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Physical Therapy Graduate Program, College of Medicine, The University of Iowa, Iowa City, Iowa 52242-1008
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Shields, Richard K., Laura Frey Law, Brenda Reiling, Kelly
Sass, and Jason Wilwert. Effects of electrically induced fatigue
on the twitch and tetanus of paralyzed soleus muscle in humans.
J. Appl. Physiol. 82(5):
1499-1507, 1997.
We analyzed the twitch and summated torque
(tetanus) during repetitive activation and recovery of the human soleus
muscle in individuals with spinal cord injury. Thirteen individuals
with complete paralysis (9 chronic, 4 acute) had the tibial nerve
activated every 1,500 ms with a 20-Hz train (7 stimuli) for 300 ms and
a single pulse at 1,100 ms. The stimulation protocol lasted 3 min and
included 120 twitches and 120 tetani. Minimal changes were found for
the acute group. The chronic group showed a significant reduction in
the torque and a significant slowing of the contractile speeds of both
the twitch and tetanus. The decrease in the peak twitch torque was significantly greater than the decrease in the peak tetanus torque early during the fatigue protocol for the chronic group. The twitch time to peak and half relaxation time were prolonged during fatigue, which was associated with improved fusion of the tetanus torque. At the
end of the fatigue protocol, the decrease in the peak twitch torque was
not significantly different from the decrease in the peak tetanus
torque. After 5 min of rest, the contractile speeds recovered causing
the tetanus to become unfused, but the tetanus torque became less
depressed than the twitch torque. The differential responses for the
twitch and the tetanus suggest an interplay between optimal fusion
created from contractile speed slowing and excitation contraction
coupling compromise. These issues make the optimal design of functional
electrical stimulation systems a formidable task.
relaxation properties
INTRODUCTION AFTER AN INJURY TO THE SPINAL CORD, slow high-endurance
muscle fibers develop fast-fatigable properties. Both histochemical (18, 35) and physiological studies (7, 15, 26, 35, 36, 41) support this
conversion from slow to fast but only in the chronically paralyzed
state (35). The acutely paralyzed soleus muscle (4-6 wk) has been
found to be relatively fatigue resistant and to respond similarly to
the normal soleus muscle (34). Hence, this study examined the
contractile properties of the paralyzed soleus muscle in humans who had
chronic and acute paralysis.
Two phenomena that appear to be preferential to fast muscle during
repetitive activation are contractile speed slowing (10, 12, 17, 23,
24, 29) and low-frequency fatigue (LFF) (13, 22, 29). Contractile speed
slowing during fatigue suggests that the same force level produced
during an unfused tetanus may be produced at a lower frequency. As
such, optimal stimulation has been defined as the lowest frequency that
still enables maximal fusion of the muscle (3-5). Alternatively,
LFF, or the selective loss of force during stimulation at a low
frequency (0-30 Hz) that persists after force at a high frequency
recovers, suggests that a higher stimulation frequency is necessary to
retain a given force level (36). Thus, at certain times during
repetitive activation of fast-fatigable muscle, changes in the
single-twitch properties may not match the changes in the tetanus
force. In particular, during fatigue, an unfused tetanus may be
attenuated less compared with the twitch force because, as the twitch
becomes slow, the tetanus should become fully fused. Furthermore, if
later stages of muscle fatigue relate to impaired
Ca2+ release and/or
impaired Ca2+ sensitivity, as
suggested by Westerblad and colleagues (39), then the single twitch may
be predisposed to greater fatigue, compared with the force induced by a
repetitive train (22).
The isometric twitch has frequently been used to provide information
about the number of active cross bridges (14). The change in the
duration of the Ca2+ transient
during fatigue, however, may produce independent effects on the twitch
and the tetanus force contractile properties (14). To establish the
changes in the twitch and tetanus during fatigue, however, requires
that both contractions be elicited periodically during the fatigue
protocol. Dubose and colleagues (10) elegantly elicited a twitch and
tetanus during fatigue of fast fatigable (FF) type motor units and slow
type (S) motor units to compare the units' contractile
properties. We used a similar activation strategy so that the changes
in both the twitch and tetanus during fatigue of paralyzed muscle could
be ascertained. The fatigue responses of the chronically paralyzed
soleus and acutely paralyzed soleus may be analogous to the responses
observed for FF and S motor units (10), respectively.
Understanding the properties of human paralyzed muscle during fatigue
may also have clinical significance because optimal methods to
stimulate have been found to be closely coupled to muscle contractile
properties (4-6). Accordingly, the purpose of this study was to
compare the twitch and tetanic contractile properties during and after
repetitive activation of the chronically (predominantly fast) and
acutely (predominantly slow) paralyzed soleus muscle in humans.
