Anaerobic energy release in skeletal muscle

during electrical stimulation in men

LAWRENCE
L. SPRIET,
KARIN
SODERLUND,
MATS BERGSTROM,
AND ERIC HULTMAN
Department
of Clinical Chemistry II, Karolinska Institute,
Huddinge University Hospital, S-141 86 Huddinge, Sweden

SPRIET,LAWRENCEL., KARIN WDERLUND, MATS BERG- occurred. Estimates of the ATP turnover rates during
STROM,AND ERIC HULTMAN. Anaerobic energy reZease in skeldynamic exercise were between 6-8 mmol kg dry musetal muscle during electrical stimulation in men. J. Appl. Physiol.
cle-l s-l, with glycolysis accounting for 6080% and PCr
62(Z): 611-615,
1987.-The
quadriceps
femoris muscles of
utilization ZO-40% of the total ATP produced. Hultman
seven men were electrically
stimulated under extended anaerand Sjoholm (12) obtained biopsies every 10 s from the
obic conditions to quantitate anaerobic energy release and the
quadriceps femoris muscle group during 50 s of continucontribution
of the glycolytic system to total ATP production.
ous electrical stimulation. The ATP turnover rate in the
Muscles were intermittently
stimulated 64 times at 20 Hz while
isometrically contracting muscles decreased from 5.6
leg blood flow was occluded. Each contraction
lasted 1.6 s and
mmol kg dry muscle- s-l during the initial 10 s to 4.0
was followed by 1.6 s of rest. The total contraction
time was
102.4 s. Muscle biopsies were taken at rest and following
16, mmol kg dry muscle- s-l in the final 10 s. The fraction
of ATP produced by anaerobic glycolysis increased from
32,48, and 64 contractions.
The ATP turnover rates during the
40 to 90% during the same time periods. Collectively
four 16-contraction
periods were 6.12, 2.56, 2.17, and 0.64
mmol kg dry muscle-l ws- contraction
time. Glycolysis prothese studies demonstrate that the regeneration from
vided 58%, phosphocreatine
40% and a decreased ATP store
PCr is limited to 30 s or less during intense muscular
2% of the consumed energy during the initial 16 contractions.
contraction. The energy required to sustain contractions
Glycolysis was responsible for 90% of the total ATP production
beyond this time under anaerobic conditions must be
beyond contraction
16. Absolute glycolytic ATP production
derived from glycolysis.
decreased to 60, 55, and 17% of the amount in the initial 16
The present investigation was designed to quantitate
contractions
during the final three periods, respectively.
In
the ATP turnover rate during short-term intense musconclusion glycolysis produced -195 mmol ATP/kg dry muscle
cular activity in men and to determine the contribution
during the initial 48 contractions
(76.8 s) and only -15 mmol
of the glycolytic system to ATP production under exATP/kg dry muscle during the final 16 contractions. Equivalent
tended anaerobic conditions. To accomplish this the
values for total ATP turnover were 278 and 16.5 mmol/kg dry
quadriceps femoris muscles were electrically stimulated
muscle.
for 100 s of contraction time during circulatory occlusion
with muscle biopsies taken every 25 s.
adenosine triphosphate
turnover rate; glycolysis; phosphocreal

tine; lactate; isometric force production;

phate; adenosine monophosphate;
inosine

adenosine
diphosmonophosphate

THEREHAS BEEN CONSIDERABLEinterestinhumanmuscle metabolism and performance during short-term maximal or near-maximal exercise (3, 5, 6, 12, 16). The high
rate of ATP production required to support intense isometric or dynamic exercise lasting Cl min is largely
dependent on the muscles ability to regenerate ATP
anaerobically. In the muscle cell, ATP is produced anaerobically in the glycolytic pathway with the formation
of lactate and hydrogen ions and through the degradation
of phosphocreatine (PCr). Approximately 30-40% of the
muscle ATP store may also be directly used to support
muscular contraction, although this contribution
is
quantitatively very small.
In recent studies, where muscle biopsies were obtained
before and following 30-50 s of maximal isokinetic cycling (16), sprinting (6) or electrical stimulation (12, 14),
substantial PCr degradation and lactate accumulation
0161-7567/87

