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Direct muscular neurotization.

Direct muscular neurotization has limited indications: loss of the distal stump of a motor nerve or avulsion of the "neural" part of one or more muscles. These lesions cannot be repaired with conventional microsurgery techniques, and without the presented technique, the denervated muscles will remain permanently paralyzed. Despite rare failures from poor local vascular or muscular conditions, direct muscular neurotization has provided the vast majority of good results, with scores similar to those obtained with good microsurgical sutures or grafts and has been adopted by several microsurgeons.

Animals↗

[Modulation of excitability in midbrain dopaminergic neurons and skeletal muscles by neuronal nicotinic receptors: perspectives from knockout mice].

Neuronal nicotinic receptors (nAChRs) are widely expressed in the central and peripheral nervous systems, and also found in several non-neuronal tissues, including skeletal muscles. Since neuronal nAChRs possess a high Ca2+ permeability, we investigated the mechanisms of intracellular Ca2+ mobilization through nAChR in midbrain dopaminergic neurons and skeletal muscles, using alpha 7-/- or beta 2-/- mice. RT-PCR study showed the existence of alpha 7 mRNA in denervated muscles of wild-type mice. Choline (alpha 7 agonist) elicited a muscle depolarization, but this component was abolished in alpha 7-/- mice. These suggest that alpha 7-nAChR up-regulated in denervated muscle may contribute to regeneration of the damaged neuromuscular synapse. Moreover, fura-2-imaging analyses in midbrain slices demonstrated that nicotine-elicited Ca2+ mobilization was diminished in beta 2-/- mice. The Ca2+ mobilization was markedly inhibited by dantrolene. Therefore, the Ca2+ influx due to beta 2-nAChR activation appears to be amplified by the recruitment of intracellular Ca2+ stores. To regulate unusual nAChR functions in neurological diseases, the search for new and selective ligands has continuously increased. We examined the effects of frog alkaloids on nAChRs expressed in Xenopus oocytes, and found that indolizidines 235B' selectively blocked alpha 4 beta 2-nAChR. Thus, the approach based on natural products can still provide a great advantage for producing novel therapeutics.

Animals↗

Emetine myopathy in the rat.

1 (-)Emetine (0.25-2.0 mg/kg i.p.) was administered to rats for up to 220 days. 2 At doses of 1.0 mg/kg or less, the animals continued to gain weight but more slowly than the untreated control animals. The physiological changes in the muscles from these animals were minimal; there was a small reduction in both the resting membrane potential and in the maximum rate of rise of the action potential. There was no atrophy or loss of muscle fibres although in the occasional muscle, hyaline fibres, necrotic fibres and split fibres were observed. There was a focal loss of myofibrillar adenosine triphosphatase (ATPase) and nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR) in Type II and Type III fibres, but no such loss in Type I fibres. 3 The animals receiving 2.0 mg/kg of (-)emetine gained weight slowly for up to 20 days but then rapidly lost weight and by 30 days they were weak and emaciated. The muscles from these animals were severly atrophied and the total muscle wet weight was reduced by almost 20%. 4 The strength of the muscles from these animals was measured in vitro using direct stimulation. They were weaker than normal both in absolute terms and when expressed in terms of tension developed/unit wet weight. 5 There was no evidence of either functional or structural denervation but surgically denervated muscles from animals in this group were indistinguishable from denervated muscles from normal rats. 6 Severe structural damage was obvious in the fibres of both extensor digitorum longus and soleus. Necrotic, hyaline and splitting fibres were common and the focal loss of myofibrillar ATPase and NADH-TR activity was extensive and occurred in Type I fibres as well as in Type II and Type II fibres. 7 It is concluded that the muscular weakness induced by (-)-emetine is due to a direct effect on the muscle fibres and that this occurs at a subcellular level. There is no evidence that functional or structural denervation plays any role in the aetiology of emetine myopathy in the rat.

Animals↗

Denervated frog skeletal muscle. Some electrical and mechanical properties.

