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At least 811 records · Page 45Linked to original sources
PubMed1980

Isometric responses in the denervated diaphragmatic muscle of the guinea pig elicited by antigen and histamine.

Denervated diaphragmatic muscle strips from the guinea pig responded in vitro to varying concentrations of histamine with isometric contractions. Dose-response curves from strips taken from several areas of the muscle (ventral, V; dorsal, D; lateral, L) had slopes which were related in the following manner: D greater than V greater than L. Nevertheless, when the curves were normalized with respect to a dose which produced maximal tension, the slopes were similar and could be superimposed. Preparations taken from animals allergized to either bovine serum albumin or ferritin responded to the antigen with isometric contractions which also differed according to the original location of the strip in the muscle (D greater than V greater than L), but were similar when normalized as above. The results obtained from the normalized curves reflect a uniform sensitivity to histamine and antigen throughout the muscle. The variations in tension developed in the different strips probably are related to their contractile mass. The isometric recordings also revealed the development of spontaneous muscular contractions, as well as the presence of response latencies to both histamine and antigen, but not to acetylcholine.

Animals↗
PubMed1994

Sarcoplasmic reticulum Ca2+ pump expression in denervated skeletal muscle.

This study was undertaken as one approach to better understand how contractile activity regulates excitation-contraction coupling phenotype in skeletal muscle. The effects of denervation on the expression of the sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (ATPase), a key protein of the contraction-relaxation cycle, was analyzed in fast-twitch (FT) and slow-twitch (ST) skeletal muscle. Muscle mass, mRNA, and protein expression of specific isoforms of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) and contractile parameters related to muscle relaxation were measured in rat soleus and extensor digitorum longus (EDL) muscles at 1, 4, 7, 14, and 28 days after sciatic nerve transection. Wet muscle mass decreased to 35% of control by 28 days of denervation in both soleus and EDL muscles (P < 0.05). Northern and Western analyses showed decreases in mRNA and protein expression of the slow Ca2+ pump isoform (SERCA2a) in the denervated soleus muscle and in the fast Ca2+ pump isoform (SERCA1) in the denervated EDL muscle, particularly at later time points. There was no change in the expression of the alternate isoform in either muscle type. Prolongation of twitch contraction times, slowed rates of tension development, and leftward shifts in frequency-tension curves were consistent with the reduced Ca2+ pump density and suggested slowed Ca2+ handling in SR or denervated ST and FT muscles. The results are in marked contrast with those previously reported in non-weight-bearing muscle induced by biomechanical unloading.

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&#xa0;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 (&#x223c;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 &#x223c;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, G&#x3b1;i 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↗
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↗
PubMed1994

Effect of muscle flap denervation on flow hemodynamics: a new model for chronic in vivo studies.

The purpose of this study was to evaluate microcirculatory dynamics following muscle flap denervation. A modification of standard cremaster muscle flap was used. Fifty male Sprague-Dawley rats were studied in two experimental groups of 25 rats each, as follows: Group I (control), after flap isolation, the neurovascular pedicle was left intact; group II (denervation), following muscle isolation at 1 cm segment of genitofemoral nerve was excised and denervated muscle was preserved in the medial border of rat hind limb. For chronic evaluation the cremaster was withdrawn from the leg and prepared for in vivo observations after days 1, 3, 7, and 14. The following measurements were taken: vessel diameters, red blood cell velocities, and number of perfused capillaries. In group II a 15% increase in arteriolar diameter was observed. Throughout the entire 14 day period denervated flaps presented 27% more perfused capillaries. Flap denervation proved to increase capillary perfusion significantly (P < 0.05). The cremaster muscle tube-flap model introduced in this study allows for chronic observation of the microcirculation.

Animals↗
PubMed1986

Characteristics of acetylcholine-activated channels of innervated and chronically denervated skeletal muscles.