$1.50 Copyright

METHODS
Seven male subjects agreed to participate in the study
(age 28.4 t 1.2 yr; height, 184 t 3 cm; weight, 82.6 t 2.2
kg). The subjects were not well trained but were healthy
and active as they regularly took part in some form of
physical activity. Voluntary consent was obtained from
all subjects following an explanation of the experimental
procedures and possible risks involved. This experiment
was part of a larger project approved by the Ethical
Committee of the Karolinska Institute.
Subjects reported to the laboratory in the postprandial
state and reclined in a semisupine position on a bed. The
lower legs were flexed over the end of the bed to 90 and
one leg, chosen at random, was attached to a strain gauge
in the frame of the bed via an ankle strap. The subject
then performed three maximal voluntary contractions
(MVC) to determine the maximal voluntary isometric
force of the knee extensors. Isometric force production
was measured with a strain gauge (AB Bofors, Karlskoga,
Sweden) and the signal was amplified (direct-current

0 1987 the American Physiological Society

611

612

SKELETAL

MUSCLE

ANAEROBIC

amp Medelec AD6, Surrey, UK), displayed on an oscilloscope (Medelec M) and recorded on ultraviolet-sensitive paper.
The leg was then prepared for electrical stimulation
of
the quadriceps femoris muscles as previously
described
(13, 15). Briefly, two large (9 X 6 cm) aluminum foil
electrodes were applied proximally
and distally to the
anterolateral
aspect of the thigh. The underlying muscles
were stimulated to contract with square-wave
pulses of
0.5 ms duration at a frequency of 20 Hz (Medelec 15-V
stimulator).
Stimulation
was intermittent
with trains
lasting 1.6 s and separated by rest pauses of 1.6 s. The
voltage used (120-180 V) produced an initial force corresponding to 22% of the maximal voluntary
isometric
force. Since stimulation
at 20 Hz produces a fused tetanus representing
70-75% of the maximal tetanic force
obtained at higher frequencies
(20), -29-32%
of the
musculature
that extends the knee was activated. The
muscle activated in this study was limited to the anterolateral aspect of the thigh as muscle needle biopsies were
taken from the vastus lateralis muscle as described by
Bergstrom
(2).
The experimental
protocol used in this study is schematically presented in Fig. 1. Before the stimulation
of
leg one, three incisions in the skin were performed following local anesthesia
and a resting biopsy was obtained. Thirty seconds before stimulation
a pneumatic
cuff around the proximal portion of the thigh was inflated
to a pressure of 250 Torr. In this manner blood flow was
occluded and a predominantly
anaerobic situation created throughout
the stimulation
period. The muscles
were then stimulated at 20 Hz for a total of 64 contractions, each lasting 1.6 s and separated by 1.6 s of rest.
The total stimulation
time was 204.8 s and the contraction time 102.4 s (Fig. 1). Muscle biopsies were taken in
the rest periods following contractions
16 and 48. These
rest periods were elongated to -3-5 s to permit time for
biopsy sampling.
The second leg was then prepared for stimulation
and
force measurement
as described above and stimulated to
contract 64 times. The time between stimulation
of legs
one and two was 30-40 min. Muscle biopsies were taken
from leg two at rest and following 32 and 64 contractions.
The isometric force production
by the activated knee
extensor muscles was continuously
recorded and the
reported data represents
the average of measurements
obtained from both legs in seven subjects. The peak force
obtained during each tetanic contraction
was used in the
of the force data.
-presentation
Muscle biopsy samples were immediately frozen (3-5
s from the insertion of the needle) in liquid freon mainBiopsy

($1, ILeg 1
Leg

1
No.
No. of contractions
Contraction

time,

set

0
I
0

Stimulation

time,

set

1
ions

16
1
r
25.6

51.2

48
I
1
76.8

51.2

102.4

153.6

32
II

64
i
102.4
204.8

representation
of experimental
design. Each contraction
lasted 1.6 s at 20 Hz and was followed
by 1.6 s of rest. Blood
flow was occluded throughout
experiment.
FIG.