The effects of denervation on several mechanical and electrical parameters of frog sartorius muscle have been investigated. In denervated muscles, there is no change in the resting potential and a relatively small change in the action potential. The first alteration in the action potential is a reduction of about 30% in the maximum rate of repolarization in muscles that have been denervated for 40 days or longer. Later, the overshoot and maximum rate of depolarization also decline. No tetrodotoxin resistant action potentials could be detected. Fibrillatory potentials were observed infrequently and in most cases in depolarized fibers. Twitch tension is significantly reduced by denervation while the tetanus tension is practically unaffected by denervation. The experiments suggest that the decline in twitch tension produced by denervation reflect a defect in some step of the excitation contraction coupling sequence. On the other hand, post-tetanic potentiation of the twitch is much larger in denervated than in control muscles. This potentiation in denervated muscles is paralleled by an increased action potential duration which returns to its pretetanic duration with a time course indistinguishable from that of the twitch potentiation.

Action Potentials↗

Effects of brain-derived neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease.

Brain-derived neurotrophic factor (BDNF) has been shown to promote the survival of developing motor neurons in vitro and to rescue motor neurons from axotomy-induced cell death in vivo. In this study, we examined the effects of exogenous BDNF on the progression of wobbler mouse motor neuron disease (MND). After clinical diagnosis at age 3 to 4 weeks, 20 affected mice received subcutaneous injections of recombinant human BDNF (5 mg/kg, n = 10) or vehicle (n = 10), three times a week for 4 weeks. In a separate experiment done to conduct a histometric analysis of the C-5 and C-6 ventral roots and to determine the number of myelinated nerve fibers, 7 wobbler mice received identical BDNF treatment. In the 10 BDNF-treated wobbler mice, grip strength declined at a slower rate (p < 0.03) and was twice as great as that of vehicle-treated animals at the end of treatment (p < 0.01). In vivo biceps (p < 0.01) and in vitro muscle twitch tensions (p < 0.02) were also greater than those of vehicle-treated mice. The biceps muscle weight was 20% greater (p < 0.05) and the mean muscle fiber diameter was significantly larger in BDNF-treated mice (p < 0.001) because the number of small (denervated) muscle fibers was markedly reduced. The number of myelinated motor axons at the cervical ventral roots studied in the additional 7 affected mice was 25% greater with BDNF treatment (p < 0.0001). This study establishes that exogenous BDNF administration can retard motor dysfunction in a natural MND and diminish denervation muscle atrophy and motor axon loss.

Animals↗

Alteration of sarcoplasmic reticulum after denervation of chicken pectoralis muscle.

To determine the neural influence on the function of the sarcoplasmic reticulum (SR) of fast-twitch skeletal muscle, the superior pectoralis muscle of adult chicken was denervated, and the SR was isolated at 20 days post-denervation. The isolated SR was probably derived from the longitudinal SR and was relatively free of contaminants. The protein profile of the SR was quantitatively changed after denervation with an increase in the M55 and 30000-mol.wt. proteins relative to the Ca2+-ATPase. Ca2+-dependent ATPase activity and phosphoenzyme formation were lower in the denervated-muscle SR; however, the enzyme catalytic-centre activity was similar to the control value. The decrease in Ca2+-ATPase activity in denervated-muscle SR was accompanied by a lower Ca2+ accumulation so that the relationship between Ca2+ accumulation and Ca2+-dependent ATPase activity was well maintained in the SR from denervated muscle. The data imply that denervation may result in a diminution of functional Ca2+ pump sites. Evidence is presented, though, which suggests that denervation affects a single class of Ca2+-binding sites of the Ca2+-ATPase, resulting in a lower affinity for Ca2+.

Adenosine Triphosphatases↗

Depolarizing neuromuscular blocking action of coryneine derived from aconite root in isolated mouse phrenic nerve-diaphragm muscles.

The mode of the neuromuscular blocking action of coryneine (a quaternary ammonium derivative of dopamine) derived from aconite root was investigated in isolated phrenic nerve-diaphragm muscles and denervated diaphragm muscles of mice. Coryneine (20-150 microM) blocked the nerve-evoked twitch response without affecting the contraction evoked by electrical stimulation of the muscle. The blocking effect was reversed by neostigmine, a cholinesterase inhibitor. The electrical charge-response curve on depolarization produced by iontophoretically applied acetylcholine (ACh) at the endplate regions in normal muscles was shifted to the right on decreasing the maximal response by 40 microM coryneine. The double-reciprocal plot revealed that coryneine reduced the apparent affinity of ACh for its receptor on decreasing the maximal response. Coryneine (20 microM-2mM) itself depolarized the endplate membrane and this effect was reversibly suppressed by 1 and 5 microM pancuronium. Coryneine 30 microM-10mM) produced contractions of denervated muscles in a concentration-dependent manner and the effects were reduced by 70nM pancuronium. These results indicate that coryneine is a depolarizing agent and a mixed-type competitive and noncompetitive neuromuscular blocker.