Preliminary results of these experiments have appeared in abstract form
(37).
METHODS After we received informed consent from the subjects, we
obtained measurements from 13 individuals with complete motor and sensory paralysis (9 men, 4 women), who were between 18 and 62 yr of
age. Nine subjects had been paralyzed for over 3 yr (3.7 ± 3.6 yr),
whereas four subjects had been paralyzed for <5 wk (4.2 ± 1.1 wk). The subjects' mean age, height, and mass were 38.1 ± 7.2 yr,
1.74 ± 0.26 m, and 72.4 ± 5.1 kg, respectively. The subjects
had complete lesions confirmed by a neurological examination,
indicating no motor or sensory information below the level of the
lesion. The lesions were upper motoneuron, and all were above the
eighth thoracic spinal level. The soleus muscle from the right leg was
studied in each subject. Because the soleus muscle does not cross the
knee joint (like the gastrocnemius muscle) and has an extremely large
moment arm compared with other plantar flexors (flexor hallucis longus,
tibialis posterior, flexor digitorum), we estimated that >80% of the
measured torque originates from the soleus muscle (34) during
electrical activation of the tibial nerve, providing that the knee is
flexed to 90° and the ankle is kept in a neutral position. This is
in agreement with the findings of others (9, 32).
Mechanical recording. The study was
conducted with the subjects seated facing the oscilloscope. The right
knee was flexed to 90°, and the foot was placed on a plate
connected serially to a force transducer (Genisco AWU-250). The
calibrated accuracy of this torque measurement system was within 1.3%
of full scale. The torque measurement system has been previously
described (34-36). Briefly, the foot was tightly secured to the
footplate via an ankle cuff with turnbuckles that directed a force
through the heel and into the footplate. This prevented the heel from
moving during activation of the plantar flexors. The force transducer was aligned perpendicular to the first metatarsal head. In addition, a
strap attached to the torque measurement system was secured over top of
the thigh (femur), which further secured the leg and foot to the torque
measurement system. Torque was calculated as the product of the
external moment arm and the perpendicular force measured from the
transducer. Force was converted to torque to facilitate between-subject
and between-study comparisons. The signal from the force transducer was
displayed on an oscilloscope and recorded on a Vetter digital recorder
(direct current to 10 kHz).
Electrical recording.
Electromyographic (EMG) signals (M waves) were obtained from surface
recordings by using bipolar silver-silver chloride electrodes that had
a 1-cm diameter and fixed 2-cm interelectrode distance. One electrode
positioned over the soleus was ~2 cm lateral to the midline at
one-third the distance from the lateral malleolus to the fibular head
(35). Slight adjustments were made in the electrode placement to
accentuate the biphasic waveform of the M wave. An additional electrode
placed over the tibialis anterior muscle was used to monitor any
inadvertent peroneal nerve activation. The signal from the electrodes
was onsite preamplified by a factor of 35 before differential
amplification. The signal was differentially amplified with an
amplifier with the following characteristics: input impedance of 15 M Electrical stimulation. The plantar
flexors were activated by electrical stimulation of the tibial nerve by
using a custom-designed constant-current stimulator with a current
range from 50 µA to 200 mA, with a total output of 400 V. The
stimulator delivered a square wave with a fixed pulse width of 250 µs. The stimulator was triggered by a digital pulse from the
data-acquisition board (Metrabyte DAS16F) housed in a microcomputer and
under custom software control. The tibial nerve was stimulated in the
popliteal fossa with a double-pronged surface-stimulation electrode
placed so that the cathode was distal to the anode (34, 35). Once the
largest biphasic M-wave response was detected, the stimulating electrode was secured to the knee by using an orthoplast and Velcro splint that has been previously described (34, 35). The electrode was
also supported by an investigator (R. K. Shields) during all stimulation.
The computer was programmed to trigger the stimulator with a 1-Hz
stimulation for 1 min. The stimulation intensity was increased until
the maximum M wave was reached. The stimulator intensity was increased
approximately two times the maximum intensity to ensure supramaximal
activation. Next, a 20-Hz train was delivered for 300 ms (7 pulses)
every second for five contractions. We used the five contractions as a
warm-up and to potentiate the muscle. After a 3-min rest, the same
20-Hz train was delivered every 1,500 ms for 180 s. Interspersed within
every cycle at 1,100 ms from the onset of the train was a single
stimulus pulse. Thus every 1,500 ms a tetanus and single twitch were
elicited (Fig. 1) and constituted 120 tetani and 120 twitches. Five minutes after the protocol, 10 additional
contractions were elicited with the use of the identical protocol. The
second set of five tetani and five twitches was used to assess
recovery. The duty cycle used in this protocol is comparable to the
duty cycle used during functional electrical stimulation for ambulation
(unpublished observation).
