Inclusion bodies in denervated skeletal muscles of mice.
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A possible role for BDNF, NT-4 and TrkB in the spinal cord and muscle of rat subjected to mechanical overload, bupivacaine injection and axotomy.
Neurotrophins play a crucial role in the regulation of survival and the maintenance of specific functions for various populations of neurons. Neurotrophin-4 (NT-4) is most abundant in skeletal muscle, and is thought to promote sciatic nerve sprouting, inhibit agrin-induced acetylcholine receptor (AChR) clustering, evoke postsynaptic potentiation and induce mitochondrial proliferation. Using Western blot analysis, immunoprecipitation and immunohistochemistry, we investigated the distribution of NT-4 in slow- and fast-type muscles. We also tested the adaptive response of this protein in the mechanically overloaded muscle, in the regenerating muscle following bupivacaine injection and in the denervated muscle. Additionally, we investigated whether TrkB phosphorylation in the spinal cord and in the sciatic nerve occurs through the interaction with BDNF or NT-4 when the innervating muscle is damaged. Markedly more NT-4 was expressed in fast-type muscles compared with the slow types. TrkB protein was more frequently observed around the edge of myofibers (neuromuscular junction) of the soleus muscle compared with the gastrocnemius muscle. TrkB tyrosine phosphorylation occurred in the spinal cord but not in the sciatic nerve 24 h after bupivacaine injection of the innervating muscle. At the same time, the amount of TrkB co-precipitating with BDNF was markedly increased in the spinal cord. A rapid activation of TrkB (1-8 h) was also observed in the spinal cord after axotomy,while the amount of TrkB co-precipitating with NT-4 was markedly lower after axotomy. These results indicate that NT-4 is preferentially distributed in fast-type muscles. Furthermore, by interacting with BDNF and NT-4, the TrkB in the spinal cord may be important for the survival of motoneurons and outgrowth of injured peripheral axons following muscle damage.
Animals↗
THE EFFECTS OF SYMPATHOMIMETIC AMINES ON CHRONICALLY DENERVATED SKELETAL MUSCLES.
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Acetylcholine↗
Method for counting motor units in mice and validation using a mathematical model.
Weakness and atrophy are clinical signs that accompany muscle denervation resulting from motor neuron disease, peripheral neuropathies, and injury. Advances in our understanding of the genetics and molecular biology of these disorders have led to the development of therapeutic alternatives designed to slow denervation and promote reinnervation. Preclinical in vitro research gave rise to the need of a method for measuring the effects in animal models. Our goal was to develop an efficient method to determine the number of motor neurons making functional connections to muscle in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). We developed a novel protocol for motor unit number estimation (MUNE) using incremental stimulation. The method involves analysis of twitch waveforms using a new software program, ITS-MUNE, designed for interactive calculation of motor unit number. The method was validated by testing simulated twitch data from a mathematical model of the neuromuscular system. Computer simulations followed the same stimulus-response protocol and produced waveform data that were indistinguishable from experiments. We show that our MUNE protocol is valid, with high precision and small bias across a wide range of motor unit numbers. The method is especially useful for large muscle groups where MUNE could not be done using manual methods. The results are reproducible across naïve and expert analysts, making it suitable for easy implementation. The ITS-MUNE analysis method has the potential to quantitatively measure the progression of motor neuron diseases and therefore the efficacy of treatments designed to alleviate pathologic processes of muscle denervation.
Algorithms↗
Chronic stimulation modifies the isotonic shortening velocity of denervated rat slow-twitch muscle.
Rat soleus muscles were denervated and stimulated in vivo for periods of up to 104 days. Stimuli used were trains of 1 ms pulses at 100 Hz delivered for periods of 1 s; trains were repeated every 10-100 s. In a majority of animals the tension of the muscles was maintained at about 10% of normal, equivalent to muscles denervated but unstimulated for 20 days. At the longest periods the stimulated muscles developed ten times more tension than ones that were denervated but not stimulated. In denervated and denervated-stimulated muscles twitch contraction and relaxation times were prolonged, compared with controls, for up to 3 weeks. Thereafter both sets showed a speeding of the isometric twitch that was greater in the stimulated muscles. At the longest periods the twitch was as short as that of a denervated fast muscle. Stimulation did not affect contralateral denervated muscles. Twitch: tetanus ratios remained high despite stimulation, and muscles showed little post-tetanic potentiation. Tension developed more rapidly in the tetani of the stimulated muscles, even allowing for larger final values. Maximum velocity of shortening was increased in many of the stimulated muscles, and there was a proportional flattening of the force-velocity curve, i.e. a/P0 increased. Maximum velocity and a/P0 increased reciprocally with twitch time to peak, so that those muscles that had twitches most changed by stimulation also had their isotonic properties modified to the greatest extent. Even at the longest period of stimulation, twitch time course and tetanic tension were not converted to those of normal fast muscle.
