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1 Département de Kinésiologie, and 2 Département de Pharmacologie, Université de Montréal, Montréal, Québec, Canada H3C 3J7
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Rat motor nerve terminals and the endplates they interact with exhibit changes to varying patterns of use, as when exposed to increased activation in the form of endurance exercise training. The extent to which these changes affect neuromuscular transmission efficacy is uncertain. In this study, the effects of habitual exercise on the electrophysiological properties of neuromuscular transmission in rat soleus muscle were investigated using a novel in situ approach. Consistent with previous reports, miniature endplate potential frequency was enhanced by habitual exercise. Other passive properties, such as resting membrane potential, miniature endplate potential amplitude, and "giant" miniature endplate potential characteristics were unaltered by the training program. Full-size endplate potentials were obtained by blocking soleus muscle action potentials with µ-conotoxin GIIIb. Quantal content values were 91.5 and 119.9 for control and active groups, respectively (P < 0.01). We also measured the rate and extent of endplate potential amplitude rundown during 3-s trains of continuous stimulation at 25, 50, and 75 Hz; at 50 and 75 Hz, we found both the rate and extent of rundown to be significantly attenuated (10-20%) in a specific population of cells from active rats (P < 0.05). The results establish the degree of activity-dependent plasticity as it pertains to neuromuscular transmission in a mammalian slow-twitch muscle.
motor activity; exercise; neuromuscular junction; synaptic transmission; endplate potential
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE MAMMALIAN NEUROMUSCULAR JUNCTION (NMJ) is continuously being remodeled in response to different physiological and pathological situations. It is known that NMJs from adult vertebrates can exhibit long-term signs of plasticity when subjected to altered usage (6, 40, 44). Among the known stimuli for neuromuscular remodeling, endurance exercise training constitutes a physiological manner of increasing neuromuscular activity to an extent that changes in both muscular and neural constituents of the NMJ occur (33). For example, in rat, habitual exercise is known to induce an overall enlargement of the neuromuscular synapse (10, 42) as well as to alter the abundance of several proteins implicated in the process of neuromuscular transmission (8, 16, 24).
It is well documented that NMJs from fast- and slow-twitch muscles have different properties. NMJs innervating the fast-twitch extensor digitorum longus (EDL) muscle are known to have higher quantal content (QC) (14, 38, 46) and miniature endplate potential (MEPP) frequency (46), whereas NMJs from slow-twitch muscle fibers have a larger endplate area (34, 35, 46) and total presynaptic vesicle pool size (38). Many differences have also been noted with respect to their adaptive capacities, fast-twitch NMJs often showing more substantial change in response to altered levels of activity (2, 16, 35, 43). In the only study to directly address the potential effect of exercise on neuromuscular transmission efficacy, Dorlochter et al. (11) have shown that, in the fast-twitch mouse EDL muscle, habitual exercise increases QC as well as the safety margin for neuromuscular transmission. Considering the differences between slow NMJs and their fast-twitch counterparts (cited above), an intracellular electrophysiological study of soleus motor endplates was carried out with the aim of determining what effect exercise may have on the efficacy of neuromuscular transmission at NMJs innervating a predominantly slow-twitch muscle. We hypothesize that transmission efficacy at soleus motor endplates may be well adapted to frequencies of activation that resemble its postural activation frequency (i.e., ~25 Hz) (19, 20) and may yet show signs of functional adaptation to increased usage when tested at higher frequency bursts that occur during treadmill running in the rat (39).