Experimental procedures. Subjects were
asked to participate in only one testing session. Previous day-to-day
correlations for reliability of the torque and relaxation properties
were 0.75-0.95 (34). Before any muscle contractions, the ankle was
passively ranged into dorsiflexion to stretch the calf muscle several
times. After patient gave consent, the right foot was placed in the
torque-measurement system. EMG electrodes were placed over the soleus
muscle and tibialis anterior muscle as previously described.
Supramaximal stimulation intensity and EMG amplifier gain settings were
established during the 60 single twitches delivered at 1 Hz and the
five 20-Hz trains delivered over 7.5 s. Next, the 20-Hz stimulation
trains and single pulses were delivered every 1,500 ms for 3 min. Ten additional cycles were delivered after 5 min of rest.
Data analysis. Force was digitally
sampled at 1,000 samples/s and analyzed using custom software. The
force was converted to torque for both the twitch and the tetanus by
taking the product of the external moment arm and the perpendicular
force measured from the transducer. The peak torque was determined for
the tetanus and twitch by taking the maximum element of the digital
torque array. Every 22.5 s, five consecutive tetani and twitches were analyzed. Thus the torque for each measured time was represented by the
mean of five consecutive contractions. The coefficient of variation for
these five contractions never exceeded 2% for any individual subject.
The speed properties of the twitch or tetanus were characterized by
determining the time to peak (TTP) and half relaxation time
(RT1/2) for the twitch and the
RT1/2 and normalized maximum rate of
relaxation (nMRR) for the tetanus. The contraction time (TTP) was the
time from the stimulus pulse to the peak torque of the twitch. The
RT1/2 was the time it took for the
maximum measured torque to drop to one-half of its value. The duration of the twitch is considered an important indicator of the frequency necessary to fuse the single twitches (14). The maximum rate of
relaxation was calculated by differentiating the torque output with
respect to time and dividing by the peak torque to derive the nMRR.
We used a repeated-measures analysis of variance to determine whether
the change in the twitch was different from the change in the tetanus
during the fatigue protocol and after 5 min of recovery. A two-tailed
test with a significance level set at 0.05 was used to test for all
differences. We used multiple-regression analysis to determine
relationships among the percent change in twitch and tetanus torque,
the twitch TTP, and the twitch
RT1/2. For all relationships, the
overall correlations for the entire data set and the range of
correlations for each subject are provided.
RESULTS The purpose of this study was to determine the effects of repetitive
activation on the twitch and tetanus of the human soleus muscle in
individuals with chronic and acute paralysis. Minimal changes were
present in the acute group. The peak torque,
RT1/2, and nMRR for the twitch and
tetanus were significantly changed in the chronic group. Contractile
slowing and excitation-contraction coupling impairment may contribute
to differences in torque between the twitch and the tetanus during
fatigue and recovery. These data are reported as means ± SD values
in the text and as means ± SE values in Figs. 1, 2, 3, 4. An example
showing the changes in the twitch and tetanus during and after
repetitive activation of a chronically and acutely paralyzed subject is
presented in Fig. 1.
Torque and contractile speed changes.
The mean peak torque for both the twitch and tetanus at 30, 60, 90, 120, 150, and 180 s, and at 5 min of recovery was significantly
(P Table 1.
Summary of descriptive statistics for the twitch and tetanus every 30 s
of stimulation protocol and recovery for the C and A groups
at 100 Hz; frequency response, 15-1,000 Hz; common mode
rejection ratio, 87 db at 60 Hz. The EMG signal was recorded on a
Vetter digital recorder (direct current to 10 kHz). The reference
electrode was placed on the tibia anterior and superior to the ankle
joint. The signal from the EMG electrodes was displayed on the
oscilloscope and used primarily to verify supramaximal stimulation.
Fig. 1.
Representative example of twitch and tetanus for an individual with
acute paralysis (A) and an
individual with chronic paralysis (B). Twitch and tetanus every 30 s
of 180-s protocol is presented. Torque curve for the individual with
chronic paralysis after 5 min of recovery is just above asterisk.
[View Larger Version of this Image (15K GIF file)]
Fig. 2.
Mean %change (±SE) for chronic group (
, twitch; 
, tetanus)
and acute group (
, twitch; 
, tetanus) plotted every 30 s during fatigue protocol and after 5 min of recovery
(A). Mean %change in torque
(±SE) plotted against mean twitch TTP (±SE) for tetanus ()
and twitch () of chronically paralyzed group
(B).
