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PubMed1988

Neural regulation of [3H]saxitoxin binding site numbers in rat neonatal muscle.

1. Neural regulation of the density of sodium (Na+) channels in rat muscle was studied by measuring specific binding of tritiated saxitoxin ([3H]STX) to muscles from rat hindlimbs during normal development and in rats in which neuromuscular function was interrupted by sciatic nerve section or neuromuscular blockade with botulinum toxin (BoTX). 2. The normal developmental increase in [3H]STX binding site numbers followed a simple exponential with a time constant of 12 days. The most rapid incorporation of channels coincided with the onset of accelerated muscle growth and increased neuromuscular activity at 2 weeks of age. 3. Elimination of neuromuscular activity retarded muscle growth and inhibited the normal incorporation of Na+ channels into neonatal muscle. Muscles denervation was more effective than BoTX paralysis: denervation at 2 weeks of age prevented the normal 3-fold increase in the binding site density between 2 and 3 weeks of age while age-matched BoTX-treated muscles incorporated an average of 66% of the normal Na+ channel incorporation. 4. Denervation and BoTX treatment were equally effective in reducing the numbers of [3H]STX binding sites in adult muscle. A reduction of 30% in binding sites brought the numbers to levels which corresponded with levels normally seen in muscles at 3 weeks of neonatal development. 5. It was concluded that the neural influence on incorporation of Na+ channels into membranes of neonatal muscle is, at least in part, mediated by neuromuscular activity.

Animals↗
PubMed1975

Acetylcholine receptors in normal and denervated rat diaphragm muscle. II. Comparison of junctional and extrajunctional receptors.

Acetylcholine (ACh) receptors have been purified separately from normal rat diaphragm muscle (junctional receptors) and from extrajunctional regions of denervated diaphragm (extrajunctional receptors) in order to compare their properties. The toxin-receptor complexes of the two receptors were indistinguishable by gel filtration and by zone sedimentation in sucrose gradients, and showed identical precipitation curves with rabbit antiserum to the eel ACh receptor. Both toxin-receptor complexes bind concanavalin A and are therefore probably glycoproteins. Low concentrations of d-tubocuratine (dTC) were more effective in decreasing the rate of toxin binding to junctional than to extrajunctional receptors. The apparent dissociation constant for dTC binding to the junctional receptor was 4.5 X 10 minus 8 M, whereas the value for the extrajunctional receptor was 5.5 X 10 minus 7 M. When the complexes were analyzed by isoelectric focusing, the junctional complex focused at approximately 0.15 pH unit lower than the extrajunctional complex. This result was also found with crude preparations of receptor. We conclude that junctional and extrajunctional receptors are similar but distinct molecules. The properties of receptors present in neonatal diaphragm muscle were also examined and found to be similar to those of receptors in denervated muscle, as shown by dTC inhibition and isoelectric focusing.

Acetylcholine↗
PubMed1992

Type-specific changes in fiber morphometry following denervation of canine extraocular muscle.

To investigate the changes that occur in extraocular muscle morphometry following denervation, 12 beagles were subjected to intracranial section of the left oculomotor nerve. The inferior and medial rectus muscles were removed from both orbits of four dogs killed at each 4-week postoperative interval. Fiber diameters and fiber-type ratios of denervated muscles were compared with those from paired muscles in the normal orbit. We found significant, persistent atrophy of the singly innervated fibers in both the global and orbital layers of denervated extraocular muscle. The multiinnervated fibers were predominantly spared from denervation atrophy. We also found a significant increase in the proportion of multiinnervated fibers in the orbital layer only. These results suggest a relative neurotrophic independence of multiinnervated fibers in extraocular muscle.

Animals↗
PubMed1989

Spatial and temporal expression of acetylcholine receptor RNAs in innervated and denervated rat soleus muscle.

