Analysis of preganglionic nerve evoked cholinergic contractions of the guinea pig bronchus.

We compared cholinergic bronchial muscle contractions induced by vagus nerve (preganglionic) stimulation (VNS) with those induced by electrical field (postganglionic) stimulation (EFS). When normalized to their respective maximum response, the frequency-response curves (10 s trains) between 4 and 16 Hz were similar between VNS and EFS; however, at frequencies of 0.1-2 Hz, and at frequencies greater than 32 Hz, the VNS contractions were significantly less than EFS. When contractions elicited by 100 pulses were examined, it was found that the responses to VNS were maximal at 10-30 Hz then declined significantly to 82-35% of maximal between 40 and 200 Hz, whereas the response to EFS was essentially unchanged at frequencies up to 60 Hz and declined only to 72% of maximal up to 200 Hz. At frequencies as low as 20 Hz, the contractions evoked by VNS faded to 45 +/- 9% of the peak contraction during 60 sec of continuous stimulation, whereas those evoked by 60 sec continuous EFS remained constant. This fade observed during prolonged VNS was not blocked by the antagonists, pirenzepine and AFDX-116, at concentrations selective for M1 and M2 muscarinic receptors, respectively; nor was the fade blocked by pre-treatment with indomethacin, propranolol, phentolamine, or choline. At frequencies greater than 10 Hz, the amplitude of the preganglionic compound action potential also faded during repetitive stimulation. The results support the hypothesis that the airway ganglion neurons innervating guinea pig bronchial smooth muscle effectively filter preganglionic stimuli, especially at low and relatively high frequencies. During continuous vagus nerve stimulation, preganglionic mechanisms may also play a role in limiting the ultimate output of airway ganglia.     

Reciprocal changes in myosin isoform mRNAs of rabbit skeletal muscle in response to the initiation and cessation of chronic electrical stimulation.

Changes in myosin heavy chain (MHC) mRNAs were studied in rabbit fast-twitch muscles during continuous electrical stimulation at 10 Hz for periods up to 3 weeks, and during the first 12 days of the recovery process that followed cessation of 6 weeks' stimulation. Two cDNA probes were used to detect MHC mRNAs specific to fast- and slow-twitch skeletal muscle in RNase protection assays and Northern- and slot-blot analyses. The isolation and base sequence of one of these probes, corresponding to the MHC gene expressed in soleus (slow-twitch), is described. At an early stage of the response to stimulation, fast MHC mRNA was replaced by slow MHC mRNA. During recovery, this process occurred in reverse but took longer. The time course of recovery was slightly faster in tibialis anterior than in extensor digitorum longus. The changes in mRNAs during both stimulation and recovery reflected changes in the corresponding muscle proteins.     

A 31P-NMR study of muscle exercise metabolism in mdx mice: evidence for abnormal pH regulation.

We have studied exercise metabolism in vivo in the mdx mouse model of Duchenne muscular dystrophy with 31P-nuclear magnetic resonance spectroscopy. Intracellular pH, ratios of phosphocreatine (PCr) to ATP and PCr to inorganic phosphate (P(i)) expressed as PCr/ATP and PCr/(PCr+P(i)) as well as tension generated at the Achilles tendon were measured during sciatic nerve stimulation. Tension was similar between the mdx and control strain C57Bl/10ScSn at 10 Hz stimulation but slightly higher than the control at 100 Hz. The PCr/ATP and PCr/(PCr+P(i)) ratios were significantly reduced in mdx vs. control muscle during exercise. Although resting muscle pH in mdx mice is more alkaline than normal muscle, the pH of mdx muscle during exercise is reduced relative to controls, as is the rate of pH recovery. Total lactate is not elevated in the cells and so it is argued that there is a reduction in the capacity to export proton equivalents in muscles of mdx mice which could be caused by an elevation in intracellular sodium. This provides more evidence of impaired ionic regulation in dystrophic muscle and could be used as an index for the evaluation in vivo of therapeutic interventions such as myoblast transfer or gene replacement therapy.     