1. Schematic

of contract

ENERGY

i
d

170

65

150

75

120

601%

; m
i

RELEASE

i,

1
0

16
Number

32
of

cant

25.6

51.2

Contraction

time,

ract

48

64

76.8

102.

ions

set

FIG. 2. Muscle
contraction
force and phosphocreatine
(PCr), ATP,
and lactate concentrations
during
intermittent
electrical
stimulation
with an occluded circulation.
Data points represent
mean of 7 subjects.
SEs for phosphocreatine
(PC,), ATP, and lactate are not included but
appear in Table 1. On left y-axis, PCr, and ATP data points correspond
to O-85 scale and lactate data points correspond
to O-170 scale.

tained at its melting point (-150C) with liquid nitrogen.

Samples were freeze-dried,
dissected free of blood and
connective tissue, and extracted with 0.5 M HClO, (1.0
mM EDTA).
The neutralized extracts (2.3 M KHCOs)
were analyzed enzymatically
(1) for ATP, ADP, PCr, Cr,
and lactate as described by Harris et al. (11). Adenosine
monophosphate
(AMP)
and inosine monophosphate
(IMP) were measured with high-pressure
liquid chromatography (HPLC) (18). Resting metabolite concentration represents the average of measurements
performed
on biopsies from both legs in seven subjects. Muscle
metabolite concentrations
are expressed per kilogram
dry muscle and all data are presented as means t SE.
RESULTS

Maximal voluntary contractions of the knee extensor

muscles in the left and right legs produced mean forces
of 651 t 45 and 657 t 49 N, respectively. Approximately
30% of the knee extensor muscle mass was electrically
stimulated to contract at 20 Hz (see METHODS), producing initial forces of 144 t 13 N in the left leg and 145 t
15 N in the right leg. These forces represented 22% of
MVC in both legs.
Isometric force production was well maintained during
the early contractions as 87.6 t 2.5% of the initial force
was held during contraction 16 (Fig. 2). In the subsequent
32 contractions force production decreased rapidly to
55.6 t 2.5 and 26.7 t 2.7% of initial at contractions 32
and 48, respectively. During the final 16 contractions
force production was extremely low, amounting to 16.8
t 2.3% of the initial force at contraction 64.
Resting metabolite concentrations were in the normal
range for human skeletal muscle (Tables 1 and 2). Muscle
ATP decreased progressively with continued stimulation
under anaerobic conditions to a low of 56.6% of the
resting concentration following 64 contractions (Table
2, Fig. 2). The muscle PCr store was 80% depleted
following 16 contractions (Table 1, Fig. 2). Continued

SKELETAL

MUSCLE

ANAEROBIC

1. Muscle metabolite concentrations

during intermittent electrical stimulation
with an occluded circulation
TABLE

No. of Contractions
Rest
PCr
Cr
Total Cr
Lactate

78.7t2.4
42.4t2.6
121.1k1.6
5.lkl.O

16 (25.6)

32 (51.2)

48 (76.8)

64 (102.4)

15.7t3.9
103.3t5.7
119.0t2.8
65.627.4

9.0t2.7
109.5t4.7
118.5t3.2
101.7k9.4

5.4t1.1
116.2t2.2
121.6t1.9
135.2k13.5

5.5t0.9
118.2t2.7
123.7t3.2
145.3k9.5

Values are means & SE in

parentheses
indicate
duration
stimulated
64 times at 20 Hz
followed by 1.6 s of rest. PCr,