In adult vertebrate skeletal muscle acetylcholine receptors are localized to the neuromuscular junction. Upon denervation, this distribution changes, with new receptors appearing in extrajunctional regions of the muscle fiber. The location of acetylcholine receptors in innervated or denervated muscle may result, in part, from the distribution of their RNAs. This was tested by assaying for receptor RNAs in junctional and extrajunctional regions of innervated and denervated rat soleus muscle using in situ hybridization and RNAase protection assays. These experiments showed alpha, beta, and delta subunit RNAs concentrated beneath the endplates of innervated muscle fibers. Following denervation, there was an unequal distribution of receptor RNAs along the muscle fiber, with highest levels occurring in extrajunctional regions near the endplate. These data are consistent with a nonuniform pattern of gene expression in adult skeletal muscle fibers.

Animals↗
PubMed1998

Localization and regulation of MuSK at the neuromuscular junction.

The receptor tyrosine kinase, MuSK, is required for the formation of the neuromuscular junction (NMJ) where MuSK becomes phosphorylated when exposed to neuronally synthesized isoforms of agrin. To understand better the mechanisms by which MuSK mediates the formation of the NMJ, we have examined how MuSK expression is regulated during development in the embryo, by neuromuscular injury in the adult and by agrin in vitro. Here we show that MuSK is associated with the earliest observable AChR clusters at the developing motor endplate and that MuSK and AChRs codistribute throughout the development of the NMJ. These two proteins are also coordinately regulated on the surfaces of cultured myotubes where MuSK and AChRs colocalize both in spontaneous and agrin-induced clusters. While MuSK is normally restricted to the motor endplate in adult muscle, denervation results in its extrajunctional expression, although a discernible concentration of MuSK remains localized to the motor endplate even 14 days after denervation. Extrajunctional MuSK is first apparent 3 days after denervation and is sharply reduced upon reinnervation. Muscle paralysis also markedly alters the expression of MuSK in adult muscle and results in increased expression of MuSK as well as increased transcription of MuSK mRNA by extrasynaptic myonuclei. Together, these findings demonstrate that MuSK expression is highly regulated by innervation, muscle activity, and agrin, while the distribution of MuSK is precisely coordinated with that of the AChR.

Agrin↗
PubMed1981

Terminal sprouting of motoneurones is a local response to a local stimulus.

Terminal sprouting was visualized in silver stained whole mounts of rat sternocostal muscles after resecting one segmental nerve. Sprouts were only found near denervated muscle fibres. The effective diffusion range of the sprout inducing factor released by denervated fibres was 50--100 micrometers. Individual terminals of the same motoneurone sprout independently of each other and only when they intercept the sprout inducing factor.

Animals↗
PubMed2000

Motoneurons of the adult marmoset can grow axons and reform motor endplates through a peripheral nerve bridge joining the locally injured cervical spinal cord to the denervated biceps brachii muscle.

Reconnection of the injured spinal cord (SC) of the marmoset with the denervated biceps brachii muscle (BB) was obtained by using a peripheral nerve (PN) bridge. In 13 adult males, a 45 mm segment of the peroneal nerve was removed: one end was implanted unilaterally into the cervical SC of the same animal (autograft), determining a local injury, although the other end was either directly inserted into the BB (Group A) or, alternatively, sutured to its transected motor nerve, the musculocutaneous nerve (Group B). From 2-4 months post-surgery, eight out of the 10 surviving animals responded by a contraction of the BB to electrical stimulations of the PN bridge. All ten were then processed for a morphological study. As documented by retrograde axonal tracing studies using horse radish peroxidase or Fast Blue (FB), a mean number of 314 (Group A) or 45 (Group B) spinal neurons, mainly located close to the site of injury and grafting, re-expressed a capacity to grow and extend axons into the PN bridge. Most of these regenerated axons were able to grow up to the BB and form or reform functional motor endplates. Many of the spinal neurons that were retrogradely labeled with FB simultaneously displayed immunoreactivity for choline acetyl-transferase and consequently were assumed to be motoneurons. Reinnervation and regeneration of the BB were documented by methods revealing axon terminals, endplates and myofibrillary ATPase activity. Our results indicate that motoneurons of the focally injured SC of a small-sized primate can, following the example of the adult rat, re-establish a lost motor function by extending new axons all the way through a PN bridge connected to a denervated skeletal muscle.