Endotoxemia causes a paradoxical intracellular pH recovery in exercising rat skeletal muscle

In resting skeletal muscle, endotoxemia causes disturbances in energy metabolism that could potentially disturb intracellular pH (pH(i)) during muscular activity. We tested this hypothesis using in situ (31)P-magnetic resonance spectroscopy in contracting rat gastrocnemius muscle. Endotoxemia was induced by injecting rats intraperitoneally at t(0) and t(0) + 24 h with Klebsiella pneumoniae endotoxin (lipopolysaccharides at 3 mg/kg) or saline vehicle. Muscle function was investigated strictly noninvasively at t(0) + 48 h through a transcutaneous electrical stimulation protocol consisting of 5.7 minutes of repeated isometric contraction at 3.3 HZ, and force production was measured with an ergometer. At rest, endotoxin treatment did not affect pH(i) and adenosine triphosphate concentration, but significantly reduced phosphocreatine and glycogen contents. Endotoxemia produced both a reduction of isometric force production and a marked linear recovery (0.08 +/- 0.01 pH unit/min) of pH(i) during the second part of the stimulation period. This recovery was not due to any phenomenon of fiber inactivation linked to development of muscle fatigue, and was not associated with any change in intracellular proton buffering, net proton efflux from the cell, or proton turnovers through creatine kinase reaction and oxidative phosphorylation. This paradoxical pH(i) recovery in exercising rat skeletal muscle under endotoxemia is likely due to slowing of glycolytic flux following the reduction in intramuscular glycogen content. These findings may be useful in the follow-up of septic patients and in the assessment of therapies.     

Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy

Abnormal mitochondria are an increasingly recognized cause of neuromuscular disease. We have used phosphorus magnetic resonance spectroscopy to monitor noninvasively the metabolism of high-energy phosphates and the intracellular pH of human skeletal muscle in vivo in 12 patients with mitochondrial myopathy. At rest, an abnormality could be demonstrated in 11 of 12 patients. Ten patients had evidence of a reduced muscle energy state with at least one of the following abnormalities: low phosphorylation potential, low phosphocreatine concentration, high adenosine diphosphate concentration, or high inorganic phosphate concentration. Two patients had abnormal resting muscle intracellular pH. In some patients phosphocreatine concentration decreased to low values during exercise despite limited work output. This was not accompanied by particularly severe intracellular acidosis. Evidence of impaired rephosphorylation of adenosine diphosphate to adenosine triphosphate during recovery from exercise was found in approximately half the patients. Phosphorus magnetic resonance spectroscopy is useful in the noninvasive diagnosis of mitochondrial myopathies and in defining the pathophysiological basis of these disorders.     

In vivo phosphorus nuclear magnetic resonance (31P-NMR) study of dystrophic hamster muscle

Skeletal muscle bioenergetics of dystrophic hamsters (DH) were studied by in vivo 31P-NMR in order to evaluate possible metabolic impairment. 31P-NMR data were obtained during rest, during muscle work that was induced by nerve stimulation at 3 frequencies (0.2, 0.4 and 1.0 Hz) and during postexercise recovery. At rest, phosphocreatine-to-inorganic phosphate ratio (PCr/Pi) was significantly (P less than 0.02) lower in adult DH (5.3 +/- 1.1; +/- 2 SD) compared with control hamsters (6.55 +/- 0.5). An increased PCr depletion was found in DH muscle during nerve stimulation and the steady-state PCr/Pi was significantly (P less than 0.05) lower at 0.4 and 1.0 Hz. Slow PCr/Pi recovery was observed in DH (0.5 +/- 0.2 units per min compared with 1.42 +/- 0.28 for control, +/- 2 SD, P less than 0.02). These findings suggest a significant in vivo mitochondrial malfunction in DH muscle that may result from either mitochondrial abnormalities or cardiac insufficiency or a combination of both.     