ENERGY

613

RELEASE

The calculation of ATP turnover rate also makes no

allowance for the presence of 0, stored or trapped in the
occluded muscle. Harris et al. (10) suggested that the
upper limit for this store was 2 mmol/kg dry muscle,
enough to produce 12 mmol ATP/kg dry muscle. Assuming that all of the stored OZ was used in the first 15 s of
contraction, the aerobic ATP production would amount
to 0.8 mmol. kg dry muscle- s-l during this period.
Subsequent contractions would then rely purely on anaerobic metabolism.
The ATP turnover rate during the initial 16 contractions was 6.12 t 0.56 mmol. kg dry muscle- s-l with
58% of the ATP derived from glycolysis, 40% from PCr
degradation, and 2% from partial utilization of the ATP
store (Fig. 3). During contractions 17-32 and 33-48 the
respective ATP turnover rates decreased to 2.56 t 0.76
and 2.19 t 0.83 mmol kg dry muscle- es-l, representing
42 and 36% of the initial rate. Glycolysis produced 8390% of the total ATP during this time as the PCr store
was largely depleted and decreases in the ATP content
contributed minimal amounts of energy (Fig. 3). The
ATP turnover rate during the final 16 contractions was
extremely low (0.64 t 0.77 mmol. kg dry muscle-o s-l)
and represented only 11% of the initial rate. Glycolysis
was again responsible for the majority (92%) of the
produced ATP.
l

mmol/kg
dry muscle; n = 7. Values in
(in s). Quadriceps
femoris muscles were
with each contraction
lasting
1.6 s and
phosphocreatine;
Cr, creatine.

2. Muscle adenine nucleotide and IMP

concentrations during intermittent electrical
stimulation under anaerobic conditions
TABLE

No. of Contractions

Rest
ATP
ADP
AMP
TAN
IMP

24.81t0.80
2.92t0.06
0.33t0.05
28.06t0.78
0.54t0.08

16 (25.6)

32 (51.2)

48 (76.8)

64 (102.4)

21.7621.23
3.59t0.25
0.44t0.09
25.79t1.47
2.39t1.09

17.2821.26
3.71t0.40
0.4320.04
21.42t1.45
7.90t1.52

15.48rtO.61
3.92t0.19
0.38t0.03
19.78k0.58
10.61t1.90

14.04tl.19
3.59k0.24
0.45t0.06
18.08tl.25
11.63t1.60

Values are means t SE in mmol/kg

dry muscle; n = 7. Values in
parentheses
indicate
duration
(in s). TAN, total adenine nucleotides;
IMP, inosine monophosphate.
ATP and ADP were analyzed
enzymatically; AMP
and IMP were analyzed
with high-pressure
liquid chromatography
(see METHODS).
TAN = ATP + ADP + AMP.

stimulation produced a slight additional decrease such

that 93% of the available PCr store was utilized following
48 and 64 contractions. Changes in Cr were reciprocal to
PCr changes and the total Cr content remained constant
throughout the stimulation period (Table 1). Muscle
lactate content increased -30-fold during the entire
stimulation period (Table 1, Fig. 2). The largest increase
occurred during the initial 16 contractions, whereas minimal lactate accumulated between contractions 48 and
64
Concentrations of ADP and AMP increased slightly
during the initial 16 contractions and remained elevated
for the entire stimulation period (Table 2). Increases in
IMP content were stoichiometrically equivalent to decreases in ATP, indicating a degradation of adenine
nucleotides via the AMP deaminase reaction. Consequently, total adenine nucleotides decreased as a function
of the decreases in ATP, reaching 64% of the resting
concentration following 64 contractions.
The occlusion of muscle blood flow during electrical
stimulation provided a closed metabolic system, limiting
the production of ATP to anaerobic processes and preventing the escape of metabolites from the muscle.
Therefore, the ATP turnover rate for each 16 contraction
periods (25.6 s) was calculated from the changes in
muscle metabolites; ATP turnover rate (mmol . kg dry
muscle-l s-l) = lLj(A[lactate])
+ A[PCr] + [Z(A[ATP])
- A[ADP]/25.6 s.The small amount of ATP production
or utilization associated with the accumulation of additional metabolites, such as pyruvate and glyc-3-P, were
neglected as they represented ~2% of the ATP turnover
rate in all cases.

