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Biochemistry
of
exercise
Regulation in Metabolism Group Colloquium Organized by E.
A.
Newsholme (Oxford) and P.
H.
Sugden
(London) and Edited by P.
H.
Sugden, 637th Meeting held at the University of Birmingham,
18-20
December
I990
Energy metabolism and fatigue during intense muscle contraction
Eric Hultman, Paul
L.
Greenhaff,* Jan-Ming Rent and Karin Soderlund
Department
of
Clinical Chemistry
II,
Huddinge University Hospital, Karolinska Institutet,
S-
I4
I
86
Huddinge,
Sweden
Introduction
Intense exercise results in a marked acceleration of
the ATP degrading processes, including increases
in the activities of myosin, Ca2+- and Na+-,
K+-
ATPases.
A
continuation of exercise at the required
intensity necessitates a corresponding increase in
the processes which re-phosphorylate the ADP
formed. Rapid anaerobic ADP re-phosphorylation
occurs at the beginning of exercise when the
O2
availability in muscle is low; however, even when
O2
transport to the muscle is maximal, the rate of
oxidative
ADP
phosphorylation
is
limited. Evidence
suggests that
80-90%
of the ATP re-synthesized
during near maximal contraction is derived from
anaerobic processes.
Indirect estimates of the anaerobic capacity of
skeletal muscle can be obtained with the use
of
the
02-deficit technique. The method has been used in
several studies
[
1-41. During sub-maximal exercise
a linear relationship exists between
O2
uptake and
exercise intensity. This relationship can be used to
predict the energy demand of power outputs which
utilize ATP at a rate above that achievable by the
maximal
O2
uptake of the exercising muscle. The
O2
deficit during intense exercise can then be esti-
mated as the difference between energy demand
and the aerobic energy production.
In a recent study by Bangsbo
et
al.
[S],
the
contribution made by anaerobic and aerobic
sources to energy production, calculated from the
O2
deficit, was found to be 80%/20% in the initial
30
s,
45%/55%
from 60 to 90
s
and
30%/70%
from 120 to 192
s.
The work intensity in this study
Abbreviation used: PCr, phosphocreatine.
*School
of
Sport
and
Exercise Science,
University
of
Birmingham, Birmingham
B
15
2TT,
U.K.
TWashington University School
of
Medicine,
Box
81 13,
St Louis, MO
63
1
10,
USA.
corresponded to 130% of
V,,,,,
and was main-
tained for a duration of 192
s.
Muscle tissue
samples were also obtained during this study and,
from the accumulation of muscle metabolites, the
contribution made by anaerobic metabolism to
energy production was calculated. There was good
agreement between the two methods in the esti-
mated anaerobic energy production.
The exercise studies discussed below deal
with muscle contractions of an even higher intensity
(near maximal intensities with durations of
1.3-30
s).
The contribution of oxidative metabol-
ism to ATP production in this situation will prob-
ably be much lower than the
20%
observed in the
study by Bangsbo et
al.
[
51.
Anaerobic energy provision
In the 1960s, Margaria
et
al.
[6,
71
reported that
supramaximal exercise of 10-15
s
duration could
be performed without significant elevation of blood
lactate above resting conditions. The total energy
provision during this short period of exercise was
attributed to the splitting of the intramuscular stores
of ATP and phosphocreatine (Per). It was postu-
lated that only when the muscle store of PCr
became depleted was glycogenolysis activated to
provide continued ATP supply through glycolysis.
However,
it
was shown in an earlier study by
Pernow
&
Wahren
[8],
that 1 min after the termina-
tion
of
5
s
of intense contraction, the lactate content
of both arterial and deep venous blood was
increased.
The muscle-biopsy technique introduced by
Jonas Bergstrom in 1962
[9]
made
it
possible to
investigate in some detail the metabolic changes
occurring in skeletal muscle during exercise. With
the use of this technique,
it
was shown that 6.6
s
of
isometric contraction decreased the PCr content by
20% and increased lactate content by
15
mmol kg-
'
347
-
1991
Biochemical Society Transactions
348
of
dry muscle
[lo].
The same technique was used
later by a series
of
workers and confirmed the
above finding (Table 1). Boobis
et
al.
