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Experimental Physiology 90.3 pp 333-340
DOI: 10.1113/expphysiol.2004.029132
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Effect of rat soleus muscle overload on neuromuscular transmission efficacy during continuous and intermittent activation

Patrice Desaulniers1, Pierre-André Lavoie2 and Phillip F. Gardiner3

1 Departments of Kinesiology2 Pharmacology, University of Montreal, C.P. 6128, Succursale Centre-Ville, Montreal, Canada3 Health, Leisure and Human Performance (HLHP) Research Institute and Spinal Cord Research Center, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Increased neuromuscular activity is known to provoke morphological and functional adaptations at the neuromuscular synapse. Most of these changes have been documented following endurance exercise training programmes. In this study, the effect of rat soleus muscle overload produced by tenotomy plus voluntary wheel-cage activity on neuromuscular transmission efficacy was investigated. The overload protocol increased miniature endplate potential (MEPP) and endplate potential (EPP) amplitudes by 17 and 19%, respectively (both P < 0.01), and increased MEPP frequency by 86% (P < 0.01). EPP amplitude rundown during continuous trains of activation was attenuated by ~10% in the overloaded group (P < 0.01). Also, during intermittent activation, the overload protocol attenuated EPP amplitude rundown, mainly by enhancing EPP amplitude recovery by ~10% during the quiescent periods (P < 0.01). Although the present results show that both the degree and direction of adaptation are similar to what has been observed at rat soleus neuromuscular junctions following an endurance training protocol, there are important nuances between the results, suggesting different mechanisms through which these changes may occur.

(Received 23 September 2004; accepted after revision 23 December 2004; first published online 7 January 2005)
Corresponding author Phillip F. Gardiner: Health, Leisure and Human Performance (HLHP) Research Institute and Spinal Cord Research Center, Max Bell Center, Room 307, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2. Email: gardine2{at}ms.umanitoba.ca


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Neuromuscular activity is a key contributor in regulating the morphology and physiology of the mammalian neuromuscular junction (NMJ). For example, neuromuscular activity is an important regulator of the quantity and distribution of acetylcholine receptors (AChRs) in skeletal muscle fibres (Lavoie et al. 1977). Also, increased neuromuscular activity in the form of endurance exercise training has been shown to increase the area occupied by the pre- and postsynaptic components of the NMJ (Andonian & Fahim, 1988; Deschenes et al. 1993; Fahim, 1997; Tomas et al. 1997; Waerhaug et al. 1992), to alter the abundance of certain proteins involved in neuromuscular transmission (Kang et al. 1995; Desaulniers et al. 1998) and to improve neuromuscular transmission (NMT) efficacy (Desaulniers et al. 2001; Dorlochter et al. 1991).

Regrettably, very little is known about NMJ adaptations incurred through models of increased activity other than treadmill running. Deschenes et al. (2000) have shown that the stimulus of resistance training is sufficient to increase soleus motor endplate area to an extent similar to that induced by endurance exercise training. Conversely, Jasmin et al. (1991) found that when rats whose plantaris muscles were overloaded by tenotomy of synergists were coerced to run on a treadmill, the G4 acetylcholinesterase (AChE) isoform increases, but to levels well below those induced by endurance exercise training (Gisiger et al. 1994; Sveistrup et al. 1995). Recently, Argaw et al. (2004) have shown NMT efficacy at rat plantaris NMJs to be significantly improved by a tenotomy-induced overload plus the stimulus of voluntary wheel-cage running.

The efficacy of NMT is a function of both the amplitude of the endplate potential (EPP) upon nerve stimulation and the degree of EPP amplitude rundown when EPPs are evoked in bursts. All previous studies detailing how neuromuscular activity impacts NMT efficacy have been conducted using continuous trains of stimuli (Dorlochter et al. 1991; Desaulniers et al. 2001; Argaw et al. 2004). When EPPs are evoked intermittently, however, neuromuscular transmission has been shown to recover significantly during the quiescent periods (Moyer & van Lunteren, 1999, 2001; Desaulniers et al. 2002). Considering the lack of knowledge regarding the effects of increased neuromuscular activity on NMT efficacy, other than those obtained via treadmill running, it would be of interest to determine how an alternative form of activity affects NMT efficacy in a muscle known to respond positively to endurance exercise training. In addition, there are presently no studies examining whether activity-dependent adaptations are in evidence when EPPs are evoked intermittently. The purpose of this study was to assess the effects of muscle overload plus voluntary wheel-cage running on the NMT efficacy of rat soleus NMJs in situ, using both continuous and intermittent stimulus patterns.