Animals↗
[Variations in the resting membrane potential of denervated and tenotomized-denervated rat skeletal muscles].
Resting membrane potential (RMP) was studied in denervated (D), tenotomized (T) and tenotomized-denervated (TD) Soleus (S) and Tibialis Anterior (TA) muscles of the rat. In TD muscles, denervation was performed 1 week after tenotomy. The measurements were performed "in vitro" at 20 degrees C, 1-7 days after denervation in D and TD muscles, and 7 days after tenotomy in T muscles. In T muscles there were not differences in comparison with the controls. In D muscles RMP decreased earlier in S than in TA. The time course of membrane depolarization was similar in TD and D muscles until the 2nd day after denervation. At the 3rd day, RMP showed a further, significant reduction in TD muscles, both in S and TA, but not in D muscles. In D muscles, the depolarization increased very slowly up to the 7th day.
Animals↗
Comparison of the mode of action of succinylcholine and succinylmonocholine on rat skeletal muscle after denervation.
The effects of equimolar concentrations (3.0 X 10(-5) M) of succinylcholine (SCh) and succinylmonocholine (SMC) were studied in-vitro at 20 degrees C in rat extensor digitorum longus muscle (EDL) 0-147 days after common peroneal nerve section. Analysis of simultaneous measurements of K+ efflux (mmolL-1 g-1) and contracture tension (mN) to SCh showed that there was a rapid increase in the mean values of both parameters up to 22-28 days after denervation (7.7 mmolL-1 g-1, 36 mN). At the end of the period studied, the contracture response declined to 4.0 mN whilst the capacity for K+ efflux remained relatively high (4.8 mmolL-1 g-1) in comparison with normal contralateral EDL muscle (n = 82) K+ efflux measurements (0.62 mmolL-1 g-1). A significant correlation (r = 0.86, P less than or equal to 0.001) was found between SCh-induced K+ efflux and contracture tension 1-56 days following nerve section which indicated that the development of the contracture response and K+ efflux were concomitant during the period specified. The ratios of maximum contracture tension/K+ efflux in response to SCh and SMC, 18-22 days after denervation were similar, 4.9 and 5.9, respectively. Results indicated that the mode of action of each agent was similar in denervated rat skeletal muscle, and that they were equally potent in their hyperkalaemic potential. Results of comparative measurements of membrane depolarization and contracture tension in response to SCh and SMC showed that both agents produced quantitatively similar responses at 7 and 14 days after denervation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Independence of changes in contraction properties and myofibrillar ATPase activity of denervated mammalian muscle on length of nerve stump.
1. Contractile properties of the fast extensor digitorum longus of one-month-old rats and of the fast peroneus longus muscles of adult rabbits were studied in vitro at 36 degrees C after nerve section close to the muscle. Changes in contraction properties (prolongation) are not observed until 48 hours after denervation in the rat and 14-30 days in the rabbit. 2. At no period after denervation are differences in twitch isometric contraction properties dependent on the length of the sectioned nerve stump. This lack of dependence of contractile behavior after denervation is in contrast to many metabolic changes which show a clear dependence on the length of the nerve stump. 3. It is concluded that the onset of denervation changes in contractile behavior are related to the loss of nerve-impulse activity, while the transient early metabolic changes are related to changes of fast axoplasmic flow, initiated after nerve section and therefore dependent on length of sectioned nerve stump.
Adenosine Triphosphatases↗
Myosin heavy chain composition in rat laryngeal muscles after denervation.