Pedunculopontine tegmental nucleus-induced inhibition of muscle activity in the rat

The connections of the pedunculopontine tegmental nucleus (PPN) have led us to propose that this structure mediates striatally induced inhibition of muscle activity by directing basal ganglia output to an inhibitory reticulospinal system (nucleus reticularis gigantocellularis and ventralis, nrGi-V). We conducted experiments in order to examine the effects of electrical stimulation of the PPN on the activity of selected neck and shoulder muscles. PPN stimulation at low rates (0.1 Hz) elicited bilateral muscle excitation. As the rate of stimulation was increased (e.g. to 10 Hz), less excitation was observed. Anodal DC current inactivation of the nrGi-V during concurrent 10 Hz PPN stimulation resulted in an augmentation of muscle activity above the levels observed during 10 Hz PPN stimulation alone. PPN stimulation (10 Hz) also profoundly inhibited cortically-induced muscle activity. Further support for our proposal stems from increased baseline activity (0.1 Hz PPN-induced excitation) in animals with ibotenic acid lesions of the PPN as compared to normal animals. Apparently, destruction of the PPN releases the musculature from tonic and/or phasic inhibition. A model is discussed which attempts to account for both the rate-dependent changes in excitation and the inhibition of cortically induced muscle activity.     

Contractile properties of rat fast-twitch skeletal muscle during reinnervation: effects of testosterone and castration

The isometric contractile properties of skeletal muscle were examined after nerve crush to establish the temporal sequence of recovery during reinnervation of normal, castrated, and testosterone-treated rats. Extensor digitorum longus muscles of male rats were studied in vivo 8 to 21 days after crushing the peroneal nerve 1 cm from the muscle. The earliest signs of functional reinnervation in normal animals were observed 8 to 9 days after nerve crush when faint muscle twitches with markedly prolonged twitch contraction times were recorded. By days 10 and 11, twitch tension was 9 to 20% of control, twitch contraction time was 149 to 183% of control, and tetanic tension was 4 to 9% of control values. The optimal frequency of stimulation was 58 to 64 Hz, the twitch:tetanus ratio was three times control values, and little or no posttetanic potentiation of twitch tension was observed. During the next 9 days there was a gradual return of all experimentally measured contractile properties toward control values; the relative rate of return was twitch tension greater than twitch contraction time greater than twitch:tetanus ratio greater than tetanic tension greater than optimal frequency of stimulation greater than posttetanic potentiation. Neither testosterone nor castration significantly altered either the rate or extent of functional reinnervation 8 to 21 days after nerve crush (P greater than 0.05). During this period the twitch:tetanus ratio for any given animal was highly correlated (r = 0.83, P less than 0.001) with the extent of functional recovery of neurally evoked muscle tension and was determined to be the most reliable index of the degree of muscle reinnervation. These data provide valuable baseline information for future studies of reinnervation of skeletal muscle.     

Mechanical properties of human ankle extensors after muscle potentiation.

The contractile properties of a muscle depend on the activation history of its motor units. At the same time as fatigue seems to impair muscle excitation-contraction coupling, post-tetanic potentiation can augment force production. The effects of post-tetanic potentiation on the mechanical muscle properties of the intact human ankle extensor muscles were investigated by a 4 degree dorsiflexion of the ankle joint during a sustained contraction. The contraction was elicited by 10 Hz electrical stimulation of the tibial nerve. The changes in the contraction torque and in the intrinsic muscle stiffness of the ankle extensors before and after prolonged electrically elicited muscle activation were measured. From the onset of continuous synchronized 10 Hz stimulation to the attainment of maximal torque, the ankle joint torque increased by 47%. At matched background contraction, the prolonged electrically elicited contraction increased the intrinsic muscle stiffness by 49%. The first stretch after prolonged stimulation gave rise to a 17% yield in the background contraction and a 73% yield in the torque increment. The findings imply that with fatigue an increase in the intrinsic stiffness of the pre-stretched muscle might operate as a "safety factor" to compensate for a reduced reflex-induced stiffness, keeping the total muscle resistance at a high level in the active muscle.     