Animals↗
PubMed1978

Acid phosphatase activity in normal and denervated chick skeletal muscle.

Histochemical and biochemical changes in acid phosphatase activity were studied in the normal and denervated gastrocnemii of chick for a maximum period of 8 weeks. In the normal muscle, fibre heterogeneity with respect muscles exhibit greater susceptibility to degenerative changes on account of denervation. Quantitatively higher enzyme levels in the denervated muscles confirm the lytic role of acid phosphatase.

Acid Phosphatase↗
PubMed1987

Clenbuterol, a beta agonist, induces growth in innervated and denervated rat soleus muscle via apparently different mechanisms.

Dietary administration of the anabolic agent, clenbuterol, has already been shown to inhibit or reverse denervation-induced atrophy in rat soleus muscles. We now show that the ameliorative effects of clenbuterol in denervated rat muscles are due principally to a large increase in protein synthesis. This results from both an increase in protein synthetic capacity and a normalised translational efficiency. The responses of innervated and denervated muscles are therefore fundamentally different, the changes in denervated muscles being reminiscent of the classical pleiotypic response of cells to growth factors.

Animals↗
PubMed1984

Glycogen-membrane complexes in denervated human skeletal muscle.

We describe an unusual intracellular complex of glycogen with smooth, cisternal, cytoplasmic membranes (glycogen-membrane complexes, GMC) in denervated human skeletal muscle. Glycogen particles were always intimately associated with these structures, although the staining intensity varied markedly with different fixation conditions. This may account for previous investigations of similar structures in which an association with glycogen was not recognized. Electron micrographs of tannic acid-enhanced specimens, and of freeze-fracture replicas, showed similarities between the GMCs and the terminal cisternae of the sarcoplasmic reticulum: (i) GMCs resembled the terminal cisternae of the sarcoplasmic reticulum in the size and asymmetric distribution of intramembranous particles seen in freeze-fracture replicas; (ii) tannic acid-enhanced thin sections of GMCs showed intense staining of the cisternal contents and irregular staining of the cytoplasmic leaflet, similar to the appearance of the sarcoplasmic reticulum terminal cisternae; and (iii) triad-like junctions were seen between the glycogen-membrane complexes and elements of the transverse tubule system.

Cell Membrane↗
PubMed1987

Kinetic basis for insensitivity to tetrodotoxin and saxitoxin in sodium channels of canine heart and denervated rat skeletal muscle.

The single-channel blocking kinetics of tetrodotoxin (TTX), saxitoxin (STX), and several STX derivatives were measured for various Na-channel subtypes incorporated into planar lipid bilayers in the presence of batrachotoxin. The subtypes studied include Na channels from rat skeletal muscle and rat brain, which have high affinity for TTX/STX, and Na channels from denervated rat skeletal muscle and canine heart, which have about 20-60-fold lower affinity for these toxins at 22 degrees C. The equilibrium dissociation constant of toxin binding is an exponential function of voltage (e-fold per 40 mV) in the range of -60 to +60 mV. This voltage dependence is similar for all channel subtypes and toxins, indicating that this property is a conserved feature of channel function for batrachotoxin-activated channels. The decrease in binding affinity for TTX and STX in low-affinity subtypes is due to a 3-9-fold decrease in the association rate constant and a 4-8-fold increase in the dissociation rate constant. For a series of STX derivatives, the association rate constant for toxin binding is approximately an exponential function of net toxin charge in membranes of neutral lipids, implying that there is a negative surface potential due to fixed negative charges in the vicinity of the toxin receptor. The magnitude of this surface potential (-35 to -43 mV at 0.2 M NaCl) is similar for both high- and low-affinity subtypes, suggesting that the lower association rate of toxin binding to toxin-insensitive subtypes is not due to decreased surface charge but rather to a slower protein conformational step. The increased rates of toxin dissociation from insensitive subtypes can be attributed to the loss of a few specific bonding interactions in the binding site such as loss of a hydrogen bond with the N-1 hydroxyl group of neosaxitoxin, which contributes about 1 kcal/mol of intrinsic binding energy.