OBJECTIVES: The effects of denervation on myosin heavy chain (MHC) expression in specific laryngeal muscles are characterized using gel electrophoresis. Observed temporal changes in MHC composition will then be used as a biologic marker in studies designed to develop strategies for laryngeal reinnervation and gene therapy. STUDY DESIGN: Animal study using an adult rat model for laryngeal paralysis. METHODS: In anesthetized rats the left recurrent and superior laryngeal nerve were divided. Animals were survived for 7, 14, 28, 90, and 180 days. Animals were euthanized and the thyroarytenoid (TA), vocalis (VOC), posterior cricoarytenoid (PCA), lateral cricoarytenoid (LCA), and cricothyroid (CT) muscle excised. Each muscle was processed for sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and densitometric measurements were obtained to determine composition of MHC fiber types. RESULTS: The changes in relative MHC composition are described for each specific laryngeal muscle. In general, a decrease in type IIB and an increase in IIA and IIX are seen after denervation. Expression of IIL in the denervated condition is variable and the relative change in type I is minimal. CONCLUSION: This study supports previous work using rat soleus muscle in which IIA/IIX expression is favored in conditions with decreased neuromuscular activity, and conversely, IIB expression is activity dependent. Expression of type I appears to be independent of neural activity. Further study will be undertaken to quantify expression of MHC components and to study factors modulating expression.
Animals↗
Factors affecting the distribution of acetylcholine receptors in innervated and denervated skeletal muscle fibers.
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Acetylcholine↗
Search for antibodies to skeletal muscle proteins in amyotrophic lateral sclerosis.
We have investigated serum from 16 patients with amyotrophic lateral sclerosis (ALS) and 15 patients with other neurological diseases (OND) for antibodies which react with skeletal muscle derived antigens. Two different preparations of skeletal muscle antigens were used: i) proteins released from rat diaphragm in organ culture and ii) proteins obtained from a muscle homogenate. We also compared antigen preparations from denervated and non-denervated muscles. A rabbit anti-serum reacted strongly with three proteins in both types of protein preparation, but none of these proteins were specific to denervated muscle. None of the 16 ALS sera could be shown to react with protein antigens from any of the muscle preparations. One of the ALS patients had an IgG lambda monoclonal protein in the setting of a multiple myeloma. This monoclonal protein did not react with protein antigen from rat muscle, human grey or white matter.
Adult↗
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↗
Neurotrophic influences are not affected by miniature end-plate potentials.
We investigated whether or not miniature end-plate potentials (MEPPs) play a part in neurotrophic influences. The sciatic nerve of mice, which supplies the extensor digitorum longus muscles, was cut either close to, or far from, the muscle. Denervation changes were evaluated using the resting membrane potential and dose-response curves obtained by plotting acetylcholine-induced contractures of muscles denervated 3 days earlier. The cessation of MEPPs and the manifestation of denervation changes occurred significantly later in muscles with long nerve stumps than in those with short nerve stumps. A single administration of ethidium bromide, a specific inhibitor of mitochondrial protein synthesis, accelerated the cessation of MEPPs in muscles with long nerve stumps without affecting the manifestation of denervation changes. We therefore conclude that MEPPs do not have neurotrophic effects.
Acetylcholine↗
Long-distance regulation of regenerating frog axons.
Following a nerve crush, damaged frog motor axons regenerate to reinnervate their denervated muscle fibre targets. The axons do this by growing down their old nerve tubes to their former synaptic sites. It is the naked basal lamina of the nerve tube that appears to direct the regenerating axons by providing a substratum over which the axons will preferentially grow. Another possible mechanism for directing the regenerating axons to the end-plates is the release of molecular signals by the cells of the nerve tube or by the denervated muscle fibres. This paper provides evidence that chemical signals do direct the regeneration process. Such signals, released several millimetres from a growing nerve tip, cause it to change direction and bend towards the source. Both the cells of the nerve tube and the denervated muscle fibres release diffusible substances and thereby establish a gradient that affects the regenerating axons.
Animals↗
Innervation regulates the metamorphic fates of larval abdominal muscles in the moth, Manduca sexta.
