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PubMed1991

Dystrophic changes in mdx muscle regenerating from denervation and devascularization.

The regenerative capacity of young mdx muscle after a denervating and devascularizing injury (DD) was examined in extensor digitorum longus (EDL) and compared with that of age-matched control mouse EDL. DD of the right EDL was produced at the age approximating the onset of dystrophy in the mdx model, and mice recovered for 2 weeks. Contralateral unoperated EDLs from mdx and control mice served as internal controls for histopathology, myofiber cross-sectional area (CSA), and ultrastructure of fiber regeneration in DD-EDL. Mdx DD-EDL were composed of small, uniformly mature myofibers with mostly peripheral nuclei. This contrasted with control DD-EDL in which fibers were centrally nucleated. In addition, the unoperated mdx EDL exhibited the central nucleation of spontaneous recovery from dystrophy. The CSA distribution of mdx DD-EDL myofibers was significantly shifted toward smaller CSA compared with unoperated mdx EDL, although mean CSA did not differ between the two mdx muscle groups. The CSA distribution of control DD-EDL was significantly different and shifted toward smaller CSA from both unoperated control EDL and from mdx DD-EDL distributions. Ultrastructural features of dystrophy were present in both mdx DD-EDL and in the unoperated mdx EDL, although they appeared more prevalent in the latter. These results suggest that short-term plasticity of mdx muscle recovery from imposed injury may be greater than that of normal muscle in establishing a regenerating fiber population.

Animals↗
PubMed2003

MR imaging in the differential diagnosis of neurogenic foot drop.

BACKGROUND AND PURPOSE: Prolonged T2 relaxation time of denervated muscle has been described in several clinical and experimental studies. The purpose of this study was to evaluate the utility of MR imaging in the diagnosis of neurogenic muscle disorders compared with that of clinical and electrophysiologic examination. METHODS: In a prospective study, 40 consecutive patients clinically presenting with a foot drop were included. MR imaging of the lower leg included axial T1-weighted and axial turbo inversion recovery magnitude (TIRM) sequences. Two readers blinded to clinical data evaluated T1-weighted images for anatomic localization of affected muscles and TIRM images for patterns of signal intensity increase. After MR imaging, a detailed neurophysiologic examination was performed. Cause of foot drop was independently determined on the basis of MR and electrophysiologic data. RESULTS: Clinical examination and electromyography (EMG) disclosed 20 peroneal nerve lesions, nine cases of L5 radiculopathy, and 11 nerve lesions extending beyond neural structures. MR imaging revealed three distinct patterns of signal intensity increase on TIRM images: peroneal nerve pattern, L5 pattern, and unspecific pattern. MR imaging and EMG findings were in agreement in 37 (92%) of 40 patients. In three patients, MR imaging revealed a more widespread involvement than did EMG. In one of these patients, denervation in the corresponding muscle was validated by follow-up EMG. No false-negative diagnoses were made by use of MR imaging as compared with use of EMG. CONCLUSION: MR imaging improves accuracy in the differential diagnosis of peripheral nerve lesions compared with that of EMG and can supplement EMG in the diagnosis of denervated muscles.

Action Potentials↗
PubMed2000

Role of denervation in modulating IIb MHC gene expression in response to T(3) plus unloading state.

Previously, we have reported that the combination of hindlimb suspension (HS) and thyroid hormone [triiodothyronine (T(3))] treatment induces the de novo expression of the fast IIb myosin heavy chain (MHC) gene in the soleus. Thus we tested the hypotheses that the induction of IIb MHC expression with HS + T(3) is prevented with denervation and that this IIb induction is regulated by transcriptional processes. Adult female rats were subjected to 2 wk of combined HS + T(3) in which one side of the lower leg was simultaneously denervated. HS + T(3) caused decreased expression of the slow type I MHC and concomitant increases in both the fast type IIx and IIb MHC isoforms in the intact soleus muscle. Denervation prevented the endogenous expression of the IIb MHC gene at both the protein and mRNA levels. Although HS + T(3) intervention was able to markedly increase the expression of the 2.6-kb IIb MHC promoter-reporter construct using direct gene transfer, this induction, however, was not inhibited by denervation. These findings collectively suggest that normal innervation is essential for inducing the unique expression of the IIb MHC in a slow muscle in response to HS + T(3); however, in the denervated muscle, there is a discordance between the regulation of the endogenous IIb MHC gene relative to the exogenous IIb MHC promoter-reporter construct.