[View Larger Version of this Image (17K GIF file)]
Fig. 3.
Mean percent change in torque (±SE) plotted against mean twitch
half relaxation time (RT1/2)
(±SE) for twitch () and tetanus () of chronically paralyzed
group (A). Mean %change in twitch torque (±SE) plotted against tetanus torque
(B). See text for correlation
coefficients.
[View Larger Version of this Image (15K GIF file)]
Fig. 4.
Mean (±SE) for twitch TTP plotted against mean (±SE) tetanus
RT1/2
(A) and mean (±SE) twitch
RT1/2 plotted against the mean (±SE) tetanus RT1/2
(B) for chronically paralyzed group.
See text for the best fit regression equations.
[View Larger Version of this Image (14K GIF file)]
0.05) less than the mean initial
peak torque in the chronic group (Table 1). After 5 min
of recovery, however, the tetanus torque was, on average, 40%
depressed, whereas the twitch torque was 50% depressed. In the acute
group, the mean peak torque for the twitch and tetanus was
significantly (P 0.05) less than
the mean initial peak torque only at 180 s of the stimulation protocol
(Table 1). Thus, relative to the chronically paralyzed group, the
acutely paralyzed soleus muscle retained its fatigue resistant
properties.
Time, s
TTP, ms
Peak Torque, Nm
RT1/2, ms
nMRR, l/s
C
A
C
A
C
A
C
A
Twitch
0
78 ± 7.07
98 ± 5.01
19.14 ± 7.19
18.21 ± 6.01
70 ± 12.24
94 ± 7.21
10.8 ± 2.54
9.41 ± 1.32
30
86 ± 5.47*
100 ± 4.32
13.37 ± 4.64*
17.63 ± 4.32
88 ± 13
96 ± 7.51
9.95 ± 1.48
8.69 ± 1.74
60
94 ± 5.40*
101 ± 5.64
8.54 ± 2.84*
17.21 ± 4.81
122 ± 10.95*
98 ± 8.01
6.75 ± 0.35*
8.81 ± 1.27
90
98 ± 10.95*
98 ± 4.70
6.05 ± 2.14*
16.80 ± 5.02
144 ± 5.47*
97 ± 6.53
5.65 ± 0.49*
8.72 ± 1.45
120
98 ± 9.87*
103 ± 4.81
4.73 ± 1.72*
16.26 ± 5.94
148 ± 13.03*
99 ± 5.13
5.55 ± 0.64*
8.60 ± 1.21
150
100 ± 10*
102 ± 5.02
4.0 ± 6.68*
15.93 ± 6.02
148 ± 23.8*
100 ± 4.06
5.42 ± 0.56*
8.44 ± 1.31
180
102 ± 8.36*
103 ± 5.62
3.78 ± 6.04*
15.65 ± 6.61*
144 ± 23.02*
102 ± 7.1*
5.33 ± 0.42*
8.39 ± 1.52*
Rec
76 ± 5.47
97 ± 4.32
12.46 ± 14.15*
18.01 ± 5.23
74 ± 5.47
92 ± 5.32
10.25 ± 1.06
9.78 ± 1.71
Tetanus
0
45.81 ± 18.8
52.71 ± 10.61
74 ± 13.4
94 ± 8.71
11.33 ± 1.16
9.97 ± 1.61
30
37.60 ± 15.5*
50.68 ± 11.20
120 ± 18.70*
94 ± 9.68
8.96 ± 0.57*
9.71 ± 1.41
60
27.98 ± 10.44*
48.12 ± 9.61
166 ± 33.6*
96 ± 7.72
6.16 ± 1.03*
9.32 ± 1.27
90
20.17 ± 6.59*
46.98 ± 4.82
184 ± 36.46*
98 ± 7.41
5.1 ± 1*
9.41 ± 1.68
120
15.46 ± 4.89*
45.60 ± 9.92
190 ± 37.4*
101 ± 6.67
5.0 ± 0.98*
9.67 ± 1.72
150
12.77 ± 4.08*
44.71 ± 9.01
204 ± 28.8*
100 ± 8.21
4.6 ± 0.53*
9.49 ± 1.49
180
11.30 ± 3.69*
44.11 ± 10.64*
204 ± 33.6*
102 ± 9.91*
4.53 ± 0.50*
8.98 ± 1.46*
Rec
26.92 ± 10.99*
53.72 ± 11.61
86 ± 5.47
94 ± 7.77
10.5 ± 0.52
10.32 ± 1.61
Values are means ± SD. TTP, time to peak; RT1/2,
half relaxation time; nMRR, normalized maximal relaxation rate; Rec,
recovery at 5 min following protocol; C, chronic paralysis; A, acute
paralysis.