The soleus muscle was chosen because its NMT efficacy has been shown to improve following endurance exercise training (Desaulniers et al. 2001) and because its fibre type make-up is effectively homogeneous, being >85% type 1 fibres (Armstrong & Phelps, 1984). This latter aspect is notable in view of the fact that NMJs innervating different muscle fibre types are known to have different morphological and functional properties (Gertler & Robbins, 1978; Prakash et al. 1995a,b; Wood & Slater, 1997; Reid et al. 1999). A subset of the control group results presented in this study has previously been published elsewhere (Desaulniers et al. 2002).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Fourteen age-matched female Sprague–Dawley rats were obtained from Charles-River (St Constant, Quebec, Canada) and housed in a light- and temperature-controlled environment. The rats were given free access to food and water. All rats included in this study were between 18 and 24 weeks old at the time of data acquisition. All procedures in this experiment were preapproved by the animal ethics committee of the University of Montreal, and were in accordance with the guidelines set by the Canadian Council on Animal Care.

Upon arrival, seven rats were randomly selected to undergo a surgical procedure aimed at inducing compensatory overload of the soleus muscle. The rats were anaesthetized with a ketamine–xylazine mixture (62 mg kg–1 ketamine, 8 mg kg–1 xylazine, I.P.) and were maintained under anaesthesia during the procedure. An incision was made along the dorsal plane of both hindlimbs. A bilateral tenotomy was then performed by sectioning the distal tendon of the medial and lateral gastrocnemius muscles, the functional synergists of the plantaris and soleus muscles. The sectioned tendons were sutured back onto the overlying hamstring musculature to prevent reattachment. During the recovery period, rats received injections of buprenorphine (0.05 mg kg–1) every 12 h for 48 h following surgery. After 7 days of recovery, the rats were placed in voluntary wheel-cages, and remained there until the electrophysiological studies were to be carried out, a period of 12–16 weeks. Unoperated age-matched control rats were kept in standard cages.

Detailed procedures of the in situ electrophysiological methodology have been described elsewhere (Desaulniers et al. 2001, 2002). Briefly, rats were anaesthetized with a ketamine–xylazine mixture (62 mg kg–1 ketamine, 8 mg kg–1 xylazine, I.P.) and were maintained under deep anaesthesia throughout the experiment with additional injections of 20.5 mg kg–1 ketamine, 2.5 mg kg–1 xylazine every 45 min. The soleus muscle and its neural branch were surgically isolated with blood supply intact. Electrophysiological recordings were carried out with the muscle submerged in heated circulating light mineral oil, with bath and rat core temperature maintained between 35 and 38°C. Recording of full-size endplate potentials was made possible by infusing µ-conotoxin G3b (Alomone Laboratories, Jerusalem, Israel) through a catheter inserted into the jugular vein. Muscle force was initially abolished by infusing µ-conotoxin at a rate of 25 µg h–1, and was maintained at very low levels by subsequently infusing at a rate of 5 µg h–1. The rat was placed on a ventilator for the duration of the experiment. At the end of each experiment, the animals were killed with an overdose of anaesthetic.

Intracellular resting membrane potential (RMP), miniature endplate potentials (MEPPs) and EPPs were recorded using KCl-filled (3.0 M) glass microelectrodes (resistance <10 M{Omega}). Once a 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 a computer hard disk for 30 s (sampling frequency, 10 kHz) and were analysed off-line. The sciatic nerve was subsequently stimulated (sampling frequency, 15 kHz) via a bipolar electrode in order to elicit single EPPs at a frequency of 0.5 Hz for 30 s. These EPPs were digitally summed and the composite EPP was used to estimate the number of evoked vesicles upon nerve stimulation (i.e. quantal content, QC).