Animals↗

Effects of external cations and calcium-channel blockers on depolarization-contraction coupling in denervated rat twitch skeletal muscles.

In the double mannitol gap arrangement the contraction was estimated in single fibres isolated from rat extensor digitorum longus (e.d.l.) muscles that had been denervated for 2-48 days. Denervation induced large changes in the characteristics of the action potential and of the twitch. Up to 15-20 days after denervation the contraction-depolarization curve was sigmoidal and the maximum amplitude of the contraction was not modified by variation of [Ca]o or [Na]o. After 15-20 days of denervation a bell-shaped curve described the relation between contraction and potential. The maximum amplitude was dependent upon the [Ca]o. In Ca-free solution no contractile response was obtained. In Na-free, Ca-containing solution the relationship between contraction and potential was not modified by the addition of divalent cations Co2+, Cd2+, Mn2+, Mg2+, Ni2+, or Ba2+. The contraction, which appeared in Ca-free solution, was restored by adding Sr2+. D600, verapamil and bepridil failed to change the amplitude of the contraction while a marked reduction was found with dihydropyridines. The reduction was overcome by increasing [Ca]o. The present results suggest that the slow calcium current is not involved in the generation of the contractile responses developed by denervated muscles in Na-free (TEA) solution.

Action Potentials↗

Intrauterine structure of foot muscles in talipes equinovarus due to high-level myelomeningocele: a light microscopic study in fetal cadavers.

The purpose of this study was to investigate the light microscopic structure of extrinsic foot muscles in talipes equinovarus (TEV) deformity that developed during intrauterine life due to high-level myelomeningocele. Ten feet of five fetal cadavers ranging in age from 18 to 20 weeks were dissected. Five feet had typical TEV deformity and the other five feet did not have any deformity (control group). Under light microscopic examination quantitative measurement of both muscle fiber sizes and fibrosis in the muscle tissue were performed to investigate the denervation muscle atrophy. Mean muscle fiber size of the TEV group was found to be significantly lower than that of the control group in all foot muscles except the gastrocnemius muscle. The proportion of fibrosis due to denervation atrophy was significantly higher in the TEV group than in the control group in all muscles. This situation was most evident in the peroneus longus muscle. It was concluded that muscular imbalance due to significant muscular atrophy might be the cause of TEV deformity that developed during intrauterine life due to high-level myelomeningocele.

Aborted Fetus↗

Mechanical function of muscle reinnervated by end-to-side neurorrhaphy.

End-to-side neurorrhaphy is a surgical technique for peripheral nerve reconstruction when end-to-end neurorrhaphy is not an option. To define the effectiveness of end-to-side neurorrhaphy as a method of nerve repair, the authors tested the null hypothesis: there is no difference in the mechanical function of skeletal muscle denervated and reinnervated by end-to-side versus end-to-end neurorrhaphy. Adult Lewis rats underwent either transection and end-to-end epineurial repair of the left peroneal nerve (n = 9) or end-to-side repair of the distal stump of the peroneal nerve to the side of the tibial nerve (n = 8). After a 6-month recovery period, isometric force (Fo) was measured, and specific force (sFo) was calculated for the extensor digitorum longus muscle of each animal. Immunohistochemical staining for neural cell adhesion molecule (NCAM) was performed to identify populations of denervated muscle fibers. The mean extensor digitorum longus muscle mass in the end-to-end group (195 +/- 32 g) was significantly greater than that of the end-to-side group (146 +/- 55 g) (p < 0.05). A significantly greater percentage of denervated fibers was identified in the extensor digitorum longus muscles of animals in the end-to-side group (9.4 +/- 3.2 percent) than in those in the end-to-end group (3.8 +/- 1.0 percent) (p < 0.05). Despite a lower muscle mass and a higher percentage of denervated fibers, neither Fo nor sFo was significantly different in the two groups. These data support the null hypothesis that, under appropriate circumstances, there is no difference in the recovery of whole muscle force and specific force production in muscles reinnervated by end-to-side versus end-to-end neurorrhaphy.