To date, electrophysiological studies have been limited to the range of muscles that lend themselves to in vitro investigations. Garber et al. (12) have shown that muscles exceeding 30 mg of weight, such as is the case with most hindlimb muscles from an adult rat, show signs of altered metabolic integrity and develop a hypoxic core at 37°C in vitro, which eventually renders the preparation ineffective over time. Also, most previous electrophysiological studies at mammalian motor endplates have been hindered by methodological limitations including pharmacological manipulations known to affect presynaptic function (18, 21, 22, 30, 44). In an attempt at minimizing these issues, we have developed a mammalian in situ approach using µ-conotoxin GIIIb, thereby allowing a reliable and physiological characterization of neuromuscular transmission in the anesthetized rat. The aforementioned toxin is quite effective in preferentially blocking muscle Na+ channels in mammalian nerve-muscle preparations (7, 21) and thus allows investigators to evoke full-size endplate potentials (EPPs) from NMJs unaltered by various manipulations that have been necessary in the past. To our knowledge, this constitutes the first description of full-size endplate responses in situ. Some of these results have already been published in abstract form (9).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal care. Female Sprague-Dawley rats in the active group were trained to run on a motor-driven treadmill at 30 m/min, 30 min/day, gradually increasing the time spent on the treadmill so that by the ninth week they were running 2 h/day. The animals were trained 5 days/wk, and the duration of the training program was 24-28 wk. This program has been used in this laboratory to induce neuromuscular adaptations in several rat hindlimb muscles, including the soleus. These changes include enhanced muscle oxidative enzyme activity and motoneuron metabolism (15, 23, 24), as well as increased nAChR number (8), synaptosomal-associated protein of 25 kDa (SNAP25) abundance (24), and motoneuron cell body calcitonin gene-related peptide content (15). Age-matched control group rats were kept cage confined. All animals were housed in a light- and temperature-controlled environment and given free access to food and water. The procedures in these experiments were approved by the animal ethics committee of the Université de Montréal and were in accordance with the guidelines set by the Canadian Council on Animal Care. All efforts were made to minimize animal suffering in these experiments.
Surgery. At least 24 h after the last training session, rats were anesthetized with a ketamine-xylazine mixture (62 and 8 mg/kg ip, respectively) and were maintained under deep anesthesia throughout the experiment with additional injections of 20.5 and 2.5 mg/kg, respectively, every 45 min. The left hindlimb was dissected so that the soleus muscle and its innervating neural branch were easily accessible for the subsequent electrophysiological experimentation. Special care was taken not to damage any of the blood supply feeding the muscle because this would adversely affect the muscle's long-term viability as well as the conotoxin's mode of delivery to the muscle.
A catheter was inserted into the left jugular vein, through which µ-conotoxin GIIIb (Alomone) could be delivered to the animal's circulatory system. We found this to be the most efficient way of obtaining the desired paralytic effect. A tracheotomy was performed so the animal could breathe via a ventilator for the duration of the experiment (Harvard miniature ventilator model 50-1700). Expired CO2 was monitored throughout the experiment and ranged from 2.7 to 4.2%. The rat rested on a heating pad (core temperature 35-37.7°C), and the spine was clamped to prevent any random movement. The left hindlimb was prepared for the electrophysiological measurements by pulling up the surrounding skin flaps to form a pool-like structure, which was filled with heated circulating light mineral oil (bath temperature 35-37.7°C).Electrophysiological recordings. Full-size EPPs were obtained by blocking muscle Na+ channels with conotoxin. Evoked force, which would begin to decrease ~10 min after an initial 500 µl injection of 25 µg/ml µ-conotoxin in saline solution, was typically abolished 45 min into the injection scheme (~100 µl/10 min). Thereafter, very low levels of force were maintained throughout the experiment by infusing 100 µl of the toxin solution when deemed necessary (approximately every 30 min).
Intracellular resting membrane potential (RMP), MEPPs, and EPPs were recorded using KCl-filled (3.0 m) glass microelectrodes (<10 M
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Mammalian muscle NMJs are typically located at the midpoint of each
muscle fiber, thereby facilitating endplate localization within a
relatively unipennate muscle such as the rat soleus. Once the
microelectrode was inserted at close proximity to an endplate, as
determined by the presence of MEPPs, the RMP was allowed to stabilize
for 2 min. MEPPs were then recorded onto FM tape (Vetter model 420-K)
for later digitization (10 kHz) and analysis as described below. An EPP
was then evoked (0.05-ms square-wave supramaximal pulse, delivered by a
S88D Grass stimulator via a bipolar electrode) and sampled (33 kHz) for
estimation of QC. These procedures were followed by 3 s of
continuous indirect stimulation evoked at frequencies of 25, 50, and 75 Hz, in either ascending or descending order of frequency, in alternate
successfully impaled muscle fibers. These trains of EPPs were digitized
(10 kHz) and stored for later analysis of stimulation-induced change of
EPP amplitude (i.e., EPP amplitude rundown). A minimum period of 3 min
was allowed to elapse between trains within a cell; intercell interval
was at least 5 min. These rest periods are sufficient to allow proper
recovery of stimulation-induced changes in EPP amplitude and MEPP
frequency (49). All cells included in this study had a RMP
of no less than 
60 mV. If any cell depolarized by more than 10 mV
during the sampling, the data were eliminated. Both groups included in
this study consisted of eight animals, and the number of endplates from
which data were acquired ranged from 3 to 11 per animal. The total
number of data points included in the passive properties and QC
analysis was 37 for the control group and 41 for the active group. The
total number of data points included in the EPP amplitude rundown
analysis depended on the frequency of stimulation and is given in Fig.