Trains of EPPs (continuous or intermittent) were then evoked by stimulating the sciatic nerve at three frequencies (25, 50 and 75 Hz). These frequencies fall within the normal operating range of soleus motor units (Hennig & Lomo, 1985). The continuous trains were 10 s in duration; the intermittent trains consisted of 25 s of activation with a 40% duty cycle (trains lasted 400 ms and were repeated every second). In an attempt to maximize data yield, continuous trains were evoked before intermittent trains, and low frequencies were tested before high frequencies. A minimum of 3 min was allowed to elapse between trains. This rest period is sufficient for the electrophysiological characteristics of endplates to recover fully from the stress of stimulation (Zengel & Sosa, 1994). All cells included in this study had a RMP of no less than –60 mV. If any muscle cell depolarized by more than 10 mV during the sampling period, the data were eliminated. The number of endplates from which data were acquired ranged from three to six per animal. The total number of data points included in the passive properties and QC analysis was 37 for the control group and 35 for the overload group. The total number of data points included in the EPP amplitude rundown analysis was dependent on the frequency of stimulation and is provided in their respective figure legends.

EPP and MEPP amplitudes and rise times, as well as MEPP frequency, were determined with the help of an event-detection software program specifically developed for this purpose. To allow the kinetics of EPP amplitude rundown and recovery to be compared among the various stimulation protocols, EPP amplitudes within a train were normalized to the amplitude of the first EPP in that train. All other values are presented as means ±S.D. Unless otherwise stated, factorial ANOVA was used to identify statistically significant main effects and interactions. Tukey's honest significant difference test was used during post hoc analysis. QC was estimated using the direct method and corrected for non-linear summation using the empirical correction value of 0.8 as proposed by McLachlan & Martin (1981). Critical level of significance was set at 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The stimulus of compensatory muscle overload combined with voluntary wheel-cage running increased soleus muscle wet weight by 94 ± 9% (P < 0.01). The average distance covered by the rats in the experimental group was 8.6 ± 3.2 km day–1. The consequent effect of this form of increased activity on MEPP and EPP characteristics is shown in Table 1. The protocol significantly increased MEPP frequency by 86%, increased MEPP amplitude by 17% and increased EPP amplitude by 19% (all P < 0.01). The outcome of both MEPP and EPP amplitudes increasing to similar extents is that no significant effect of overload on QC could be established (increased by 7% when corrected for non-linear summation; P= 0.27).


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  		Table 1.  EPP and MEPP characteristics at control and overloaded rat soleus NMJs
 
Figure 1 compares EPP amplitude rundown in the control group versus the overload group during continuous activation at all three tested frequencies. Control group EPP amplitudes (% of initial EPP) after 10 s of continuous activation were: 56.8 ± 12.7% (25 Hz); 51.1 ± 12.8% (50 Hz); and 42.3 ± 12.9% (75 Hz). Overload group EPP amplitudes (% of initial EPP) after 10 s of continuous activation were: 65.9 ± 12.8% (25 Hz); 62.8 ± 14.1% (50 Hz); and 54.8 ± 13.6% (75 Hz). Significantly greater rundown occurred as the stimulation frequency increased from 25 to 50 to 75 Hz for both groups (all P < 0.01). There was a significant group effect at all three tested frequencies (P < 0.01). These group differences, in which overload group values were significantly greater than control group values, became significant at 250 ms (or pulse no. 7) for 25 Hz, at 200 ms (or pulse no. 10) for 50 Hz and at 160 ms (or pulse no. 12) for 75 Hz. Once significant, all group differences remained significant for the duration of the stimulation protocols, except at 75 Hz, at which post hoc analysis revealed no significant difference at time points 0.5 and 2 s. Not shown are the initial pulses because, as expected, significant EPP amplitude rundown occurred within the first two to three pulses at all three frequencies for both groups (P < 0.01).