Characteristics of the ACh-activated channels before and after denervation of the frog interosseal muscle were studied using the patch clamp technique. Acetylcholine sensitivity was increased on extrajunctional portions of the muscle 7, 42, and 73 days after sectioning of the sciatic nerve. Nonjunctional regions of the innervated muscle appeared to contain one type of ACh channels having a conductance of 28 pS and a mean channel lifetime of 3.8 ms at -90 mV. The denervated muscles contained two classes of channels with conductance of 18 and 28 pS which were present as early as 7 days postdenervation and remained for 93 days. The channel open times of the innervated muscles increased with membrane hyperolarization. The open times of the channels present at 42 days postdenervation showed longer lifetimes than those of innervated muscles and were 10.8 ms and 9.6 ms at -90 mV. These channels also showed less voltage dependence than the control fibers.

Acetylcholine↗
PubMed1978

Adenyl cyclase in normal and denervated skeletal muscles.

Adenyl cyclase (AC) has been studied in homogenates and crude plasma membranes from normal and denervated red and white skeletal muscle from male rats. Basal-, NaF- and epinephrine-stimulated activities were increased in homogenates of both types of muscles after nerve transection, supporting a possible role of the cAMP-AC system in the neurotrophic control of skeletal muscle. AC-specific activity was increased 10 times in crude plasmic membranes from normal muscle if compared to that of homogenate. It was decreased in crude plasmic membrane from denervated muscle. The correlation of our results with other results on cAMP concentrations and cAMP phosphodiesterase (PDE) activities in denervated muscle suggests that factors other than AC and PDE might control the synthesis and degradation of cAMP.

Adenosine Triphosphate↗
PubMed2000

Hybrid fibrillation potentials and positive sharp waves.

Fibrillation potential configurations are characterized as initially positive triphasic waveforms, whereas positive sharp waves appear biphasic with an initial positive deflection. Careful observation of single muscle fiber discharges in denervated muscle, however, can reveal many different-appearing and stable firing waveforms that resemble a bifid positive sharp wave or some form of combined fibrillation potential and positive sharp wave. In this investigation, a number of atypical-appearing single muscle fiber discharges are hypothesized to arise from particular interactions between the muscle fiber and recording electrode. Single muscle fiber potentials are modeled as originating from a single denervated muscle fiber's former endplate and midfiber region as well as from the fiber's tendinous termination for both a compressed and sealed end effect. The modeled waveforms' appearance corresponds well to those obtained clinically and the necessary interpotential summated templates' temporal domains are feasible for action potential termination at the electrode with subsequent reinitiation beyond the proposed peri-electrode compressed region. It is hypothesized that the majority of hybrid waveforms are the result of a single muscle fiber action potential terminating at a recording electrode while also initiating a "skipped" activation of the muscle fiber past the electrode resulting in the summation of two distinct time-locked waveforms.

Action Potentials↗
PubMed1994

Sodium channels aggregate at former synaptic sites in innervated and denervated regenerating muscles.

The role of innervation in the establishment and regulation of the synaptic density of voltage-activated Na channels (NaChs) was investigated at regenerating neuromuscular junctions. Rat muscles were induced to degenerate after injection of the Australian tiger snake toxin, notexin. The loose-patch voltage clamp technique was used to measure the density and distribution of NaChs on muscle fibers regenerating with or without innervation. In either case, new myofibers formed within the original basal lamina sheaths, and, NaChs became concentrated at regenerating endplates nearly as soon as they formed. The subsequent increase in synaptic NaCh density followed a time course similar to postnatal muscles. Neuromuscular endplates regenerating after denervation, with no nerve terminals present, had NaCh densities not significantly different from endplates regenerating in the presence of nerve terminals. The results show that the nerve terminal is not required for the development of an enriched NaCh density at regenerating neuromuscular synapses and implicate Schwann cells or basal lamina as the origin of the signal for NaCh aggregation. In contrast, the change in expression from the immature to the mature form of the NaCh isoform that normally accompanies development occurred only partially on muscles regenerating in the absence of innervation. This aspect of NaCh regulation is thus dependent upon innervation.

Animals↗
PubMedDate not supplied

Increased T3 deiodination in dystrophic and neonatally denervated mouse muscle.