Animals↗

Thoracic polyradiculopathy--abdominal wall swelling and sensory symptoms in diabetes mellitus.

We describe two patients with type 2 diabetes who presented with abdominal pain secondary to thoracic polyradiculopathy. In the first patient abdominal pain occurred in association with marked abdominal distension; extensive negative gastrointestinal investigations were performed before the correct diagnosis was made by electromyography showing thoracic paraspinal muscle denervation. In the second case, truncal sensory symptoms alone were evident at the time of diagnosis of diabetes mellitus. While muscle laxity was absent, extensive paraspinal muscle denervation was detected. Tolrestat, an aldose reductase inhibitor, was associated with good clinical response of symptoms due to peripheral neuropathy and thoracic polyradiculopathy. The pathogenesis of thoracic polyradiculopathy is uncertain but is likely to be the result of multiple infarcts along the course of thoracic spinal nerves accounting.

Abdominal Muscles↗

Protein composition of cockroach muscles: identification of candidate recognition macromolecules.

The protein composition of each of the coxal depressor muscles from the leg of the cockroach, Periplaneta americana, was analyzed by SDS polyacrylamide gel electrophoresis. The proteins from each muscle were fractionated according to their extractability in Ringer's solution, 1% Triton X-100 and 1% SDS. The gel protein patterns of the fractionated muscles revealed some biochemical differences that could be correlated with mechanical and ultrastructural differences observed among the muscles. In addition, proteins were detected that were considered to be candidate recognition macromolecules that are responsible for the intercellular recognition process that enables regenerating motor neurons to specifically recognize and make stable, functional connections only with the muscles to which they were originally connected. The major evidence for this identification of candidate recognition macromolecules was that their presence in the muscle could best be correlated with innervation by an identified motor neuron. In addition, these proteins remain present in denervated muscles for at least as long as it takes for the original innervation pattern to be reformed by the regenerating motor neurons.

Actins↗

Motor units and histochemistry in rat lateral gastrocnemius and soleus muscles: evidence for dissociation of physiological and histochemical properties after reinnervation.

A reexamination of the question of specificity of reinnervation of fast and slow muscle was undertaken using the original "self" nerve supply to the fast lateral gastrocnemius (LG) and slow soleus muscles in the rat hindlimb. This paradigm takes advantage of the unusual situation of a common nerve branch, which supplies both a fast and slow muscle, and of the opportunity to keep the reinnervating nerve in its normal position. In addition it provides a test of the effects of cross-reinnervation among muscles of the same functional group. The properties of soleus and LG muscles and of individual muscle units were characterized in normal rats and in rats 4-14 mo after cutting the lateral gastrocnemius-soleus (LGS) nerve and suture of the proximal stump to the dorsal surface of the LG muscle. Individual muscle units were functionally isolated by stimulation of single motor axons to LG or soleus muscle contained in teased filaments in the L4 and L5 ventral roots. Motor units were classified as fast contracting fatiguable (FF), fast contracting fatigue resistant (FR), and slow (S) on the basis of criteria described in the cat by Burke et al. and applied to rat muscle units by Gillespie et al. Muscle fibers were classified as fast glycolytic (FG), fast oxidative glycolytic (FOG), and slow oxidative (SO) on the basis of histochemical staining for myosin ATPase, nicotinamide-adenine dinucleotide diaphorase (NADH-D), and alpha-glycerophosphate (alpha-GPD). Reinnervated muscles developed less force and weighed less in accordance with having fewer than normal motor units and having lost denervated muscle fibers. Normal LG contained a small proportion of S-type motor units (9%), whereas the majority (80%) of control soleus units were S type. After reinnervation, each muscle contained similar proportions of fast and slow motor units with S-type units constituting 30% of units in both muscles. When compared with the normal motor-unit sample, there was no significant change in average twitch and tetanic force in reinnervated muscles for each type of motor unit. However, the range within each type was greater, and there was considerable overlap between types. Twitch contraction time was inversely correlated with force in normal and reinnervated muscles as shown previously in self- and cross-reinnervated LGS in the cat. Changes in proportions of motor units in reinnervated LG were accompanied by corresponding changes in histochemical muscle types. This contrasted with reinnervated soleus in which the proportion of muscle fiber types was not significantly changed from normal despite significant change in motor-unit proportions.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphatases↗