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PubMed2006

The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss and muscle wasting. In muscles of ALS patients, Nogo-A-a protein known to inhibit axon regeneration-is ectopically expressed at levels that correlate with the severity of the clinical symptoms. We now show that the genetic ablation of Nogo-A extends survival and reduces muscle denervation in a mouse model of ALS. In turn, overexpression of Nogo-A in wild-type muscle fibres leads to shrinkage of the postsynapse and retraction of the presynaptic motor ending. This suggests that the expression of Nogo-A occurring early in ALS skeletal muscle could cause repulsion and destabilization of the motor nerve terminals, and subsequent dying back of the axons and motor neurons.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Aquaporin 4: lack of mRNA expression in the rat regenerating muscle fiber under denervation.

The recently identified water channel aquaporin 4 is a major component of the orthogonal arrays observed with freeze-fracture electron microscopy. We examined the expression of aquaporin 4 mRNA and protein in rat regenerating muscle under innervated and denervated conditions. We found decreased sarcolemmal immunostaining of aquaporin 4 in denervated regenerating muscle as opposed to innervated muscle. Quantitative reverse transcription-polymerase chain reaction revealed that aquaporin 4 mRNA was expressed in the innervated regenerating muscle; whereas it was not expressed in denervated muscle. Thus, lack of aquaporin 4 protein may be due to lack of aquaporin 4 mRNA in the denervated regenerating muscle. We conclude that the nerve supply influences expression of aquaporin 4 at the mRNA level in regenerating muscle.

Animals↗
PubMed1985

Sensory reinnervation of cat peroneus brevis muscle spindles after nerve crush.

Results are presented of examining the postcrush sensory reinnervation of cat peroneus brevis muscle spindles previously investigated physiologically by Hyde and Scott. It is shown that primary and secondary endings were successfully restored in their final form in the early stages of recovery. The primary endings were shorter than normal and had fewer transverse bands; 12% were judged to be hyperinnervated. Some secondary endings showed signs of growth through the primary region apparently designed to establish secondary terminals in the opposite pole. This is compared with the collateral regeneration of intact motor axons in partially denervated muscle. It is concluded that the defects observed in the regenerated sensory endings had no effect on their functional recovery.

Animals↗
PubMed2003

Transients in acetylcholine receptor site density and degradation during reinnervation of mouse sternomastoid muscle.

The degradation rates of acetylcholine receptors (AchRs) were evaluated at the neuromuscular junction during and just after reinnervation of denervated muscles. When mouse sternomastoid muscles are denervated by multiple nerve crush, reinnervation begins 2-4 days later and is complete by day 7-9 after the last crush. In fully innervated muscles, the AChR degradation rate is stable and slow (t1/2 approximately 10 days), whereas after denervation the newly inserted receptors degrade rapidly (t1/2 approximately 1.2 days). The composite profile of degradation, which a mixture of the stable and the rapid receptors would give, is not observed during reinnervation. Instead, the receptors inserted between 2.5 and 7.5 days after the last crush all have an intermediate degradation rate of t1/2 approximately 3.7 days with standard error +/- 0.3 days. The total receptor site density at the endplate was evaluated during denervation and during reinnervation. As predicted theoretically, the site density increased substantially, but temporarily, after denervation. An analogous deleterious substantial decrease in density would be expected during reinnervation, without the intermediate receptor. This decrease is not observed, however, because of a large insertion rate at intermediate times (3000 +/- 700 receptor complexes per micro m2 per day). The endplate density of receptors thus remains relatively constant.

Animals↗
PubMedDate not supplied

Histologic consequences of inferior oblique anastomosis to denervated lateral rectus muscle.

Secondary muscular neurotization has been proposed as a means of restoring contractility to paretic extraocular muscle. We studied this technique by anastomosing healthy inferior oblique muscle to lateral rectus muscle that had been denervated either orbitally or intracranially in 20 dogs. Nerve and muscle fiber growth from the inferior oblique to the lateral rectus was demonstrated but no new neuromuscular junctions were formed. Regeneration of the lesioned sixth nerve occurred frequently and may explain the restoration of function claimed after this procedure.