*
Significantly different from the initial (time
0) for each respective dependent variable, P
0.05.
The twitch RT1/2 and nMRR were
significantly slower (P 0.05) from
the initial values at 60, 90, 120, 150, and 180 s of the stimulation
protocol in the chronic group (Table 1). The tetanus RT1/2 and nMRR were significantly
slower from the initial at 30, 60, 90, 120, 150, and 180 s in the
chronic group. However, for both the twitch and the tetanus, the
RT1/2 and nMRR were not significantly different from the initial after 5 min of recovery. This disassociation between torque and relaxation speed after 5 min of recovery was apparent in both the twitch and the tetanus. In the acute group, the
twitch and tetanus RT1/2 and nMRR were
significantly slower (P 0.05) only
at 180 s of the stimulation protocol (Table 1). Thus the minimal change
in contraction speed for the acute group is consistent with a muscle
composed of primarily slow fibers (10, 17, 27).
There was a significant increase (P 0.05) in the twitch TTP (slower) at 30 s of the repetitive stimulation
protocol and every 30 s thereafter during the stimulation protocol in
the chronic group. The twitch TTP was also not significantly different
from initial after 5 min of recovery. This indicates that any torque enhancement for the tetanus attributed to longer TTPs was possible only
during the fatigue protocol and not after 5 min of recovery. No
significant changes were present in the twitch TTP in the acute group.
The percent change in the twitch peak torque for the chronic group was greater than the percent change for the tetanus peak torque at 30, 60, 90, and 120 s and after 5 min of recovery (P < 0.05) (Fig. 2A). Early during the fatigue protocol, the improved fusion of the tetanus appeared to be associated with the slowed twitch TTP and RT1/2 (Fig. 1). The significant difference in the change in torque between the twitch and the tetanus after 5 min of recovery, however, cannot be attributed to improved summation from contractile slowing because near-full recovery of the twitch speed (TTP) was already apparent (see Table 1). Thus the 20-Hz train (tetanus) was able to overcome some fatigue after 5 min more effectively than the single pulse (twitch), even though the tetanus became unfused. There was no significant difference between the percent change in torque for the twitch vs. the tetanus in the acute group.
Relationship between torque and twitch
TTP. Regression analysis indicated that there was an
association between the percent change in the tetanus torque and the
twitch TTP for the chronically paralyzed group (overall correlation,
0.65; range of correlations for each subject, 0.84-0.97). There
was also an association between the percent change in the twitch peak
torque and the twitch TTP (overall correlation, 0.70; range of
correlations, 0.88-0.98). The mean percent change in the tetanus
peak torque was significantly less (P 0.05) than the mean percent change in the twitch peak torque when
the mean TTP was 86, 94, and 98 ms, respectively (Fig. 2B). Regression analysis also
indicated that there was a close association between the percent change
in the tetanus torque and the twitch
RT1/2 for the chronically paralyzed
group (overall correlation, 0.82; range of correlations,
0.77-0.98). There was also an association between the percent
change in the twitch torque and the twitch
RT1/2 for the chronically
paralyzed group (overall correlation, 0.85; range of correlations,
0.90-0.99). The mean percent change in the tetanus peak torque was
significantly less (P 0.05) than
the mean percent change in the twitch peak torque when the mean
RT1/2 was 88, 122, 144, and 148 ms, respectively (Fig.
3A),
corresponding to 30, 60, 90, and 120 s of the fatigue protocol.
Relationship between the twitch and
tetanus. The relationship between the percent change in
the twitch peak torque and the percent change in the tetanus peak
torque for the chronic group was best described by the second-order
regression equation: %change in twitch peak torque = 1.54 (%change
tetanus peak torque) + 0.00655 (%change tetanus peak torque × %change tetanus peak torque) 2.46, with an overall multiple
correlation coefficient of 0.98 (range for each subject,
0.97-0.99) (Fig. 3B). The
quadratic fit supports the finding that the twitch torque declined at a
faster rate than the tetanus torque while the torques were high (at the start of the protocol), but later the tetanus tension and twitch tension declined similarly. This is evident in Fig.
3B.
The overall correlation between the twitch TTP and the tetanus RT1/2 was 0.83 (range, 0.58-0.98). This relationship was best described by the linear-regression equation: twitch TTP = 0.281 (tetanus RT1/2) + 59.23 (Fig. 4A). Similarly, the overall correlation between the change in the twitch and tetanus relaxation properties during the fatigue protocol was 0.87 (range, 0.80-0.98). Thus the mean twitch RT1/2 was predictable from the linear regression equation: twitch RT1/2 = 0.546 (tetanus RT1/2) + 33.48 (Fig. 4B). Thus the mechanisms contributing to slowing the speed of torque production or relaxation during the twitch and tetanus appear to covary during fatigue of chronically paralyzed muscle.