Animals↗
PubMed1987

Effect of pyridostigmine on tetanic contracture of innervated and denervated rat skeletal muscle.

Pyridostigmine has been reported to cause histological damage and decrements in tetanic contracture of skeletal muscle. Cholinesterase inhibition, decreased transmitter release and desensitization of postsynaptic receptors have all been proposed as mechanisms for these effects. The purpose of the present study was to determine whether the effect of pyridostigmine to decrease tetanic contracture was due to pre- or postsynaptic action. Rats with innervated or chronically denervated hindlimbs were given pyridostigmine (25 mg/kg) s.c. by infusion for four days. Tetanic contracture (20, 50, 100 Hz) was evoked by sciatic nerve stimulation in the innervated muscles and direct muscle stimulation in the denervated muscles. Pyridostigmine significantly decreased the contracture of innervated triceps surae muscle in a frequency dependent manner. Post-tetanic potentiation was reduced from control muscle responses. In denervated muscle pyridostigmine had no effect on contracture or post-tetanic potentiation. These results show that innervation is required for the detrimental effect of pyridostigmine and that the drug has no effect on skeletal muscle.

Animals↗
PubMed1985

Tendon adaptation to different long term stresses and collagen reticulation in soleus muscle.

Leg immobilization with or without soleus muscle denervation was studied in young rabbits. Muscle and tendon were maintained in extension, i.e., in the most lengthened position. Length measurements performed on sarcomeres, muscle fibers and tendon-plus-muscle complexes suggest the following progression in tendon growth rates: normal less than denervated-extended less than innervated-extended. Collagen reticulation was studied as a function of fiber location along these tendons by measuring hydrothermal isometric tension (HIT). Large variations were observed depending on fiber location, and significant modifications were induced by immobilization in extension. The results are discussed in relation to stress as a possible factor controlling collagen maturation in connective tissues.

Adaptation, Physiological↗
PubMed2007

Molecular and cellular defects of skeletal muscle in an animal model of acute quadriplegic myopathy.

Muscle denervation and concomitant high-dose dexamethasone treatment in rodents produces characteristic pathologic features of severe muscle atrophy and selective myosin heavy filament (MyHC) depletion, identical to those seen in acute quadriplegic myopathy (AQM), also known as critical illness myopathy. We tested the hypothesis that defective pre-translational processes contribute to the atrophy and selective MyHC depletion in this model. We examined the effects of combined glucocorticoid-denervation treatment on MyHC and actin mRNA populations; we also studied mRNA expression of the myogenic regulatory factors (MRFs), primary transcription factors for MyHC. Adult female rats were subjected to proximal sciatic denervation followed by high-dose dexamethasone (DD) treatment (5 mg/kg body weight daily) for 7 days. Disease controls included rats treated with denervation alone (DN) or dexamethasone alone (DX). At 1 week the plantaris atrophied by approximately 42% in DD muscles. DD treatment resulted in selective MyHC protein depletion; actin protein concentration was not significantly changed. Despite an increase in total RNA concentration in DN and DD muscles, MyHC and actin mRNA concentrations were significantly decreased in these muscles. MyHC mRNA showed a significantly more extensive depletion relative to actin mRNA in DD muscles. Glucocorticoid treatment did not influence a denervation-induced increase in the mRNA expression of the MRFs. We conclude that a deleterious interaction between glucocorticoid and denervation treatments in skeletal muscle is responsible for pre-translational defects that reduce actin and MyHC mRNA substrates in a disproportionate fashion. The resultant selective MyHC depletion contributes to the severe muscle atrophy.