3. At the end of each experiment (i.e., when muscle fibers were no
longer being successfully impaled), the animals were euthanized with an
overdose of anesthetic.
Analysis. For each cell, average MEPP amplitude, frequency, and rise time were obtained from 15-20 3-s time bins (i.e., 45-60 s of recordings), which were analyzed using a specially designed event detection software with the amplitude threshold set at 150 µV. Individual MEPPs were not included if they occurred on the tail end of a previous MEPP. Giant MEPPs (GMEPP), defined here as a MEPP having either three times the mean MEPP amplitude or three times the rise time, were removed from the pool of MEPPs and analyzed separately. The following criteria were retained as minimum requirement for a cell to be included in this study: EPP and MEPP rise time <1 ms and mean MEPP amplitude and frequency >225 µV and >1/s. QC was estimated using the direct method and corrected for nonlinear summation using the empirical correction value of 0.8, as proposed by McLachlan and Martin (31).
Statistics. The results are expressed as means ± SD. Student's t-test was used to compare data sets pertaining to QC. ANOVA was employed to analyze the data produced in the rundown experiments. A Tukey's honest significant difference procedure was used as a followup test. Pearson product moment coefficient of correlation was used to establish extent of linear relationships between variables. Maximum probability of error was set at 5%.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have attempted to determine whether regular motor activity has
a beneficial effect on the functional aspects of the NMJ in the adult
rat soleus muscle by a novel in situ electrophysiological design. An
example of the data acquired in these experiments is shown in Fig.
1. The traces highlight some of the
measurements retained as dependent variables.
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Of particular concern in these types of experiments is the variable
yield of data from animal to animal. It is possible that combining data
from several experiments having dissimilar yield can bias the range of
data and influence mean values. A way of addressing this problem is to
show how data distribution from a single high-yield experiment is
similar to that from all experiments, independent of yield. Figure
2 clearly shows that both these
distributions are very similar, the yield-independent plot (all data
points) having only a slightly larger range than the single highest
yield experiment for both groups included in the present study. This suggests that combining data from varying yield experiments will have a
negligible effect on mean values, and we therefore feel justified in
combining all data points because no discernible bias is being
introduced into the analysis.
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Effect of activity on MEPPs and QC.
Table 1 summarizes the main results of
this study as they pertain to passive membrane properties and QC.
Regular physical activity increased the frequency of MEPPs at motor
endplates of rat soleus muscle (see also Fig. 2A) but had no
significant effect on MEPP amplitude or rise time, nor on GMEPP
characteristics [mean GMEPP amplitude (µV)/frequency
(min
1); control: 960 ± 102/1.2 ± 0.5, active
911 ± 76/1.1 ± 0.9]. The mean evoked EPP amplitude was on
average larger in the active group of rats, as was the corrected value
of QC (see also Fig. 2B). This represents a 31% increase in
the number of synaptic vesicles released on a single nerve impulse from
cells that have been active on a long-term basis.
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Effect of activity on EPP rundown.