DISCUSSION
The major findings of this study were that repetitive activation of the chronically paralyzed soleus muscle caused 1) a significant reduction in the torque and a significant slowing of the contractile speeds of both the twitch and the tetanus; 2) a significant depression of the torque but near full recovery of the contractile speeds of both the twitch and tetanus after 5 min of recovery; 3) the twitch peak torque to decline faster than the tetanus peak torque early during the fatigue protocol, which was closely associated with the slowing twitch contractile properties; 4) a greater depression of the peak twitch torque compared with the tetanus peak torque after 5 min of recovery, although the contractile speeds were fully recovered; 5) the twitch TTP and twitch RT1/2 to be highly correlated to changes in the tetanus RT1/2; and 6) significantly greater changes (fatigue and contractile slowing) in the twitch and tetanus than in the acutely paralyzed soleus muscle.
The twitch and the tetanus of the chronically paralyzed soleus muscle undergoes contractile property slowing during repetitive activation that is characteristic of fast-fatigable whole muscle (25, 27) or FF motor units (10, 17, 29). That is, the contractile slowing is closely associated with the significant fatigue seen in fast muscle during repetitive activation. Conversely, the twitch and tetanus of the soleus muscle from individuals with short-term paralysis (6 wk or less) respond as would be expected from a slow endurance muscle (27) or type S motor units (10, 17, 29). As such, the soleus muscle that is recently paralyzed fatigues very little and shows minimal change in contractile properties. From previous work (35, 36) and from the findings in this study, the acutely paralyzed soleus muscle does not appear to convert to highly fatigable muscle within 6 wk of spinal cord injury but in the chronic state becomes highly fatigable (3 yr or more). Moreover, the human chronically paralyzed soleus muscle demonstrates other properties that are characteristic of fast-fatigable fibers, including slowed contractile speeds during fatigue (10, 17, 29, 30) and LFF (21, 22, 29, 36). Change in contractile speeds and LFF may influence the tetanus torque differently depending on whether it is early or late during a repetitive activation protocol or after 5 min of rest.
The present results indicate that contraction speed of the chronically paralyzed soleus muscle changes markedly when activated for even short time periods (30 s) and shows a close association to fatigue (35). "Muscular wisdom," as reported by Marsden et al. (28), suggests that if the activation frequency decreases to match the slowing contractile properties then less fatigue will develop. The 20-Hz stimulation used in this study, however, caused an unfused tetanus at the start of the activation protocol in the chronic group, but by 30 s the twitches started to fuse. The change in train torque was less than the change in the twitch torque at a time when the twitch TTP and RT1/2 experienced the greatest relative change (slowing). These findings suggest that the contractile speed slowing contributed to the reduced fatigue of the tetanus within the first 2 min of the stimulation protocol.
A higher frequency (60 Hz) at the start of the protocol would appear to create a better match for the faster contractile properties of chronically paralyzed muscle early in the activation protocol. However, several factors should be considered before activation of unfatigued chronically paralyzed muscle with high frequencies (60 Hz). First, high-frequency stimulation may induce rapid neuromuscular transmission compromise (33), which emphasizes the need to precisely reduce the frequency at the appropriate times. Second, the initial torque produced with a high frequency (60 Hz) may far exceed the torque required to perform a functional task (walking, standing, grasping). Furthermore, the torques produced with higher frequencies may exert a strain on the musculoskeletal system that could induce serious injury. Demineralized long bone (16), in combination with the suggestion that chronically paralyzed muscle may have an increased specific tension (27, 35), suggests that high-frequency stimulation of nonfatigued chronically paralyzed muscle may be deleterious to the musculoskeletal system.