T3, free iodide levels and morphological features were compared in normal, 129 ReJ dy/dy dystrophic and neonatally denervated skeletal muscles of mice, killed 6 hr after a single intraperitoneal injection of iodine-labelled hormone. Both the dystrophic andthe denervated muscles were found to contain equal amounts of T3 but more iodide than the normal specimens. Increased iodide levels are considered to reflect augmented T3-catabolism by muscle dehalogenase and may indicate low free hormone levels in the soluble enzyme fraction of the cell, despite its normal overall T3 content. The close light-microscopic resemblance of 129 ReJ dy/dy dystrophy and neonatal denervation is confirmed. The possibility is discussed that one or several of the muscular dystrophies are forms of target organ hypothyroidism.

Animals↗
PubMed1975

Increased collagen and glycoprotein contents of the denervated cremaster muscle of the bonnet monkey, Macaca radiata.

Denervation of genitofemoralis in the bonnet monkey for 60 days resulted in a significant increase in neutral salt-soluble, alkali-soluble and insoluble collagens as well as glycoproteins. The hydroxyproline content of the salt-soluble and insoluble collagens in the muscle increased on denervation. These changes are discussed to imply the impairment of the action of specific structural genes.

Animals↗
PubMed1993

Calcium influx and protein phosphorylation mediate the metabolic stabilization of synaptic acetylcholine receptors in muscle.

During neuromuscular synapse development, the degradation rate of ACh receptors (AChRs) accumulated in the synaptic portion of the muscle membrane is drastically reduced under neural control, their half-life t1/2 increasing from 1 d to about 12 d. Recent evidence suggests that the metabolic stability of synaptic AChRs is mediated by the muscle activity induced by the nerve. We have now investigated the pathway linking muscle activity and metabolic stabilization of synaptic AChRs in organ cultured rat muscle. Soleus and diaphragm muscles were denervated for 14-40 d, a procedure leading to the destabilization of synaptic AChRs, and conditions required to restabilize synaptic AChRs in the denervated muscle were analyzed. The activity-dependent stabilization of synaptic AChRs in chronically denervated endplates required calcium entry through dihydropyridine-sensitive Ca2+ channels activated by high-frequency stimulation for approximately 6 hr and was specific for synaptic AChRs. As in vivo, extrasynaptic AChRs were not stabilized, and their t1/2 remained 1 d. The stabilization process was not dependent on de novo protein synthesis, and it could also be brought about by elevated cAMP levels. Furthermore, it required shorter stimulation periods in the presence of the phosphatase inhibitors okadaic acid and calyculin A, whereas blockade of protein kinases with high doses of staurosporine blocked the stabilization. Activity-dependent, dihydropyridine-sensitive as well as cAMP-dependent phosphorylation of myosin light chain was observed. These findings are consistent with the notion that muscle activity initiates AChR stabilization via the activation of calcium-dependent protein phosphorylation reactions.

Alkaloids↗
PubMed1982

Binding of myasthenia gravis antibodies to different acetylcholine receptor preparations.

A group of myasthenia gravis (MG) patients was studied in order to demonstrate the differential ability of acetylcholine receptor (AChR) antibodies to bind to AChRs from different sources. Four different AChR sources were used: human muscle, denervated rat muscle, normal rat muscle and the electric organ of the electric ray, Torpedo californica. We demonstrated that AchR antibodies from MG patients tested reacted best with receptors from human muscle, and least with the electric ray receptor. The patients were classified into three categories, each representing an antibody level pattern. THe most common pattern was that in which the antibody level for human AchR is highest, followed by decreasing values for AchRs of denervated rat muscle, normal rat muscle, and that of the electric organ of the electric ray. No correlation was found between the patient-specific antibody pattern and a clinical description of the MG patient.

Animals↗
PubMed1976

Noise analysis of drug induced voltage clamp currents in denervated frog muscle fibres.