Muscle phosphorus magnetic resonance spectroscopy oxidative indices correlate with physical activity

The purpose of this study was to assess the effect of physical deconditioning on skeletal muscle's oxidative metabolism as evaluated by phosphorus-31 magnetic resonance spectroscopy ((31)P MRS). Twenty-seven subjects without muscle disease, representing a wide range of fitness levels, were evaluated with (31)P MRS. Spectra were obtained at rest and during recovery from in-magnet exercise. The data show a significant correlation between maximum resting metabolic equivalent (MET) score and the following (31)P MRS recovery indices: adenosine diphosphate and phosphocreatine recovery half-time; initial phosphocreatine resynthesis rate; calculated estimation of mitochondrial capacity; pH at end of exercise; and phosphocreatine depletion. In addition, significant differences between the deconditioned and conditioned group were found for all of the aforementioned recovery indices. At rest, only the inorganic phosphate concentration was significantly different between the two groups. These data indicate that physical activity level should be taken into account when assessing patients' oxidative metabolism with (31)P MRS.     

Parametric Studies on Electroacupuncture-Like Stimulation in a Rat Model: Effects of Intensity, Frequency, and Duration of Stimulation on Evoked Antinociception

We have found that electroacupuncture-like stimulation of defined sites in the hindlimb of the rat inhibits a nociceptive withdrawal reflex. The lightly anaesthetized rat was used and tail withdrawal from a noxious radiant heat stimulus was the nociceptive reflex. Standard stimulation of hindlimb meridian points femur-futu (ST-32), fengshi (GB-31), and zusanli (ST-36) consisted of a 2-ms square voltage pulse at 4 Hz for a duration of 20 min, applied at 20 times the threshold to evoke muscle twitch. This produced two types of inhibition of the reflex; one was an increase in the latency of up to 80% during the stimulation, termed the brief antinociception, and the other was a post stimulation increase of up to 60% lasting greater than 1 h, termed the persistent antinociception. When the stimulus intensity was reduced to 10 times threshold, the latency during stimulation increased up to 50%, but the persistent response did not occur. Stimulation at threshold produced neither effect. When the train duration was altered, 10 min of stimulation produced only the brief effect, whereas 40 min of stimulation produced both effects, although the persistent effect lasted only 20 min. Stimulation at 6 Hz produced responses similar to those at 4 Hz, whereas stimulation at 2 Hz produced smaller effects. At 8 Hz, only the brief antinociception was elicited. With a pulse duration of 0.2 ms, the brief response was observed but the persistent response was markedly attenuated, whereas 5 ms produced responses similar to those with 2 ms. These data suggest that high-intensity, low-frequency electrical stimulation of meridian points in the rat hindlimb produces both brief and persistent antinociceptive effects on the tail withdrawal reflex, and both effects are dependent upon the parameters of stimulation. The persistence of the latter effect beyond the period of stimulation suggests events occurring after direct synaptic activity, possibly mediated via plastic changes at spinal and/or supraspinal levels.     

High expression of MHC I in the tibialis anterior muscle of a paraplegic patient

A long-term paraplegic man presented exclusively (>99%) myosin heavy chain I (MHC I) in the tibialis anterior muscle (TA). This was coupled to a slow speed of contraction, a high resistance to fatigue, and a rapid resynthesis of phosphocreatine after an electrically evoked fatiguing contraction when compared with the TA muscles of 9 other paraplegic individuals. In contrast, the MHC composition of his vastus lateralis, gastrocnemius, and soleus muscles was that expected of a muscle from a spinal cord injured individual. This information may be of clinical importance in terms of the expected morphological and functional adaptations of skeletal muscle to different types of electrical stimulation therapy.     