Animals↗
PubMed1991

Comparison of stimulation and insulin effects on denervated mouse soleus muscles.

A comparison has been made between the responses of denervated mouse soleus muscles to direct electrical stimulation, as reported by earlier workers, and to incubation with supraphysiological concentrations of insulin. The parameters of interest were resting membrane potential (RMP), qualities of the active state, the amount of alpha bungarotoxin (BUTX) binding, and chemosensitivity, as measured by the strength of acetylcholine (ACh)-induced contractures. In all aspects, the changes recorded after insulin, were in the same direction as with direct stimulation, however, owing to the time limitations of in vitro testing, were smaller. It is suggested that the effects of electric shocks on denervated muscles are the result of activation of the insulin receptor, or some similar macromolecule, which appears to be sensitive to the membrane potential. The possible interrelations between acetylcholine and insulin receptors in neurotrophic control are discussed.

Animals↗
PubMedDate not supplied

Increased creatine kinase and spontaneous activity on electromyography, in amyotrophic lateral sclerosis.

INTRODUCTION: Mild to moderate elevation of muscle creatine kinase (CK) is commonly observed in amyotrophic lateral sclerosis (ALS). Although the determinants of increased the CK in ALS remain uncertain, we hypothesize that fasciculations and muscle denervation can be involved by damaging the muscle fibre. PATIENTS AND METHODS: We studied 87 ALS patients in whom CK determination was performed. In 47, a standardized EMG investigation was performed. In 22 patients a second CK determination was performed a mean of 5 months later. CK values were compared between different patients arranged in groups as determined by the number of regions with fasciculation as detected on the clinical examination, and the number of muscles with fasciculation or with fibrillation potentials as observed on EMG. RESULTS: 43% of our population had an increased CK value. Four out of 5 patients with suspected ALS had an increased CK value. The number of patients with increased CK value was not different between sexes, or between bulbar and spinal-onset patients. CK value was not related with disease duration, and did not change at the second measurement. CK value was not different between the groups studied. CONCLUSION: The fasciculations,and the signs of denervation on EMG, are not determinants for high CK values in ALS patients, which are still unknown. Increased CK can be useful in the differential diagnosis of patients with lower motor neuron disorders.

Adult↗
PubMed1998

Nitric oxide synthase in rat neuromuscular junctions and in nerve terminals of Torpedo electric organ: its role as regulator of acetylcholine release.

The distribution of nitric oxide synthase on peripheral motor system was studied using a specific antibody against the neuronal isoform of nitric oxide synthase (nNOS). The immunoreactivity for nNOS was detected on the sarcolemmal surface of muscle cells, in intramuscular axons and in neuromuscular synapses. At the neuromuscular junctions, ultrastructural immunolabeling demonstrated that nNOS immunoreactivity was localized mainly into the presynaptic nerve terminals as well as adjacent postsynaptic muscle membrane. Similar immunostaining pattern was present in frog muscles and Torpedo electric organs. After chronic muscle denervation, nNOS immunoreactity at endplate level decreased during the first week but it was upregulated after 30 days of denervation. In denervated endplates, nNOS immunoreactivity was localized in the terminal Schwann cells covering the degenerated neuromuscular junctions whereas nNOS was not detected in Schwann cells under normal conditions. In Torpedo synaptosomes, acetylcholine (ACh) release elicited by potassium depolarization was inhibited by NO donors such as sodium nitroprusside. In contrast, application of inhibitors of NOS activity, aminoguanidine (AMG) and N(omega)-Nitro-L-arginine methyl esther (L-NAME) increased acetylcholine release. These results indicate that nNOS is present at the motor nerve terminals in a variety of vertebrates and that it may be involved in the physiological modulation of ACh release and in the regulation of muscle response to nerve injury.