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  		Figure 1.  EPP amplitude rundown during continuous trains of activation in the control ({circ}) and overloaded (•) conditions
The degree of EPP amplitude rundown in response to 10 s of continuous activation of the sciatic nerve. EPP amplitudes are normalized to the first EPP in the train. The overload procedure significantly attenuated percentage EPP amplitude rundown at all 3 frequencies (25 Hz, A; 50 Hz, B; and 75 Hz, C). The numbers of trains included in this analysis were, for the control and overloaded groups, respectively: 30 and 30 (25 Hz); 26 and 26 (50 Hz); and 23 and 25 (75 Hz).

 
The outcome of stimulating control and overloaded soleus NMJs intermittently is shown in Fig. 2. An example of the data acquired during the intermittent protocols is provided in Fig. 3. As was the case with the continuous stimulation protocols, significant rundown occurred within the first few pulses of the initial intermittent train, and EPP amplitude remained significantly depressed (as compared to first EPP of the first train) for the duration of the intermittent stimulation protocols (all frequencies, both groups P < 0.01). Significant intratrain EPP amplitude rundown occurred within each train at all frequencies for both groups (P < 0.01). Control group percentage EPP amplitude rundown values during intermittent activation (trains 2–25) were: 16.1 ± 2.4% (25 Hz); 19.6 ± 2.1% (50 Hz); and 22.2 ± 4.3% (75 Hz). Overload group percentage EPP amplitude rundown values were: 16.4 ± 1.9% (25 Hz); 20.4 ± 0.5% (50 Hz); and 22.4 ± 3.1% (75 Hz) (group effect; n.s.). Significant intertrain rundown (EPP amplitude rundown comparison of the first EPP of each individual train for each group) occurred only between the first train and subsequent trains, but not otherwise (P < 0.01; all frequencies, both groups). Control group EPP amplitudes of the first pulse for each intermittent train (excluding train 1, when both groups have an initial value of 100%) were: 77.4 ± 11.9% (26 Hz); 76.1 ± 9.8% (50 Hz); and 77.5 ± 10.4% (75 Hz) (frequency effect; n.s.). Overload group EPP amplitudes of the first pulse for each train were: 83.9 ± 5.8% (25 Hz); 83.4 ± 9.6% (50 Hz); and 84.4 ± 9.2% (75 Hz) (frequency effect; n.s.). Control group EPP amplitudes of the last pulse for each intermittent train were: 61.4 ± 13.4% (25 Hz); 58 ± 11.1% (50 Hz); and 55.4 ± 13.1% (75 Hz) (frequency effect; P < 0.01). Overload group EPP amplitudes of the last pulse for each train were: 66.6 ± 8.3% (25 Hz); 62.8 ± 6.9% (50 Hz); and 60.5 ± 8.6% (75 Hz) (frequency effect; P < 0.01). The amplitudes of the first and last EPPs were significantly higher in the overload group at all three frequencies (P < 0.01).



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  		Figure 2.  EPP amplitude rundown during intermittent trains of activation in the control ({circ}) and overloaded (•) conditions
The degree of EPP amplitude rundown in response to 25 400 ms trains repeated every second. EPP amplitudes are normalized to the first EPP in the train. The overload procedure significantly attenuated the decrease of EPP amplitude at all 3 frequencies (25 Hz, A; 50 Hz, B; and 75 Hz, C). The numbers of data sets included in this analysis were, for the control and overloaded groups, respectively: 25 and 24 (25 Hz); 24 and 24 (50 Hz); and 21 and 22 (75 Hz).

 


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  		Figure 3.  Electrophysiological recordings of EPPs during intermittent activation
Representative examples of EPP amplitude rundown and recovery in the control (A) and overloaded conditions (B). Shown are the first and last (25th) trains of the stimulation protocol, which consisted of 400 ms trains repeated every second for 25 s. The traces show the combined effect of overload on EPP amplitude, and on the kinetics of EPP amplitude rundown and recovery. Pulses are evoked at 25 Hz. Calibration bar is 3 mV and 40 ms.