DISCUSSION

This study estimated the ATP turnover rate in electrically stimulated skeletal muscle under anaerobic conditions. The stimulation period was extended to 100 s of
contraction time and the contribution of the glycolytic
system to total ATP production was determined.
Electrical stimulation was used to induce muscular
contraction, since a constant contraction stimulus could
be delivered to the muscles for a predetermined length
of time, independent of volitional effort. This minimized
the possibility of central fatigue-limiting muscular performance and metabolism as may occur in normal exercise tasks of maximal intensity where the subject vol- 100

-80

<

ATP

co

.-6(-J;

.5
08

-40

-20

2
Q)
2
9

25.6
Contract

51.2
ion

76.8
t ime,

102.4

set

FIG. 3. Muscle
ATP turnover
rates and force production
during
intermittent
electrical
stimulation
at 20 Hz with an occluded circulation. Energy
contributions
from phosphocreatine
(PC,) and ATP utilization and glycolysis
are indicated.

614

SKELETAL

MUSCLE

ANAEROBIC

untarily works to exhaustion. The muscles were stimulated at a frequency of 20 Hz in an attempt to avoid the
fatigue reported to occur at higher frequencies (50-100
Hz). The cause of this high-frequency fatigue is believed
to be impaired neuromuscular transmission or failure of
membrane excitation (9). We also used intermittent electrical stimulation to increase the energy demand on the
muscles, as ATP is required to pump Ca2+back into the
sarcoplasmic reticulum during the relaxation process and
to reactivate the muscle to a high force state. Therefore,
the stimulation protocol was designed to maximize the
possibility that fatigue or low force production would
coincide with exhaustion of the muscles ability to produce ATP anaerobically.
The ATP turnover rate during the initial 16 contractions (25.6 s) in the present study was 6.12 t 0.56 mmol
kg dry muscle- s-l. Glycolysis provided 58% of the total
ATP, PCr degradation 40%, and partial depletion of the
ATP store 2% (Fig. 3). These findings compare favorably
with estimates of ATP turnover of 6-8 mmol kg dry
muscle-lo s-l during 30 s of maximal isokinetic cycling
and sprinting (6, 16). In dynamic exercise, glycolysis
accounted for 60-80% of the total ATP and PCr 20-40%.
The ATP turnover rate during 25 s of continuous
stimulation at 20 Hz was previously estimated at 5.1
mmol kg dry muscle- s-l (12). Comparing the ATP
turnover rates during 25 s of intermittent and continuous
electrical stimulation revealed that the energy cost of
activating and relaxing the muscles 16 times was -20%
higher than during one continuous contraction (present
study, 12). This occurred in spite of the fact that initial
force productions were similar and force decreased less
after 25 s of continuous (95% of initial) vs. intermittent
(87.6% of initial) stimulation. Consequently, the increased ATP requirement during intermittent work appeared to be the energy cost associated with repeatedly
activating and relaxing the muscles.
Following PCr depletion, both force production and
ATP turnover rates rapidly decreased during contractions
17-48 (Fig. 3). It is not known whether the fatigue
experienced during this period was largely biochemical
as the rate that ATP could be produced was now solely
dependent on glycolysis. In addition to the lack of PCr,
glycolytic ATP turnover decreased to 55-60% of the rate
during the initial 16 contractions. The reduced glycolytic
rate possibly resulted from the substantial increases in
muscle acidity which accompanied the stimulation (21).
Increased acidosis may have reduced the activity of regulatory glycolytic enzymes directly and/or interfered
with excitation-contraction
coupling, thereby reducing
the ATP requirements. The potential inhibiting effects
of lowered muscle pH on energy metabolism are discussed in the accompanying paper (21).
During the final 16 contractions the ATP turnover
rate decreased to 0.64 mmol kg dry muscle- s-l or 11%
of the rate during the initial 16 contractions. Glycolysis
provided the majority of the produced ATP but the
absolute ATP turnover from glycolysis was only 17% of
the rate in the initial 16 contractions. Muscle pH was
6.45 at the beginning of this period, possibly accounting
for the low glycolytic ATP production (21). PCr was
l