Acetylcholine↗
PubMed1976

[Pharmacological studies on degeneration and regeneration of the peripheral nerves. (2) Effects of methylcobalamin on mitosis of Schwann cells and incorporation of labeled amino acid into protein fractions of crushed sciatic nerve in rats].

Male Wistar rats (140 to 150 g) in which the unilateral sciatic nerve had been crushed were treated consecutively with methylcobalamin (5, 50 and 500 mug/kg/day i.p.) or saline immediately after the nerve-crush. Thereafter, they were periodically sacrificed for biochemical and histological examinations. At different intervals after the nerve-crush, L-leucine-4,5-T (20 mu Ci/100g, specific activity 15 mCi/m mole) or L-leucine -14C(U) (15 muCi/100g, specific activity 270 mCi/m mole) was given i.p. to some rats of each group and 3 hr later they were sacrificed to determine the rate of leucine incorporation into protein fractions of the crushed nerve and the denervated muscles. The nerve and muscles of the contralateral side served as control. Longitudinal sections of proximal and distal stumps of the sciatic nerve were prepared and stained with hematoxylin and eosin. As compared with saline group, repeated injections of 5, 50 and 500 mug/kg/day of methyl-cobalamin caused a significant increase of the in vivo incorporation of radioactive leucine into the protein fraction of the crushed sciatic nerve 5 to 7 days after the crush. In contrast, a recovery of the increased incorporation of leucine into the crushed nerve was more rapid in methylcobalamin groups than in the saline group. On the other hand, methylcobalamin (5 approximately 500 mug/kg/day i.p.) had no significant effect on the leucine incorporation into the denervated muscles (m. gastrocnemius, m. tibialis anterior and m. soleus). In addition, consecutive injections of methylcobalamin (5 approximately 500 mug/kg/day) did not affect the mitosis of Schwann cells during the period of Wallerian degeneration of the crushed sciatic nerve. These results suggest that methylcobalamin possesses a stimulating effect on proteosynthesis in Schwann cells at the initial stage of axon regeneration and it may facilitate neural regeneration.

Animals↗
PubMed1995

Pathogenetic mechanisms of post-polio syndrome: morphological, electrophysiological, virological, and immunological correlations.

To understand the mechanism of post-poliomyelitis muscular atrophy (PPMA) and the post-polio syndrome (PPS) in general, we performed the following studies: (1) histopathology in spinal cord sections from patients who died 9 days to 44 years after acute paralytic poliomyelitis; (2) enzyme histochemistry, immunocytochemistry (for lymphocyte subsets, MHC antigens and N-CAM) and polymerase chain reaction (PCR) for poliovirus RNA in the muscle biopsies from symptomatic or asymptomatic muscles of post-polio patients; (3) determination of lymphocyte subsets and circulating IgG or IgM antibodies against GM1 and poliovirus; (4) virological studies in the spinal fluid for oligoclonal bands and search for poliovirus genome with PCR; (5) electrophysiological studies including single fiber EMG, fiber density and macro-EMG; and (6) [31P] exercise MRS spectroscopy on previously affected muscles to search for a metabolic correlate of fatigue. These studies concluded that in PPS a continuing dysfunction is present in the spinal cord motor neurons, resulting in ongoing muscle denervation and reinnervation first evident at the axonal branch points. Symptoms are related to attrition of the oversprouting motor neurons which after a period of time cannot support all their axonal sprouts, resulting in failure of re-reinnervation. In some patients with PPS there is also an ongoing immune activation and presence of defective viral particles in the spinal fluid. However, their role in the pathogenesis of PPS is presently unknown.

Acute Disease↗
PubMed1977

Cytochemical localization of acetylcholine receptors at the neuromuscular junction by means of horseradish peroxidase-labeled alpha-bungarotoxin.