 
EPP amplitude recovery during the quiescent periods of intermittent stimulation is plotted in Fig. 4. Percentage recovery is indicative of the percentage of EPP amplitude recovered versus the percentage of EPP amplitude lost. For example, if EPP amplitude falls by 40% (i.e. to 60% of initial EPP amplitude) and then recovers to 80% of initial amplitude during the quiescent period, then the percentage recovery is 50%. For both groups, significant recovery occurred at all three stimulation frequencies (P < 0.01). The effect of the overload protocol on percentage recovery of EPP amplitude was significant among the groups at all three frequencies (P < 0.01), with greater recovery being the consequence of increased neuromuscular activity. Percentage recovery was greatest when soleus NMJs were activated at 75 versus 50 and 25 Hz for both groups (P < 0.01).



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  		Figure 4.  Percentage EPP amplitude recovery during quiescent periods of intermittent activation in the control ({circ}) and overloaded (•) conditions
See results for definition of ‘percentage recovery’. * Significantly different from control group at same frequency of activation. {dagger} Significantly different from percentage recovery at 25 and 50 Hz.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The objective of these experiments was to determine the extent of activity-dependent change in NMT efficacy at the rat soleus NMJ when motor unit activity is increased via a hypertrophic stimulus. The results of this study show that overloaded soleus NMJs acquire a 19% increase in EPP amplitude (Table 1) and demonstrate an attenuated EPP amplitude rundown during continuous trains of activation by 9–13% (Fig. 1). The extent of these adaptations is comparable to those incurred via endurance exercise training, which increases EPP amplitude by 22% and lessens EPP amplitude rundown during continuous activation by 7–10% at rat soleus NMJs (Desaulniers et al. 2001). We can therefore conclude that the protocol increased the efficacy of NMT.

Interestingly, although Argaw et al. (2004) have shown that the protocol of overload plus voluntary wheel-cage running improves NMT efficacy at rat plantaris NMJs, their results show that the stimulus greatly increases quantal content (~100%), decreases MEPP amplitude and exacerbates the percentage EPP amplitude rundown. Thus, although the results of previous studies suggest that endurance training affects the physiology of neuromuscular junctions innervating fast- and slow-twitch muscle similarly (Dorlochter et al. 1991, Desaulniers et al. 2001), and the present results indicate that the extent and direction of physiological changes at soleus NMJs are similar whether they are induced by protocols of endurance training or overload plus voluntary wheel-cage running, NMJs of fast-twitch muscle seem to respond in specific ways to the different types of activity.

Despite the comparable improvement in NMT efficacy at rat soleus NMJs in response to the different activity protocols, there are important nuances between the results, suggesting that the mechanism(s) through which these changes occur may be different. Endurance training has been shown to increase EPP amplitude by increasing QC. Conversely, our results show that overloaded soleus NMJs acquired the increased EPP amplitude via a mechanism that increases MEPP amplitude. It is well known that small muscle fibres (with a high input resistance) produce larger MEPPs than large muscle fibres (with a low input resistance). Although no direct measure of muscle fibre hypertrophy was carried out in the present study, the increased total muscle weight that occurs when soleus is overloaded has been shown to derive mainly from an increase in size of its predominant fibre type (Williams & Goldspink, 1981). In this study, the overloaded soleus wet weight increased by 94%, indicative of at least some degree of muscle fibre hypertrophy. All other factors being equal among the groups, the overloaded soleus fibres should therefore have produced smaller MEPPs due to a decreased input resistance, yet MEPP amplitude increased 17% in the overloaded group.

MEPP amplitude, for the most part, is thought to depend on the postsynaptic density of AChRs (Katz & Thesleff, 1957). However, several presynaptic factors, such as variations in the size of vesicles and in the intravesicular transmitter concentration, might also affect this variable (Atwood & Karunanithi, 2002). Karunanithi et al. (2002) have shown that functional differences in synaptic strength among glutamatergic neurones of Drosophila NMJs result from intrinsic differences in vesicle size; however, no similar results have ever been demonstrated at the mammalian cholinergic NMJ. Alternatively, although an increased postsynaptic AChR density is possible, it must be considered unlikely because of physical limitations related to the size of the receptor. Estimates of postsynaptic AChR density range from 20000 to 30000 sites µm–2 (Fertuck & Salpeter, 1974; Edwards, 1979; Land et al. 1980), which would signify a quasi-complete saturation of AChRs on the surface of the junctional folds (Edwards, 1979). The contribution of either of these factors to the observed change in MEPP amplitude remains unknown.