ENERGY

RELEASE

already depleted at the onset of the final period and ATP

fell slightly from 62 to 57% of the resting level. Despite
what appears to be one of the largest decreasesin muscle
ATP concentration reported in healthy men, no occurrences of rigor were found. The mean ATP concentration
after 64 contractions was 14.04 mmol kg dry muscle-1o
S - with a range of 8.56-18.41. In the subject with the
largest decrease, ATP fell to 33% of the resting content.
Sahlin et al. (17) electrically stimulated rat muscle
poisoned with the glycolytic inhibitor iodoacetic acid
(IAA) and reported the development of rigor when ATP
fell to -40% of the resting concentration. In nonpoisoned
control muscle at fatigue, the ATP content was reduced
by 25% and rigor did not occur. The authors suggested
that rigor development in IAA-poisoned muscle was the
result of the near depletion of ATP (17). In the nonpoisoned muscle the accompanying acidosis appeared to
prevent a critical ATP decrease and rigor development
by inhibiting muscular contraction. The findings of the
present study are consistent with these suggestions as
muscle pH was reduced to 6.43 following 64 contractions
(21). Such extreme acidosis may have inhibited muscular
contraction preventing ATP from decreasing to critically
low levels consistent with rigor development.
Previous investigations have reported reasonable correlations between decreased force production and ATP
turnover rates during intense muscular activity (8, 12).
However the findings of Hultman and Sjoholm (12)
suggested an increased efficiency of contraction (expressed as force production for a given ATP turnover
rate) as continuous electrical stimulation at 20 Hz was
prolonged past 10 s. Despite the general agreement between decreased force production and ATP turnover
rates found in the present study, the muscles appeared
more efficient during contractions W-32 (Fig. 4). Crow
and Kushmerick (7) reported a similar phenomenon in
contracting fast-twitch mouse muscle. At the onset of
electrical stimulation the energy cost for a given force
was three times higher in fast-twitch vs. slow-twitch
l

loo-

80-

u) 60Q)
=I
5
Ti
t 40..Ic
z
ox

20r\
ATP turnover

rate

O0

25.6
Contraction

4. Muscle
(o-- -0) expressed
contractions.
FIG.

time,

force production
(u)
as a percent
of values

set

and ATP turnover

rates
measured
during
initial
16

SKELETAL

MUSCLE

ANAEROBIC

muscles. Following 15 s of contraction the energy cost

was unchanged in slow-twitch muscles but reduced to
50% of the initial rate in fast-twitch muscles. The authors suggested their findings were possibly due to a
reduction in the rate of actin-myosin turnover (7). A
similar occurrence in human muscle could explain the
present findings as approximately 50% of the fibers in
the vastus lateralis are fast-twitch (19).
However a direct comparison between ATP turnover
and externally measured force production is complicated
since force production was recorded as the peak force
obtained during each 1.6 s contraction and not the tension-time integral. In addition, as stimulation is prolonged, relaxation time increases from -50 ms to values
above 150ms (4). The recorded,external force during 1.6s contraction at 20 Hz is the summation of the force
produced by each of the 32 impulses delivered once every
50 ms. A longer relaxation time therefore means that
force production by each impulse is held longer reducing
the total energy need.
In summary, significant glycolytic ATP production
during electrical stimulation was maintained during the
initial 48 contractions (76.8 s). Approximately
90, 55,
and 50 mmol of ATP/kg dry muscle were produced
during the initial three 16 contraction periods, respectively. During the final 16 contractions only 15 mmol of
ATP were regenerated through glycolysis.
The authors thank the entire staff of the Department of Clinical
Chemistry II for excellent collaboration in this investigation.
This work was supported by grants from the Swedish Medical
Research Council (02647), the Swedish Work Environment Fund (81Ol73), and the Swedish Sports Research Council. L. L. Spriet was the
recipient
of a Postdoctoral Research Fellowship from the Medical
Research Council of Canada.
Address for reprint requests and present address: L. L. Spriet, School
of Human Biology, University of Guelph, Guelph, Ontario NlG 2W1,
Canada.
Received 22 April 1986; accepted in final form 4 September 1986.
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3.

BERGSTROM,
J., R. C!. HARRIS,E. HULTMAN,AND L.-O. NORDESJO.Energy rich phosphagens in dynamic and static work. In:

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ENERGY

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