Torque and contractile speed changes during the fatigue protocol. The twitch peak torque declined more rapidly than the tetanus peak torque during the first 2 min of the fatigue protocol in the group of subjects with chronic paralysis. At 1 and 2 min, the percent decline in the twitch was ~18 and 15% lower than the tetanus, respectively. We suggest that this was caused by a better fusion of the tetanus during the 20-Hz protocol because of the slowed twitch contractile speeds, especially within the first 2 min of the protocol. At 150 and 180 s of the fatigue protocol, the twitch torque was not reduced significantly more than the tetanus torque (4-7%). During LFF, there is a purported decrease in the amount of Ca2+ released per impulse but an overabundant release of Ca2+ during tetanic stimulation (21, 22, 39). Thus it may be expected that the single twitch would be further depressed than the fused tetanus at the end of the fatigue protocol. Perhaps neuromuscular transmission became a factor toward the later stages of the stimulation train, but this notion was not supported by our previous M-wave analysis of chronically paralyzed muscle (35). Hence, another explanation is that toward the later stages of the fatigue protocol (150-180 s) the 20-Hz stimulation was not high enough to adequately overcome the progressive excitation-contraction coupling impairment (LFF) or compensate for other causes of fatigue (individual cross bridges). Thus optimal fusion may have become a less important factor if the uncoupling between the activation system and the contractile apparatus (LFF) became more prominent as the fatigue protocol progressed. Accordingly, one plausible explanation is that by 150 s of the fatigue protocol both the 1-Hz (twitch) and 20-Hz (tetanus) activations represented low frequencies that were unable to differentially overcome the severe LFF induced.
Torque and contractile speed changes during recovery. After 5 min of recovery, the twitch peak torque and the tetanus peak torque remained significantly depressed for the chronic group (Fig. 2A). However, almost full recovery was present for all measures of contractile speed (RT1/2, nMRR, TTP) for the twitch and tetanus after 5 min of rest. The recovery of contractile speed is evident by the unfused nature of the recovery curve in Fig. 1. Hence, at 5 min of recovery, the tetanus torque no longer shows the fusion that was present during the later stages of the fatigue protocol. Despite this loss of fusion, the fatigue of the tetanus after 5 min of recovery was significantly less than the fatigue of the twitch.
The greater decline of the twitch torque compared with the tetanus
torque after 5 min of recovery suggests that the 20-Hz stimulation was
now adequate to overcome the excitation-contraction coupling impairment
more effectively than the 1-Hz activation. The improved ability to
overcome excitation-contraction coupling impairment with the 20-Hz
train and not the 1-Hz pulse suggests that some properties of LFF
continue to change after brief periods of recovery (29). Hence, the
further recovery at 20 Hz after 5 min shown in this study is in
agreement with our recent finding that LFF becomes more pronounced as
recovery time increases (36). That is, immediately after fatigue of
paralyzed muscle we found a preferential recovery of torque at only the
higher frequencies (40 Hz) (36). After 5 min of recovery, however,
frequencies of 
20 Hz showed preferential recovery of torque, whereas
frequencies <15 Hz showed little or no recovery (36). This phenomenon
has been referred to as delayed-onset muscle fatigue (29) and may explain why the twitch and tetanus were similarly depressed at the end
of the fatigue protocol but were not similarly depressed after 5 min of
recovery.
Most intriguing was that the mechanism causing reduced torque appeared to covary with the mechanism causing the slowing of the contractile speeds during fatigue but became independent of the speed properties after 5 min of recovery. A similar disassociation between the speed and the force levels during recovery has been reported by Hultman and Sjoholm (19) after electrical activation of the human quadriceps muscle.
Because M waves are fully recovered in chronically paralyzed muscle after this type of fatigue protocol (35), any continued decline in torque must be attributed to changes beyond the sarcolemma. As such, single-fiber experiments may shed light on the mechanisms contributing to the LFF fatigue so prominent in human chronically paralyzed muscle (36). For example, in single mouse muscle fibers, LFF has been attributed to decreased Ca2+ sensitivity and/or reductions in overall tetanic Ca2+ levels (39). In addition, some loss of force is the result of reduced force output of the individual cross bridge (11). Thus some of the recovery of torque in the chronically paralyzed muscle may reflect improved force production at the cross-bridge level. However, most of the delayed loss of torque in chronically paralyzed muscle appears to be from excitation-contraction coupling compromise because there is near-full recovery of torque at higher frequencies (36). Interestingly, Westerblad and colleagues (39) recently demonstrated in single mouse fibers that the reduced force during LFF was almost entirely attributed to reduced tetanic Ca2+, which was believed to be caused by reduced Ca2+ release. Several reasons have been proposed for the reduced Ca2+ release, including failure of t-tubular conduction (39, 40) and a change in the Ca2+ pumping ability of the sarcoplasmic reticulum (SR) (2).