Actins↗
PubMed1994

Release and synthesis of acetylcholine at ectopic neuromuscular junctions in the rat.

1. The ability of axons in the superficial fibular nerve to synthesize and release acetylcholine (ACh) has been studied before and after the formation of ectopic neuromuscular junctions (NMJs) with denervated soleus muscles of adult rats. 2. The central end of the severed fibular nerve was transplanted to the surface of the soleus muscle. After 3.5-5 weeks the soleus muscle was denervated in one group of rats by cutting the tibial nerve, allowing the formation of functional ectopic NMJs within a few days. In other rats the tibial nerve remained intact, preventing the formation of functional ectopic NMJs. 3. A month later the content of ACh, the levels of activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), and the amount of ACh released by depolarization by exposure to 50 mM KCl were measured in segments of isolated muscles that (i) contained normal or ectopic NMJs, (ii) were free of nerve or (iii) contained nerve that had not made NMJs. 4. Regions of muscles with ectopic nerve growth in which new NMJs had not formed contained substantial amounts of ACh and ChAT but no AChE. No detectable release of ACh could be evoked from these regions. 5. In muscles in which ectopic NMJs had formed after cutting the tibial nerve, the amounts of ACh and ChAT were about one-fifth of those in the regions of innervation of control muscles. ACh release could be evoked from the region of ectopic nerve growth in amounts nearly as great as those released from NMJs in normal and contralateral control muscles. 6. We conclude that the ability of the terminal parts of mature motor axons to synthesize and store ACh is largely independent of functional contact with muscle fibres. By contrast, the ability to release ACh in substantial amounts only develops when NMJs are formed. The possible significance of this situation for the development of synapses is discussed.

Acetylcholine↗
PubMed1992

Calcium current activation and charge movement in denervated mammalian skeletal muscle fibres.

1. Calcium current (ICa) activation was studied in denervated extensor digitorum longus muscle fibres of the rat. Denervation was performed by surgically removing 6-8 mm of the sciatic nerve at the sciatic notch. Controls were normal fibres from non-operated rats. Electrical recordings were carried out using the double Vaseline-gap technique. 2. Current-voltage (I-V) curves showed that the ICa amplitude increased during the first 4-6 days after denervation and subsequently decreased during the second week. Between days 4 and 6 after denervation, the peak ICa amplitude (at 0 mV) was -5.9 +/- 0.5 microA/microF (mean +/- S.E.M.) as compared with -4.8 +/- 0.3 microA/microF in normal fibres. Between days 14 and 15 after denervation, the ICa amplitude was -2.9 +/- 0.4 microA/microF. 3. The time constant of ICa activation (tau a) was significantly increased by denervation. At 0 mV, tau a in normal fibres was 44.8 +/- 1.4 ms. Between 4 and 6 days after denervation tau a was 58.1 +/- 4.8 ms, and between 14 and 15 days after denervation, 55.8 +/- 3.8 ms. 4. The time constant of deactivation (tau d) decreased after denervation. At -10 mV, the tau d in normal fibres was 103.4 +/- 14 ms. The value decreased to 74.5 +/- 8.6 and 74.0 +/- 17 ms between days 4 and 6 and days 14 and 15 of denervation respectively. 5. Charge movement (Qon) was reduced progressively without major changes in the steepness (k) and position on the voltage axis of the Qon-Vm relationship. The fitted parameters under control were Qmax = 15.4 nC/microF, mid-point potential Vq1/2 = -25.2 mV and k = 11.9 mV. Between days 14 and 15 of denervation, the values for Qmax, Vq1/2 and k were 6.7 nC/microF, -36.8 mV and 11.3 mV respectively. 6. Calcium permeability (PCa) in normal and denervated fibres at stages during denervation was calculated according to the Hodgkin-Huxley model. At 0 mV PCa was 1.24 x 10(-5) cm/s in normal fibres, and 7.43 x 10(-6) cm/s after 2 weeks of denervation. 7. The m infinity-Vm relationship was shifted to more positive potentials after denervation without significant changes in the steepness factor k. The V1/2 value in normal fibres was -4.4 mV, and 5.8 mV after two weeks of denervation. 8. The ICa sensitivity to nifedipine was not modified in the different groups of denervated fibres studied. With 10 microM-nifedipine, the 1-(ICa in nifedipine/ICa control) relationships were 0.74 +/- 0.03 in normal fibres and 0.76 +/- 0.12, 14 days after denervation.