Although the improvement of NMT efficacy during intermittent trains was not as considerable as during continuous trains (the overload procedure attenuated the percentage of EPP amplitude lost by ~5% following each individual train, Fig. 2), the effect was nonetheless significant. As could be expected from the data presented in Fig. 1, the percentage EPP amplitude was greater at the end of the first intermittent train in the overload group. However, the subsequent trains (trains 2–25) seem to maintain this improvement via an enhanced intertrain recovery mechanism rather than an attenuated EPP amplitude rundown mechanism. In fact, the percentage EPP amplitude rundown in trains 2–25 of the intermittent protocol ranged from ~16 to ~22%, depending on the frequency of activation, and was not significantly different between the groups. Conversely, the percentage recovery was significantly improved by ~10% in the overload group at all three tested frequencies (Fig. 4). The outcome of these effects is an improved NMT efficacy in the overloaded group when activated intermittently, but in a manner that departs from the activity-dependent improvements in NMT efficacy that occur during continuous trains of activation, which come about through an attenuation of EPP amplitude rundown.

Even though EPP amplitude recovery was incomplete during the intermittent trains, EPP amplitudes within each group recovered to almost identical values regardless of the frequency of activation and thus level of rundown in the previous train. Hence, as previously reported, the percentage recovery was greatest when rundown was greatest (Desaulniers et al. 2002; Moyer & van Lunteren, 1999, 2001). Unlike previous reports on diaphragm muscle, however, our results show that soleus NMJs seem to possess a threshold regarding how much recovery can occur in a recovery period such as the one allotted in this study (i.e. 600 ms). Moyer & van Lunteren (1999) have suggested that high-frequency trains of activation may trigger a faster recovery phase than when trains are evoked at lower frequencies, implying the existence of a frequency-dependent second-order exponential time course for EPP amplitude recovery. An alternative possibility may be that partial recovery from short bursts of EPPs (400 ms) may be frequency independent and simply occur on a shorter time scale than the allotted recovery period (600 ms). Further recovery beyond the levels noted in this study may require considerably longer rest periods. Li & Schwarz (1999) have shown in Drosophila that the pool of readily releasable docked vesicles represents a subset of vesicles that is in equilibrium with the larger intracellular pool of vesicles. Considering that a complete vesicular cycle from docked to fused to docked requires ~2 min (Reid et al. 1999), the aforementioned equilibrium may account for the incomplete recovery noted in our study. If 100% recovery of docked vesicles can only occur once the total vesicle pool is completely replenished, then the quiescent periods employed in this study are undoubtedly of insufficient length to allow for full recovery during intermittent stimulation. Studies employing variable recovery periods during intermittent neuromuscular activation are needed to resolve this issue.

In conclusion, compensatory overload combined with voluntary wheel-cage activity induced significant adaptations at rat soleus NMJs. The data show that increased EPP and MEPP amplitudes were induced by the stimulus. The outcome of stimulating NMJs with continuous or intermittent trains also confirms that the combined overload stimulus was effective in improving NMT efficacy when EPPs are evoked in bursts. When compared with previous findings, our results indicate that the degree and direction of activity-induced adaptations at rat soleus NMJs occur similarly, irrespective of the type of activity implemented, but also suggest that the locus of change may not be the same for endurance and hypertrophy-inducing stimuli. These adaptations most likely help to conserve the integrity of NMT over time, and could delay the onset of neuromuscular fatigue.


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 Introduction
 Methods
 Results
 Discussion
 References
 
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   Acknowledgements
 
This work was supported by a grant to P. F. Gardiner from the Natural Science and Engineering Council of Canada.





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