Assessment of Metabolism and Microcirculation of Healthy Skeletal Muscles by Magnetic Resonance and Ultrasound Techniques

PURPOSE: To assess metabolism and microcirculation of healthy skeletal muscle by magnetic resonance (MR) and ultrasound techniques and to compare these data with muscle histology, and anthropometric and blood parameters. METHODS: Thirty-four healthy volunteers were selected such that their measured aerobic capacity (VO2max) per body weight ranged between 23 and 66 mL/minute/kg to render a large variability of skeletal muscle capillarization as a result of their different physical activity. We analyzed body composition, blood parameters, and skeletal muscle fiber size and capillarization in biopsies of the vastus lateralis muscle. These data were compared with knee extensor cross-sectional area (CSA) obtained by MR imaging, microcirculation of the vastus lateralis muscle by contrast-enhanced ultrasound (CEUS), and its energy and lipid metabolism measured with 31P and 1H MR spectroscopy. Statistical analysis was performed using Pearson's correlation coefficient and significance was tested at a level of .5%. RESULTS: The variable physical activity was reflected in a large variability of vastus lateralis muscle perfusion and metabolism at rest with highest histologic capillarization and CEUS-perfusion values observed in the best-trained volunteers. Levels of high-energy phosphates, such as phosphocreatine, were positively correlated with CSA (r= .5) and histologic fiber size (r= .6 for type IIA and IIX fibers), while phosphocreatine concentration was significantly negatively correlated to myocellular lipids (r=-.6) and trimethyl ammonium containing compounds (r=-.8). Local blood volume measured in vivo with CEUS was positively correlated with several histologic capillarization parameters. CONCLUSIONS: Dedicated MR- and CEUS-methods deliver (patho-)physiologic information about capillarization and fiber characteristics of skeletal muscles in vivo and hence establish a useful diagnostic tool for muscular diseases.     

Staircase, fatigue, and caffeine in skeletal muscle in situ

The specific locus of impairment in excitation-contraction coupling that is associated with skeletal muscle fatigue has not been identified. In the present study the phenomena of staircase and fatigue were studied in the rat gastrocnemius muscle in situ, and the effect of caffeine (50 mg kg-1) given prior to or during 5 minutes of stimulation was observed. A 10 Hz indirect stimulation resulted in a staircase response that proceeded for 10.4 +/- 1.6 (mean +/- SD) seconds, reaching a peak force value that was 70-75% higher than the initial contraction. After 5 minutes of stimulation and 20 minutes of rest, the staircase response was longer (17 +/- 3.1 seconds) and proceeded more slowly when the stimulation regimen was repeated. Caffeine accelerated the fatigue and reversed the effect of fatigue on the staircase response. Since caffeine enhances the release of Ca2+ from terminal cisternae, it is postulated that the accelerated fatigue in the presence of caffeine is indicative of a reduced availability of Ca2+ for release. This hypothesis would also explain the slower progression of staircase in the fatigued muscle.     

Variable-frequency trains offset low-frequency fatigue in human skeletal muscle.

Variable-frequency trains that exploit the catchlike property of skeletal muscle can augment force production in fatigued skeletal muscle. The present study is the first to examine the effect of such trains during recovery. The quadriceps femoris muscles of 12 healthy individuals were fatigued using six-pulse, 14.3-Hz trains delivered at a rate of 1/s for 3 min. The force-generating ability of the muscle was tested with several constant-frequency trains (8.3-100 Hz) and a variable-frequency train before and after fatigue and at 2, approximately 13, and approximately 38 min of recovery. The variable-frequency train produced significant augmentation of force versus the best constant-frequency train (12.5 Hz) in acute fatigue and during recovery. The fatiguing protocol also induced low-frequency fatigue (LFF); the time courses of the degree of LFF and the amount of variable-frequency train force augmentation were inversely related (r = 0.629; F = 38.024; P 相似文献   

The force–frequency relationship is altered in regenerating and senescent rat skeletal muscle

Maximal tetanic tension was elicited at 200, 150, and 150 Hz in control tibialis anterior muscles and at 150, 100, and 100 Hz in 14-day regenerating muscles of young (3 months), adult (18 months), and old (31 months) Fischer 344/Brown Norway F1 rats, respectively. In contrast to young rats, increasing stimulation frequency from 50 to 150 Hz did not elicit significantly greater tetanic tension in control or regenerating muscles of old rats. At higher stimulation frequencies, tetanic fade was prevalent in control and regenerating muscles of adult (250–300 Hz) and old rats (200–300 Hz), but was only present at 14 days of recovery in regenerating muscles of young rats (300 Hz). The decreased efficacy of rehabilitative and physical medicine procedures in adult and elderly patients who have suffered skeletal muscle injury could be explained, in part, by the postulate that tetanic fade is indicative of inadequate synaptic transmission. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1265–1274, 1998.     