1. Voltage clamp currents were recorded during iontophoretic application of steady doses of acetylcholine (ACh), carbachol or suberyldicholine to hyperpersensitive extrasynaptic regions of chronically denervated frog muscle fibers. Autocorrelation functions of drug induced current fluctuations were calculated and estimates of conductance gamma and average open time tau of the extrasynaptic ion channels were derived. 2. The average open time of an extrajunctional channel induced by acetylcholine is tauACh = 11 +/- 1-6 msec (+/- S.E.) at -80 mV and 8 degrees C. Carbachol and suberyldicholine open channels of tauCarb = 3-9 +/- 0-4 msec and tauSubCh = 19 +/- 2-5 msec (+/- S.E.) duration under the same conditions. The average open time of the extrasynaptic channel produced by each drug is three to five times longer than the value found for junctional channels in normal fibres. 3. The average open time of the extrajunctional channel is dependent on temperature and membrane potential. Lowering the temperature or increasing the membrane potential increases the average open time of the channels induced by any one of the drugs. 4. The conductance of a single extrajunctional channel opened by the action of acetylcholine is estimated to be gammaextra = 15 +/- 1-8 pmho (+/- S.E.). This is somewhat lower than the value of gammaep = 23 +/- 2 pmho (+/- S.E.) found for the conductance of a single open channel in the junctional membrane of normal fibres. The extrasynaptic channels opened by the action of carbachol and suberyldicholine have similar conductances to those produced by ACh. 5. The autocorrelation function of drug-induced current fluctuations, recorded at the former end-plate region of chronically denervated fibres often shows both a fast and a slow time constant. They correspond in value to the time constant of the autocorrelation function obtained from end-plate currents in normal fibres and from extrasynaptic currents in denervated fibres respectively. This could indicate that two populations of channels exist at the former end-plate region of denervated muscle fibres.

Acetylcholine↗
PubMed1989

Activity-independent modulation of acetylcholine receptor levels in rat skeletal muscle following neonatal denervation.

Following denervation of adult muscle, levels of acetylcholine receptor (AChR) increase; normal, low levels are restored only after muscle reinnervation. After neonatal denervation, we found a large initial increase in AChR levels during the first days postsurgery, as in adult denervated muscle. However, 1 week after denervation, total AChR levels decreased in the absence of any sign of reinnervation. By 3 weeks after surgery, near-normal levels of AChR were restored and extrajunctional AChR had disappeared. Thus, in sharp contrast to adult muscle, in young denervated muscle a down-regulation of AChR occurs without recovery of innervation and normal muscle contractile activity. These results suggest that different mechanisms regulate the levels of AChR in developing and adult skeletal muscle.

Acetylcholinesterase↗
PubMed1986

In vitro and in vivo activation of the insulin receptor kinase in control and denervated skeletal muscle.

Skeletal muscle rapidly develops severe insulin resistance following denervation, although insulin binding is unimpaired. Insulin-stimulated receptor tyrosyl kinase activity was studied in intact and 24-h denervated rat hind limb muscles using three preparations: (a) solubilized insulin receptors incubated +/- insulin with gamma-[32P]ATP and histone H2b; (b) soleus muscles prelabeled in vitro with [32P]phosphate with subsequent insulin-stimulated phosphorylation of the receptor in situ; (c) assessment of in vivo activation of muscle receptor tyrosyl kinase by insulin. The latter was achieved by solubilizing muscle insulin receptors in the presence of phosphoprotein phosphatase and kinase inhibitors and measuring receptor-catalyzed histone H2b phosphorylation in the presence of limiting (5 microM) gamma-[32P]ATP. Receptors isolated 5 and 30 min after intravenous insulin injection catalyzed 32P incorporation into histone H2b twice as fast as those from saline-treated controls; insulin stimulated histone H2b labeling exclusively on tyrosine. In vivo activation was demonstrated using solubilized and insulin-agarose-bound receptors. Autophosphorylation of the beta-subunit and receptor tyrosyl kinase activity toward histone H2b was stimulated by insulin in denervated muscles as in controls, although the biological response to insulin, in vitro and in vivo, was markedly impaired after denervation, suggesting a postreceptor defect. The method developed to assess insulin-stimulated receptor activation in vivo seems useful in characterizing mechanisms of insulin resistance.

Animals↗