Animals↗
PubMedDate not supplied

Pro-opiomelanocortin-derived peptides in transected and contralateral motor nerves of the rat.

An immunocytochemical method was used to reveal beta-endorphin and alpha-melanotropin peptides in nerve profiles at the neuromuscular junctions in the soleus and extensor digitorum longus muscles of the adult rat. After unilateral section of the sciatic nerve, the proportion of endplates with immunoreactive nerve profiles increased in the denervated muscles even after the axonal material in the distal nerve segments had degenerated. When the nerve was sectioned in the mid-thigh region the proportion of immunoreactive endplates increased with time up to 24-36 h after the nerve section and then eventually declined. The incidence of immunoreactive nerve profiles also increased in the proximal stump. After unilateral sciatic nerve section there was also an increase in the incidence of immunoreactive endplates in the contralateral muscles. The increases in the contralateral muscles could be detected at an earlier time if the nerve was sectioned closer to the spinal cord. The possibility is discussed that the expression of pro-opiomelanocortin peptides in the motor nerves is tonically suppressed in the normal adult but the inhibition is released after section of the nerve. The findings indicate that a signal is transferred from the site of injury in the transected nerves to the motor nerves of the contralateral limb via a transneuronal mechanism through the spinal cord.

Adrenocorticotropic Hormone↗
PubMed1986

[Histochemical studies of the denervated posterior cricoarytenoid muscle following direct long-term stimulation in an animal experiment].

Histochemical evaluation (ATP-ase, NADH-Diaphorase, PAS) of the posterior cricoarytenoid muscle of the sheep was performed after long-term direct electrical stimulation to determine the changes of fibre type ratio and muscle metabolism. For comparison, histochemical results of a normal and a denervated, not stimulated posticus muscle are described.

Animals↗
PubMed1986

Surgical sympathetic denervation increases alpha 1-adrenoceptor-mediated accumulation of myo-inositol trisphosphate and muscle contraction in rabbit iris dilator smooth muscle.

Sympathetic denervation of the iris muscle produces increases in both the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) and in muscle contraction in response to norepinephrine (NE). To shed more light on the biochemical basis underlying this supersensitivity we investigated: the effects of NE on PIP2 breakdown, measured as myo-inositol trisphosphate (IP3) accumulation, and on muscle contraction in normal and denervated rabbit iris dilator; and the effects of denervation on selected biochemical properties of this muscle. The data obtained from these studies can be summarized as follows: The EC50 values (microM) for NE-induced IP3 accumulation in normal and denervated dilators were 14 and 3, respectively. This accumulation of IP3 was blocked by prazosin (1 microM). The EC50 values (microM) for NE-induced contraction for the normal and denervated muscles were 10 and 0.6, respectively. The NE-induced muscle contraction was blocked by prazosin (1 microM). The t1/2 values (s) for IP3 accumulation in normal and denervated muscles were 31 and 11, respectively, and for contraction the values were 19 and 9, respectively. Denervation increased significantly (15-18%) the basal labelling of phosphoinositides from myo-[3H]inositol, but not from 32P or [14C]arachidonic acid. Denervation had little effect on the activities of the enzymes involved in phosphoinositide metabolism. However, the activities of protein kinase C and Ca2+-ATPase increased in the denervated muscle. It is concluded that sympathetic denervation of the iris dilator renders the coupling between alpha1 receptors and PIP2 breakdown into IP3 and 1,2-diacylglycerol (DG) more efficient.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1998

JTP-2942, a novel thyrotropin-releasing hormone analogue, protects against spinal motor neuron degeneration in the wobbler mouse.