With the onset of metamorphosis, the abdominal muscles of the moth, Manduca sexta, follow one of three developmental fates: maintenance, respecification, or death. The maintained muscles retain their larval size and morphology throughout adult development. The respecified and dying muscles dedifferentiate, which involves regression, nuclear degeneration, and myofibril breakdown. Nuclei in both dying and respecified muscles also proliferate. The amount of nuclear degeneration is greater in the dying muscle fibers, and the amount of nuclear proliferation is greater in the respecified muscles. Four to ten days after pupation, the sizes of the respecified muscles stabilize while the dying muscles are lost. During regression, a subset of the respecified muscle fibers die. The surviving respecified muscle fibers grow and differentiate during the last half of adult development. In respecified muscles, denervation triggers an increased amount of nuclear degeneration and a decreased amount of nuclear proliferation. As a result, denervated respecified fibers experience increased muscle regression including an increased loss of muscle fibers and sometimes muscle death. Surviving respecified fibers still grow and differentiate yet are only 5 to 12% of the control size. Denervation triggers dedifferentiation in maintained muscles, resulting in fiber loss and occasionally muscle death. The percentage of fibers which dedifferentiate varies between different muscles. Denervation also triggers nuclear proliferation, with the amount of nuclear proliferation correlated with the extent of dedifferentiation of the individual muscle fibers. The dedifferentiated maintained fibers subsequently undergo differentiation in the absence of muscle growth.
Abdominal Muscles↗
Changes in responsiveness to extracellular ATP in chick skeletal muscle during development and upon denervation.
Skeletal muscles in developing chick embryos were tested for responsiveness to adenosine 5'-triphosphate (ATP), a substance known to depolarize chick skeletal muscle in culture. The sensitivity to extracellular ATP was tested at various stages of development in five different muscles; pectoralis superficia, anterior latissimus dorsi, posterior latissimus dorsi, sartorious, and gastrocnemius. At the earliest time that muscles were tested (Embryonic Day 6, stage 30 of Hamburger and Hamilton, 1951) application of ATP(50-100 microM) elicited vigorous contractions in all five muscles, but within a few days (Embryonic Day 17, stage 43) none of the muscles contracted in response to ATP. Sensitivity declined at approximately the same time in all five of these muscles. Intracellular recordings made from muscle fibers near the time of hatching (Embryonic Days 18-21 or Postnatal Days 1-2) indicated that the loss of the ability to contract in response to ATP was due to the total loss of responsiveness to ATP. Surgical denervation of the anterior latissimus dorsi and posterior latissimus dorsi was performed in a series of chicks 1-2 days after hatching, and the ability of these muscles to contract in response to ATP was tested 3-10 days after the surgery. Contractions in response to ATP were present in many of the muscles. Thus denervation of muscles in newly hatched chicks led to the reappearance of sensitivity to ATP. The disappearance of ATP responsiveness shortly after muscles become innervated and the reappearance of ATP responsiveness following denervation suggest that the expression of ATP responsiveness is regulated by motor neurons.
Adenosine Triphosphate↗
Stabilizing neuromuscular contacts increases motoneuron survival after neonatal nerve injury in rats.
Following sciatic nerve crush at birth the rat soleus muscle is rendered permanently weak. This reduction in muscle force is caused by the loss of a proportion of its motoneurons. Furthermore, motoneurons that survive and reach the muscle fail to reoccupy a sufficient number of denervated muscle fibres to compensate for the loss of neurons. Both the loss of motoneurons and poor reinnervation may be due to the inability of the regenerating axons to establish and maintain neuromuscular contacts. Application of leupeptin, an inhibitor of a calcium-activated neutral protease and some serine proteases, is known to help in the maintenance of neuromuscular contacts during development and axonal sprouting. Here we examined whether protecting new neuromuscular contacts formed between regenerating axons and denervated muscle fibres after nerve injury, would influence the survival of motoneurons and improve muscle recovery. This study shows that in muscles treated with leupeptin the reduction in weight and force output after nerve crush at birth was significantly less than in those that were untreated. Moreover, the number of motor units in the leupeptin-treated muscles was significantly higher than in untreated muscles. Thus, treating regenerating nerve terminals with leupeptin during early stages of reinnervation rescues motoneurons and improves muscle recovery.
Animals↗
Perfusion parameters and pressure at zero flow in canine gracilis muscle flaps.
The perfusion parameters and pressure at zero flow were examined in island gracilis muscle flaps in dogs under sodium pentobarbital anesthesia. Complete surgical isolation of the muscle preparation was obtained. Normal blood flow in denervated muscle in situ was 8.0 +/- 0.8 ml/min/100 g tissue as measured by electromagnetic blood flowmetry. The artery supplying each flap was occluded with a microclip and the drop in pressure distal to the clip was observed. The lowest pressure obtained following occlusion was the pressure at zero flow. A positive pressure at zero flow in the vascular bed was thereby identified at a pressure of 10.3 +/- 1.2 mm Hg.
Animals↗