Action Potentials↗
PubMed1983

[Effect of chronic presynaptic neuromuscular transmission blockade on the properties of frog muscle fiber membranes].

It has been discovered in experiments on frogs that muscle denervation removes the membrane rest potential, increases the input resistance and time constant of the membrane, expands the zone of muscular fiber sensitivity to acetylcholine. Long-term disturbance by tetrodotoxin of the excitation conduction in the motor nerve or presynaptic blockade of neuromuscular transmission by hemicholinium-3 do not change the membrane rest potential and time constant of the membrane or the size of the zone of muscular fiber sensitivity to acetylcholine but increase the input resistance of the muscle membrane. It is inferred that in the frog, presynaptic blockade of the excitation conduction from the nerve to the muscle is not equivalent to its denervation.

Acetylcholine↗
PubMed1975

Acetylcholine receptors in normal and denervated rat diaphragm muscle. I. Purification and interaction with [125I]-alpha-bungarotoxin.

Acetylcholine receptors have been purified from junctional regions of normal rat diaphragm muscle and from extrajunctional regions of denervated diaphragm. The reaction of purified receptors with [122I]-alpha-bungarotoxin has been investigated by kinetic methods. The toxin-receptor complexes dissociated in a biphasic manner at 35 degrees with a rapidly dissociating component (t1/2 = 4 hr) and a slowly dissociating component (t1/2 is greater than or equal to 100 hr). The association reaction between toxin and receptor did not obey simple second-order kinetics but could be analyzed in terms of two classes of binding sites corresponding to the two rates of dissociation. This treatment of the data allowed derivation of association rate constants for the two sites. Value obtained for the dissociation constants were 3.7 times 10(-10) and less than or equal to 0.4 times 10(-10) M for the junctional receptor and 1.7 times 10(-10) and is less than or equal to 0.2 times 10(-10) M for the extrajunctional receptor. In each case it is the more tightly binding component that associates and dissociates more slowly. Receptors present in crude preparations were comparable to purified receptors in their reaction with [125I-alpha-bungarotoxin. The validity of the two site model is discussed in relation to the kinetic studies.

Acetylcholine↗
PubMed1986

Assessment of facial reinnervation by use of chronic electromyographic monitoring.

The study of muscle reinnervation has been difficult because of lack of an accurate, reproducible method to monitor return of function. Visual assessment relies on subjective interpretation. Histology provides anatomic, not functional, information. Electromyography and anatomic tracing have been most effective in evaluating physiologic return of muscle function. It has been difficult to assess the timing of functional return electromyographically because measurements are intermittent and electrode placement varies. A method was designed to allow long-term monitoring of electromyographic (EMG) activity in the facial musculature of the rabbit. Sixteen rabbits were monitored for at least 1 month or until return of normal EMG activity was identified. Various levels of injury (nerve crush, transection without repair, and transection with immediate end-to-end anastomosis) were evaluated. EMG evidence of reinnervation was seen in all animals with nerve crush injuries as well as those with anastomoses. Physiologic continuity of the nerves was then evaluated by retrograde transport of horseradish peroxidase. All muscles showing return of EMG activity had uptake of HRP into the appropriate brain stem motor neurons. The denervated muscles showed no HRP uptake. The information gained in this study shows potential for use of this technique in comparing functional return of muscle activity between different reinnervation methods.

Animals↗
PubMed1979

The fine structure of denervated and reinnervated muscle spindles: morphometric study of intrafusal muscle fibers.