JTP-2942, a novel thyrotropin-releasing hormone (TRH) analogue, exhibits a strong acetylcholine release-enhancing effect in the rat hippocampus and frontal cortex. This molecule has a more powerful and prolonged action on cholinergic neurons than TRH. Here we studied whether JTP-2942 treatment can ameliorate motor dysfunction and spinal motor neuron degeneration in the wobbler mouse. After clinical diagnosis at postnatal age 3-4 weeks, wobbler mice received intraperitoneal injections of JTP-2942 (2 mg/kg per day) for 4 weeks (long-term treatment) or 2 weeks (short-term treatment), TRH (50 mg/kg per day) for 4 weeks or vehicle in a blind fashion. Compared with the vehicle, long-term administration of JTP-2942 potentiated grip strength, attenuated muscle contractures in the forelimbs, reduced denervation muscle atrophy and protected spinal motor neurons. After cessation of JTP-2942 (short-term treatment), motor dysfunction deteriorated rapidly. Symptomatic and neuropathological progression were not retarded in mice that received TRH or short-term JTP-2942 treatment. Our results indicate that JTP-2942 may have therapeutic potential for lower motor neuron disease or motor neuropathy.

Animals↗
PubMed1973

Acetylcholine receptor and ion conductance modulator sites at the murine neuromuscular junction: evidence from specific toxin reactions.

The perhydro derivative of histrionicotoxin reversibly blocks the excitatory ionic transduction system in the synaptic and sarcolemmal membranes of mammalian skeletal muscle cells. The efficacy of perhydrohistrionicotoxin as an antagonist at the post-synaptic membrane is increased by the transient presence of acetylcholine in the endplate of innervated muscles and at extrajunctional receptors in denervated muscles. alpha-Bungarotoxin and [(3)H]monoacetyl-alpha-bungarotoxin block the endplate acetylcholine receptors, each binding to the same extent. The effect of bungarotoxin is partially reversible. These electrophysiological results, together with the effects of perhydrohistrionicotoxin and/or d-tubocurarine on the binding of [(3)H]monoacetyl-alpha-bungarotoxin at endplates of murine diaphragm muscle and on the bungarotoxin-elicited irreversible blockade of neuromuscular transmission, suggest that at least two types of sites participate in the synaptic excitation by acetylcholine. One site, competitively blocked by bungarotoxin and by curare, is presumably the acetylcholine receptor. Binding of bungarotoxin at this site is responsible for an irreversible blockade of neuromuscular transmission. The second site, competitively blocked by bungarotoxin and perhydrohistrionicotoxin, is proposed to be part of the cholinergic ion conductance modulator. Binding of bungarotoxin to this site does not result in an irreversible blockade.

Acetylcholine↗
PubMed2004

Dissociation between mechanical and myoelectrical manifestation of muscle fatigue in amyotrophic lateral sclerosis.

Motor fatigue, during 30 seconds of maximum voluntary isometric contraction (MVIC) was simultaneously evaluated by the decline in mechanical force output, and from the compression in the power spectrum obtained from surface electromyogram (sEMG). Measurements were performed in patients diagnosed with amyotrophic lateral sclerosis (ALS) and normal control (NC) in two muscle groups, elbow flexors (EF) and ankle dorsiflexors (DF). The decline in force output, as a manifestation of mechanical fatigue, was digitally calculated online by partitioning the force versus time curve to determine the percent of MVIC reduction over a 30 sec period and was expressed as force fatigue index (FFI). The compression in the sEMG power spectrum, as a manifestation of myoelectrical fatigue, was tracked by calculating the median frequency shift (MFS) from the first 5 sec to the last 5 sec of the 30 sec MVIC using digital Fast Fourier Transformation. In ALS patients, the significantly higher reduction in mechanical force output during the 30 sec MVIC (higher FFI) was accompanied with significantly less compression in the sEMG power spectrum (less MFS) as compared to NC (P < or =0.005) in the two muscle groups. This dissociation between the mechanical and myoelectrical manifestation of muscle fatigue in ALS indicates that a reduction in muscle fiber conduction velocity (MFCV) may be a contributing peripheral factor in the pathogenesis of muscle fatigue in ALS. Alterations in motor unit functionality, especially in type II fast motor unit muscle fibers, and structural damage in denervated muscle fibers may contribute to the lower MFCV during motor fatigue in ALS patients.

Adult↗