Figure 2, C-E, shows the extent of EPP
amplitude rundown (after 3 s) at 25, 50, and 75 Hz for both
groups. The drop lines indicate mean value for each group, which is
also plotted in Fig. 3A. Such
modest differences in mean value, accompanied by surprisingly large
standard deviations, result in nonsignificant differences. However, on
closer inspection, it is clear that, in all cases, a subset of
terminals showed a rather large degree of exercise-induced adaptation
in EPP amplitude rundown resistance (Fig. 2,
C-E). We have consequently divided the
response for both groups into quartiles after ranking according to the
amplitude of the plateau EPP, which is obtained by averaging the last
five EPPs in a train [quartile assignments: Q1-Q2 (resistant),
Q3-Q4 (fatigable)]. The quartiled data are plotted in Fig. 3,
B-D.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Rat motor nerve terminals and the endplates they interact with exhibit changes to varying usage. Our experiments show that, under physiological conditions, neuromuscular transmission efficacy can be enhanced by habitual exercise, an EPP evoked by stimulation of the motor nerve innervating a soleus muscle belonging to an active rat being on average 22% larger than an EPP evoked with an equivalent rise time in a corresponding sedentary animal. QC was also significantly increased in active rats (31% corrected for nonlinear summation, 22% uncorrected; both P < 0.01), which is suggestive of a change in synaptic transmission properties. These results are in accordance with previously reported alterations of QC induced by regular physical activity, which has been shown to increase by 30% in mouse EDL (11). The present results show that this adaptation also occurs in rat soleus muscle, in which motor units belonging to sedentary animals are active 30% of the time in vivo (20). Despite such frequent postural activation, daily bouts of increased firing prompt functional remodeling at the soleus NMJ.
We have found endurance exercise to have no effect on MEPP amplitude (Table 1). Endurance-trained rats have previously been shown to possess an increased quantity of motor endplate-associated acetylcholine receptors (8). The current results therefore support the interpretation that these additional receptors increase the effective endplate area rather than increasing receptor density at motor endplates. We conclude this because the latter scenario would influence the postsynaptic response to a single quantum of transmitter, thereby increasing MEPP amplitude (26). A control MEPP frequency of 3/s (Table 1) is at the higher end of previously reported frequencies of spontaneous synaptic activity for rat soleus muscle (1, 28, 38, 48). This may be related to differences in age and temperature but may also reflect the use of certain selection criteria pertaining to MEPP frequency (see Analysis above). A 100% increase in MEPP frequency at endplates of active rats is consistent with the results of previous experiments (1). Other factors being equal, enlarged pre- and postsynaptic elements, which have been shown to be a consequence of endurance exercise at rat soleus muscle (2, 10), would necessarily induce a higher MEPP frequency by means of an enlarged area over which MEPPs could occur.
Typical estimates of QC for adult rat soleus muscle are quite variable and depend on factors such as temperature (17), age (1, 27, 45), and presence of drugs (36). A reliable assessment of QC for adult rat soleus obtained from full-size EPPs in vitro at room temperature is 61.8 (46). Previous studies examining the effect of temperature on neuromuscular transmission have shown that QC increases by 20% as incubation temperature increases from 23 to 37°C (17). Our estimated QC of 91.5 for control soleus is 48% higher than the aforementioned estimate. A QC value of 86.9 for adult rat soleus has recently been reported (38), although it is not clear at what temperature this value was obtained.
At the normal adult NMJ, the number of quanta released by a nerve impulse greatly exceeds the amount required to reach the threshold for generating a muscle action potential. Soleus nerve terminals have been found to release 3.5 times as many quanta as are required (46). Although no attempts were made to quantify this safety factor in the present investigation, a 31% increase in quantal output from NMJs belonging to active rats most likely increases this margin. This interpretation is in accordance with the results of previous experiments showing a 30% increased QC to be paralleled by an increased safety factor (11).
This safety factor is thought to be essential at times when neuromuscular transmission is under stress, as during high-frequency activation. Thus 3-s trains of EPPs at 25, 50, and 75 Hz were evoked to determine whether the rate and extent of EPP amplitude rundown can be altered by regular use. If we are justified in assigning the Q1-Q2 and Q3-Q4 quartiles to NMJs having resistant and fatigable neuromuscular transmission, respectively, then the effect of exercise we have found indicates improved EPP amplitude rundown resistance in the most fatigable population of NMJs. This effect is most likely presynaptic in origin because MEPP amplitude, thus presumably endplate reactivity, was unchanged by the exercise program, and it suggests a change in the cellular machinery involved in the fusion and cycling of synaptic vesicles.