The cytochemical localization of acetylcholine (ACh) receptors at the neuromuscular junction was investigated with a procedure utilizing alpha-bungarotoxin (alpha-BtX) labeled directly with horseradish peroxidase (HRP). Following incubation of tissues in the conjugate and reaction for peroxidase, activity was observed on the junctional folds of the motor endplate. A uniform layer of reaction product approximately 15 nm thick occurred over the apical portions of the junctional folds. Membranes at the bases of the synaptic cleft showed only small amounts of reaction product. Non-junctional regions of the muscle fiber were unreactive. Activity was also observed in the membrane of the axon facing the muscle surface, often including the axolemma overlying the "active zones" of the nerve terminal. Such presynaptic activity was still evident on nerve terminals disjuncted from the synapse by enzymatic treatment prior to incubation in the conjugate. This localization indicates the possible presence of presynaptic ACh receptors within the axolemma. In muscle denervated for 7-12 days, motor endplates were reactive and parajunctional sarcolemma showed slight activity, but most extrajunctional regions contained no obvious accumulations of reaction product. Activity at all sites was prevented by preincubation of tissues in native alpha-BTX prior to incubation in the conjugate and reaction for HRP. This procedure represents a simple and convenient method for the high resolution localization of ACh receptors.

Animals↗
PubMed1987

Augmented synaptic release by one excitatory axon in regions in which a synergistic axon was removed in lobster muscle.

1. In the lobster, every fibre of the lateral abdominal extensor muscle is innervated by two excitatory axons. When one of the excitatory axons (the common excitor) was removed chronically by intracellular injection of pronase, terminals of the remaining axon (the specific L1 excitor) showed augmented transmitter release. 2. Evidence as to the mechanism of this strengthening can be obtained taking advantage of the peculiar innervation pattern of the abdominal extensors. The L1 excitor axon of one segment sends a branch to part of the next posterior segment. The common excitor axon innervates only muscle fibres of its own segment. 3. 10-20 days after removing the common excitor axon of segment II, the quantum content of release of terminals of the L1 excitor axon was measured in segments I, II and III. Terminals of the L1 excitor axon of segment I which innervate segment II released much more transmitter than controls, while the terminals of the same axon innervating segment I remained normal. Similarly, terminals of the L1 excitor axon of segment II became 'stronger' in segment II but remained normal in segment III. 4. It is concluded that only those terminals of one axon which innervate targets with reduced innervation increased the average release rate. It seems that the signal for synaptic strengthening, after removal of a synergistic axon, is generated and acts locally in partially denervated muscle fibres.

Action Potentials↗
PubMed1987

Two-site immunoassay for acetylcholinesterase in brain, nerve, and muscle.

Two-site methods were developed for immunoassay of acetylcholinesterase (AChE; EC 3.1.1.7) in crude extracts of rat and human tissues. A radiometric assay for human AChE utilized a specific monoclonal AChE antibody adsorbed to polystyrene microtiter wells at alkaline pH. AChE bound strongly to this antibody after 24 h at 4 degrees C. Bound enzyme was detected with an 125I-labeled antibody against a different AChE epitope. The assay signal was quasi-linearly related to AChE concentration in purified and crude samples, with a detection threshold near 100 pg. Tetrameric and dimeric AChE behaved equivalently in the assay. Two-site methods with a different pair of species-selective antibodies worked equally well for immunoassay of rat AChE. Assays of the rat enzyme showed that immunoreactivity was lost as rapidly as enzyme activity during heating to 54 degrees C. On the other hand, immunoreactivity was preserved despite loss of enzyme activity after exposure to anticholinesterases or trypsin. A biotinylated second antibody detected by alkaline-phosphatase-conjugated avidin was used to develop an AChE enzyme-linked immunosorbent assay (ELISA) with a sensitivity similar to that of the radiometric assay. Either the ELISA or the radiometric immunoassay may be useful whenever proteolysis or other mechanisms are suspected of dissociating enzyme activity and immunoreactivity. In denervated muscle and ligated peripheral nerve, application of the two-site method showed closely parallel variations in immunoreactivity and enzyme activity.