The fine structure of normal, denervated, and reinnervated muscle spindles in lower lumbrical muscles of rats was studied morphometrically at time intervals ranging from 3-14 months. In control spindles, the mean transverse area of mitochondria was estimated to be more than twice as large in nuclear chain than in typical nuclear bag fibers. Following denervation, there was a severe decrease of the mean number and transverse area of mitochondria, and a moderate, but statistically significant decrease of the mean transverse area of intrafusal muscle fibers (IMFs) despite an increase of the number of IMFs. At 12-14 months of reinnervation, changes of the transverse areas of IMFs were statistically insignificant, but the mean values for the mitochondria were incompletely restored. At 4 x 3 months, after fourfold repeated crush injuries to the nerve, most of the values estimated (transverse area of mitochondria; number, shape, and transverse area of IMFs and nuclei) tended to approach those in denervated rather than in reinnervated IMFs. The differences of the reactions of intra- and extrafusal muscle fibers following complete motor and sensory denervation appeared to be in accordance with their normal dimensional dissimilarities.

Animals↗
PubMed2005

Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression.

Electrical activity arising from motor innervation influences skeletal muscle physiology by controlling the expression of many muscle genes, including those encoding acetylcholine receptor (AChR) subunits. How electrical activity is converted into a transcriptional response remains largely unknown. We show that motor innervation controls chromatin acetylation in skeletal muscle and that histone deacetylase 9 (HDAC9) is a signal-responsive transcriptional repressor which is downregulated upon denervation, with consequent upregulation of chromatin acetylation and AChR expression. Forced expression of Hdac9 in denervated muscle prevents upregulation of activity-dependent genes and chromatin acetylation by linking myocyte enhancer factor 2 (MEF2) and class I HDACs. By contrast, Hdac9-null mice are supersensitive to denervation-induced changes in gene expression and show chromatin hyperacetylation and delayed perinatal downregulation of myogenin, an activator of AChR genes. These findings show a molecular mechanism to account for the control of chromatin acetylation by presynaptic neurons and the activity-dependent regulation of skeletal muscle genes by motor innervation.

Acetylation↗
PubMed1977

Properties of isolated adult rat muscle fibres maintained in tissue culture.

1. Adult rat skeletal muscles were dissociated by collagenase treatment and trituration, and the isolated muscle fibres were maintained in vitro for 2-3 weeks. At various stages, the fibres were examined physiologically and morphologically. 2. The isolated fibres underwent some changes characteristic of muscle denervated in vivo. For instance, input resistance increased and extrajunctional acetylcholine (ACh) receptors appeared. In addition, the beginning stages of apparent muscle fibre fragmentation were observed. 3. In other respects, the cultured isolated fibres behaved differently than in vivo denervated fibres. Fibrillation developed only occasionally in vitro. The onset of ACh supersensitivity was slower (6 days) than after denervation in vivo (2-3 days). Some fibres developed localized regions of destriation, which apparently was due to loss of in-register alignment of myofibrils.

Acetylcholine↗
PubMed1983

Ca2+-activated protease in denervated rat skeletal muscle measured by an immunoassay.

Right hind leg muscles of adult male rats were denervated by transecting the sciatic nerve, while muscles of the left leg served as a control. On days 4, 9, and 18 after denervation, the rats were killed and the extensor digitorum longus and soleus muscles removed. Extracts were prepared which contained the Ca2+-activated protease. The molecular weight of the protease in the extracts, measured immunologically on Western blots of SDS-polyacrylamide gels, was identical to that of purified standard protease and was unaffected by denervation. The amount of protease in each extract was measured by a solid phase immunoassay using monospecific IgG labeled with 125I, and the results were expressed as units of protease activity per milligram noncollagen protein. There were increases of 40 to 80% in the mean values obtained for both denervated muscles compared with controls. Because the protease is probably localized on the cell membrane, these modest increases are likely to be a consequence of a generalized over-development of muscle membranes which follows denervation.

Animals↗