Changes in the pause in muscle spindle discharge during a sequence of twitches.

A study was made of the change in duration of the pauses in discharge from spindle afferents occurring during a series of isometric twitches of the cat's triceps surae muscle. These were induced by stimulation of the muscle nerve at frequencies of 0.1 to 1.0 Hz. At frequencies of 0.2 Hz and higher, the duration of the pause exhibited by group II and tonic and phasic group Ia afferents decreased progressively until stabilizing within 5 to 15 s. The time course of this change was largely independent of the frequency of stimulation, but the eventual duration in the steady state was strongly dependent on the frequency, being shorter at higher rates. At a given frequency, the pause was shorter at longer muscle lengths. The decrease in pause duration was not accompanied by a parallel change in duration or amplitude of the muscle tension responses, indicating that it arose from some alteration intrinsic to the spindle organ. We suggest that the progressive change in sensory discharge could serve the initial reinforcement of repetitive movements.     

Brain and muscle energy metabolism studied in vivo by 31P-magnetic resonance spectroscopy in NARP syndrome.

Phosphorus magnetic resonance spectroscopy (31P-MRS) was used to study in vivo the energy metabolism of brain and skeletal muscle in two members of an Italian pedigree with NARP syndrome due to a point mutation at bp 8993 of mtDNA. In the youngest patient, a 13 year old girl with retinitis pigmentosa, ataxia, and psychomotor retardation, there was an alteration of brain energy metabolism shown by a decreased phosphocreatine content, increased [ADP] and decreased phosphorylation potential. The energy metabolism of her skeletal muscle was also abnormal, as shown by resting higher inorganic phosphate and lower phosphocreatine concentrations than in normal subjects. Her mother, a 41 year old woman with minimal clinical involvement, showed a milder derangement of brain energy metabolism and normal skeletal muscle. Findings with MRS showed that this point mutation of mtDNA is responsible for a derangement of energy metabolism in skeletal muscle and even more so in the brain.     

Improvement of dy/dy dystrophic diaphragm by 3,4-diaminopyridine

Concerns have been raised that inotropic agents may worsen function of dystrophic muscle due to structural fragility. Studies tested the hypothesis that force increments elicited by potassium (K(+)) channel blockade can be maintained during the course of repetitive stimulation. In vitro twitch force of dy/dy dystrophic mouse diaphragm was significantly lower than normal (796 versus 1271 g/cm(2)). 3,4-Diaminopyridine (DAP) increased twitch force of dystrophic diaphragm by 111 +/- 12% (P <.0001) and increased force at stimulation frequencies of 5-50 Hz by 41-77%. During fatigue-inducing stimulation, force augmentation by DAP was well maintained in dystrophic muscle throughout 25 Hz (P =.0047) and 50 Hz (P =.0059) stimulation. These findings indicate that the K(+) channel blocker DAP augments the force of dystrophic muscle to values close to that of normal muscle over a range of stimulation frequencies. Furthermore, these functional increments can be achieved without causing force to eventually deteriorate below that of untreated dystrophic muscle during fatiguing stimulation. It is possible that DAP may be useful for the clinical management of a variety of disorders causing muscle weakness.     

Brain energy metabolism studied by 31P-MR spectroscopy in a case of migraine with prolonged aura

The brain and skeletal muscle oxidative metabolism of a patient with prolonged aura was studied by phosphorus magnetic resonance spectroscopy. We found that the phosphocreatine to ATP ratio in brain was reduced, while the inorganic phosphate to phosphocreatine ratio and the calculated ADP concentration were increased. The phosphorylation potential and percentage of maximal rate of ATP synthesis were also altered. Intracellular pH and inorganic phosphate concentration were normal. In muscle we found a low post-exercise recovery of phosphocreatine. These data indicate an impairment of energy oxidative metabolism both in brain and muscle.