesis that skeletal muscle denervation increases satellite cell susceptibility to apoptotic cell death. Apoptosis may play a causative role in the depletion of satellite cells in long-term denervated skeletal muscle.

Animals↗
PubMed1983

Denervation increases the degradation rate of acetylcholine receptors at end-plates in vivo and in vitro.

We have studied the effect of denervation on the degradation of the existing junctional acetylcholine (ACh) receptors at end-plates in rat muscles. ACh receptors were labelled by injecting animals with iodinated alpha-bungarotoxin (I-alpha BT); 1 day later the left hemidiaphragm was denervated. The degradation of bound I-alpha BT in normal and denervated muscles was examined in organ culture, beginning at various times after denervation in vivo. The original, pre-labelled end-plate ACh receptors are degraded more rapidly after denervation. The rate of degradation begins to increase shortly after the nerve is cut and reaches a maximum value at about 9 days of denervation. Muscles denervated only on transfer to organ culture also show an increase in the degradation rate of bound I-alpha BT with increasing time of denervation (time in culture). In normal diaphragm muscles, the initial rate of degradation of functional ACh receptors, after correcting for non-degradative loss of I-alpha BT, is 0.0018 h-1 (t1/2 = 383 h). The maximal rate at denervated end-plates is 0.0073 h-1 (t1/2 = 94 h). For soleus, sternomastoid, plantaris and intercostal innervated muscles the apparent rate of ACh receptor degradation either in vitro or in vivo ranged from 0.0005 h-1 to 0.002 h-1. The rate of loss of bound I-alpha BT in vivo is more rapid at denervated end-plates than at innervated end-plates. For diaphragm muscles, the rates of I-alpha BT degradation measured in organ culture are able to describe the relative rates of loss of I-alpha BT from innervated and denervated muscles in vivo. At short times after labelling, a fraction (10-20%) of the I-alpha BT bound to innervated muscles is degraded more rapidly than the remaining toxin. The possibility that these I-alpha BT binding sites are degraded at the rate characteristic of extrajunctional receptors on denervated muscle fibres is discussed.

Acetylcholine↗