In mammals, evoked transmitter release at the NMJ is triggered by Ca2+ influx through voltage-dependent Ca2+ channels at active zones (25, 32). The rate at which EPP amplitude rundown occurs at the onset of a train of stimulation seems to be related to the quantity of vesicles docked in the immediate vicinity of the active zones (4, 47). Increased length of active zones and percent of axolemma occupied by active zones has previously been observed in active rats (42), and we have previously shown that habitual exercise increases the abundance of transported SNAP25 within motor axons (24), a protein that is known to be essential for the docking and fusion of synaptic vesicles (41). Accordingly, enlarged active zones from exercised animals could support more fusion-ready vesicles and account for the relative resistance in the rate of rundown observed in Q3-Q4 terminals (Fig. 3). Enlarged active zones can also account for the exercise-induced enhancement of QC, as research on amphibian muscle has shown a good correlation between active zone length and QC (5, 37).
In our experiments, the extent of plateau rundown (i.e., EPP amplitude rundown after 3 s) most likely reflects the rate at which vesicles are being cycled from the reserve pool to the docked position. Vesicle recycling and replenishment (reuse) is not a factor here, considering that an entire cycle from docked to fused to docked in adult rat soleus takes ~2 min (38). The improved EPP amplitude rundown resistance in exercised Q3-Q4 terminals at 50 and 75 Hz (Fig. 3, C and D) therefore implies a more efficient and/or a more widespread reserve-to-docked cycling system in these terminals. The lack of further rundown between the fifth and plateau EPP at 25 Hz for both groups (Fig. 3B) suggests neuromuscular transmission efficacy in control rats to be well adapted to this rate of activation, which corresponds to its postural activation frequency in vivo (19, 20).
The changes in neuromuscular transmission efficacy that we have observed in these experiments seem to have occurred within different NMJ populations (Fig. 4). For example, the Q1-Q2 motor nerve terminals did not exhibit enhanced plateau rundown resistance, yet these same terminals account for most of the improvement in QC, whereas Q4 terminals showed improved plateau rundown resistance yet no improvement in QC. It is therefore conceivable that these changes reflect the total load of activity to which the specific motor nerve terminals are subjected. Thus the Q1-Q2 terminals may already be active enough in the control group to have reached the threshold for enhanced EPP amplitude rundown resistance, whereas changes in QC may require a substantial rise in the muscle's activity level which are not attained by the Q4 terminals during this form of exercise. This heterogeneity of responses consequently implies different mechanisms by which these changes take place or may be related to a gradation effect of a single mechanism.
It is particularly interesting to note that the changes in neuromuscular transmission efficacy in the soleus have occurred in the same direction as previously reported changes in the EDL (11), although fast- and slow-twitch NMJs are known to have different morphological and functional properties. A possible explanation for this is that the adaptations we have shown in a subset of NMJs reflect changes occurring in the ~15% of fast-twitch fibers within the soleus muscle (3) and that we are oversampling from this fiber population. However, this is highly unlikely given the smaller diameter of fast- vs. slow-twitch muscle fibers within this muscle (13). Therefore, the results suggest improved neuromuscular transmission efficacy to be a genuine activity-dependent adaptation at NMJs innervating slow-twitch muscle fibers and suggest that the adaptive capacity of the neuromuscular synapse is not directly related to fiber type as determined by histochemical methods. It is also conceivable that the previously reported changes in the mouse EDL are specific to that species and that reproducing these experiments in a fast-twitch muscle from the rat would yield different results. Thus the true value of our in situ approach will become apparent as larger plantar flexor muscles (i.e., plantaris and gastrocnemius), previously ineffective under in vitro conditions, will be analyzed under various physiological and pathological situations.
In conclusion, we have investigated the effects of exercise on neuromuscular transmission efficacy in the slow-twitch rat soleus muscle. The data indicate that enhanced QC and EPP amplitude rundown resistance are the functional consequences of regular activation, particularly at frequencies above what is considered postural activation for rat soleus motor units. The data also suggest that the mechanisms involved are sensitive to the quantity of activity placed on the neuromuscular synapse, as the adaptations have occurred within different motor nerve terminal populations within the muscle.
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ACKNOWLEDGEMENTS |
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This work was supported by a grant to P. F. Gardiner from the Natural Science and Engineering Research Council of Canada.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. F. Gardiner, Département de Kinésiologie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7 (E-mail: gardinep{at}tornade.ere.umontreal.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 19 May 2000; accepted in final form 11 October 2000.
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RESULTS
DISCUSSION
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)
and active (
). Arrows establish the distribution range
for the single highest yield experiment for each parameter and group.