Acetylcholinesterase↗
PubMed1995

Schwann cell processes guide regeneration of peripheral axons.

Terminal Schwann cells overlying the neuromuscular junction sprout elaborate processes upon muscle denervation. We show here that motor axons use these processes as guides/substrates during regeneration; in so doing, they escape the confines of endplates and grow between endplates to generate polyneuronal innervation. We also show that Schwann cells in the nerve provide similar guidance. Axons extend from the cut end of a nerve in association with Schwann cell processes and appear to navigate along them. The processes extend from axotomized nerves at the same rate and in the same manner as they do from axon-containing nerves. The rate of process extension limits the rate at which axons regenerate. Thus, Schwann cell processes lead and guide peripheral regeneration.

Animals↗
PubMed1987

Expression of myosin heavy chain isoforms in regenerating myotubes of innervated and denervated chicken pectoral muscle.

Monoclonal antibodies were prepared to stage-specific chicken pectoral muscle myosin heavy chain isoforms. From comparison of serial sections reacted with these antibodies, the myosin heavy chain isoform composition of individual myofibers was determined in denervated pectoral muscle and in regenerating myotubes that developed following cold injury of normal and denervated muscle. It was found that the neonatal myosin heavy chain reappeared in most myofibers following denervation of the pectoral muscle. Regenerating myotubes in both innervated and denervated muscle expressed all of the myosin heavy chain isoforms which have thus far been characterized in developing pectoral muscle. However, the neonatal and adult myosin heavy chains appeared more rapidly in regenerating myotubes compared to myofibers in developing muscle. While the initial expression of these isoforms in the regenerating areas was similar in innervated and denervated muscles, the neonatal myosin heavy chain did not disappear from noninnervated regenerating fibers. These results indicate that innervation is not required for the appearance of fast myosin heavy chain isoforms, but that the nerve plays some role in the repression of the neonatal myosin heavy chain.

Animals↗
PubMed1988

[Electric stimulation and neuromuscular diseases. Effects on denervated and dystrophic muscle].

The literature on the effects of electrical stimulation on denervated and dystrophic muscles is reviewed. Analysis of the information supplied suggests that denervated muscles of experimental animals may benefit from the treatment that cannot be used on human patients due to technical limitations. However electrical stimulation can be used in the treatment of dystrophic muscles in human.

Adult↗
PubMed1979

Local development of action potentials in slow muscle fibres after complete or partial denervation.

Pyriformis muscles of Rana temporaria were completely or partially denervated by cutting the sciatic nerve or some of the small nerve branches entering the muscle. One stimulating and one to three recording microelectrodes were inserted along the fibres in order to compare the electrical activity at these points. In an early period following denervation action potentials of variable size and shape could be observed; these action potentials were often composed of two, sometimes of three or four, components. The size of individual components depended on the position of the recording microelectrode. Individual components could occasionally be triggered separately by adjusting the strength of the stimulating current pulse; propagation of these "all or none" responses was absent. In other fibres one component of the action potential could trigger another one several millimetres apart, thus indicating propagation. Conduction velocities were approximately 0.4 m/s. In partially denervated slow fibres, endplate potentials were confined to one lateral segment of the fibres, while the action potential occupied the denervated part of the membrane. The amplitudes of endplate and action potentials varied inversely with distance. Rough estimates of the length constant of the slow fibre membrane were calculated from the spatial decay of action potentials, endplate potentials and hyperpolarizing electrotonic potentials; mean values obtained were 2.5, 4.8 and 7.7 mm respectively. The results suggest that following denervation Na channels are built into discrete areas of the slow fibre membrane and that this process depends on the amount of denervation in individual fibres.

Action Potentials↗