Single-fiber experiments may also shed light on the mechanisms contributing to prolonged relaxation during fatigue in human chronically paralyzed muscle. First, a reduced rate of Ca2+ uptake by the SR or an increased affinity between troponin and Ca2+, both in response to metabolic products, have been implicated (1, 31, 39). Second, a Ca2+ binding protein, parvalbumin, present only in type II fibers assists in quickly removing Ca2+ during muscle relaxation (31). However, during repetitive activation, the parvalbumin becomes saturated, which significantly reduces the Ca2+ uptake capabilities and available Ca2+ for activation. This may explain why there was a close association between the decline in torque and the change in relaxation properties of paralyzed muscle during fatigue, also obtained in other studies (35, 36). Finally, the cross-bridge attachment and detachment rates are thought to be significantly altered by metabolic products (11). During recovery, however, the prolonged reduction in torque despite full recovery of the contractile speeds shown in this study suggest that cross-bridge detachment rate and/or rates of Ca2+ release and uptake (SR pump) are near-fully recovered 5 min after the fatigue protocol. However, reduction of the overall tetanic Ca2+ concentration levels may explain why torque remains depressed at lower frequencies despite full recovery of these contractile speeds in chronically paralyzed muscle.
Relationships between torque and relaxation properties. There was a high correlation between the twitch and tetanus torque relaxation properties during the fatigue protocol (r = 0.87). Thomas et al. (38) found a good association between the twitch and tetanus forces in human motor units studied by using microneurography but found poor associations between the twitch and tetanus relaxation rates. Conversely, our data support that monitoring the RT1/2 from the tetanus provided similar information as that derived from the single-twitch RT1/2 in chronically paralyzed muscle.
Numerous authors report whole muscle slowing with fatigue (5, 10, 17, 19, 30). Bigland-Ritchie et al. (4) reported significant increases in RT1/2 but no significant changes in twitch contraction times during fatigue of the human adductor pollicis muscle. In the present study, the absolute change in the twitch TTP was less than the absolute change in the twitch RT1/2 for the chronically paralyzed soleus muscle, but the changes occurred linearly during the fatigue protocol (r = 0.83). The human adductor pollicis muscle is predominantly slow and fatigue resistant, and thus minimal changes may occur in the contractile properties. The acutely paralyzed soleus muscle is primarily a slow oxidative muscle like the adductor pollicis, and the relaxation property changes observed most likely reflect the few fast glycolytic fibers present. Thus the ability to detect clear associations between the twitch TTP and the RT1/2 may rely on assessing muscle with large percentages of fast-fatigable fibers. In the predominantly fast, chronically paralyzed soleus muscle, the changes in the twitch TTP and the twitch RT1/2 during fatigue were correlated and consistent with the findings of Dubose et al. (10) for FF motor units.
The isometric twitch contraction time provides an estimate of the speed of motor unit and whole muscle shortening. Close (8) found that in whole muscle the velocity of shortening is approximately a linear relationship to the inverse of the twitch contraction time across a wide range of muscles and species. However, the twitch contraction time depends on several factors such as muscle length (20), temperature (20), and previous activation history (30) as well as fatigue. Although muscle length was constant, we did not control the effects of temperature in this study. The twitch contractile speeds are known to become faster with increased temperature (25-40°C) (20). The significant slowing observed during the repetitive activation protocol in this study may have been conservative because some increase in muscle temperature would be expected. Perhaps the increased temperature contributes to the rapid return of contractile speeds after 5 min of rest.
In summary, this study verified that the long-term-paralyzed soleus muscle in humans shows properties that are characteristic of fast-fatigable muscle. The differential responses observed between the twitch (1 Hz) and the tetanus (20 Hz) during repetitive activation of the chronically paralyzed soleus muscle suggest there is a complex interplay between optimal fusion created from contractile speed slowing and excitation-contraction coupling compromise. As such, optimal fusion from contractile speed slowing appears to attentuate fatigue of the tetanus compared with the twitch early during repetitive activation. Toward the end of the repetitive activation protocol, both the twitch and tetanus are similarly depressed, suggesting that both frequencies (1 and 20 Hz) are similarly unable to overcome LFF. However, during recovery, less than optimal fusion properties (because of full recovery of the contraction speed) do not prevent greater recovery of the tetanus, which suggests some preferential recovery at 20 Hz that is not present at 1 Hz. Accordingly, the 20-Hz stimulation frequency now appears to more effectively override the excitation-contraction coupling compromise compared with the single twitch. The changing mechanical properties of human paralyzed muscle during fatigue and recovery make the optimal design of functional electrical stimulation systems a formidable task.
ACKNOWLEDGEMENTS
We thank Carol Leigh for manuscript preparation and Dave Walker for technical assistance.
FOOTNOTES
Address for reprint requests: R. K. Shields, The Univ. of Iowa, College of Medicine, Physical Therapy Graduate Program, 2600 Steindler Bldg., Iowa City IA 52242-1008.
Received 29 July 1996; accepted in final form 7 January 1997.
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