[
131
reported
a
marked increase in muscle lactate concentration
after
6
s
of cycling at
a
high power output. The PCr
concentration in the post-exercise biopsy sample
was
35%
lower than the value measured at rest.
Jacobs
et
al.
[
14,
191
systematically examined the
question whether anaerobic glycolysis started
before the depletion of the muscle PCr store. They
showed a lactate accumulation
of
51
mmol kg-' of
dry
muscle and a PCr decrease of
60%
after
30
s
of
maximal dynamic exercise. Furthermore, a high
accumulation of lactate had already occurred after
10
s
of
exercise. Similar results were reported by
Jones
et
al.
[15]
after
10
s
of isokinetic exercise
(Table
1).
Another way to study the metabolism of
contracting muscle
is
to stimulate the muscle elec-
trically. The muscle blood flow to the quadriceps
femoris muscle can be occluded, inhibiting trans-
port to and from the muscle compartment. In tan-
dem with the muscle-biopsy technique, this
provides a versatile method to investigate the utili-
zation
of
substrates and accumulation of products
during muscle contractions of varying durations
and intensities.
A near-maximal contraction intensity can be
Table
I
Rates of anaerobic ATP provision from PCr degradation and glycolysis during intense contraction
Type of exercise
ATP
production
(mmol
kg-'
s-')
from:
Duration
(4
PCr glycolysis Ref.
Intermittent electrical stimulation.
50
Hz
occluded circulation
Intermittent electrical stimulation.
50
Hz
occluded circulation
Isometric contraction
Cycling
Cycling (male)
Cycling (female)
lsokinetic cycling
60
revlmin
I40 revJmin
Cycling
lsokinetic cycling
Running
Cycling
Running
0-
I
.28
0-2.56
0-5
0-10
10-20
20-30
0-30
0-6.6
0-17.1
0-6
0-30
0-10
0-30
0-10
0-30
0-10
0-30
0-10
0-30
0-30
0-30
0-30
0-30
0-30
9.0
5.0
5.3
4.2
2.2
0.2
2.
I
3.5
3.8
4.9
I
.9
-
-
-
-
5.
I
I
.4
4.4
0.7
2.0
I
.4
I
.9
I
.3
I
.9
2.0
[I
11
4.4
[I21
5.3
4.5
4.5
2.
I
3.7
3.5
4.2
4.8
4.0
6.0
3.4
2.9
2.
I
8.0 ~51
5.8
9.3
6.5
4.4 [I61
3.8
[I81
4.
I
POI
5.9
~71
2.6 ~91
Volume
19
Biochemistry
of
Exercise
achieved using a stimulation frequency of 50 Hz. At
this frequency, a stimulation for 1.28
s
was enough
to
produce a PCr degradation of 11 mmol kg- of
dry muscle and a lactate accumulation of 2 mmol
kg-
'
of dry muscle
[
113. When the contraction time
was increased to 2.56
s,
the PCr content fell further
and the lactate accumulation amounted to
8.5
mmol
kg- of dry muscle.
During
5
s
of stimulation of the quadriceps
muscle group at a frequency of 50
Hz
with muscle
blood flow occluded, the PCr utilization rate was 5.3
mmol
s-l
kg-l. With continued stimulation, the
rate decreased progressively averaging
2.2
mmol
s-l
kg-' between the 10th and 20th second of
contraction and 0.2 mmol
s-'
kg-' between the
20th and the 30th second of contraction. The
anaerobic energy provision from glycolysis was
4.5
mmol of ATP
s-l
kg-l during the initial 20
s,
but
decreased thereafter to 2.1 between the 20th and
30th second of contraction. Force generation
declined during the first 20
s
of
contraction to
80%
of the initial value and decreased further to about
60% of the initial value after 30
s
of contraction
A series of similar studies has been per-
formed involving different types of maximal
dynamic exercise (Table 1). In some of these
studies, biopsy samples were obtained after 6-10
s
of exercise and then again after 30
s
[13, 151. The
PCr degradation rate was very high initially,
decreasing the PCr store in the muscle by more
than
50%
during the first 10
s
of contraction. The
rate of ATP provision from glycolysis showed a
similar pattern of change with a high initial rate
during the first 10
s
of contraction, decreasing
significantly as exercise was continued (Table 1).
It
is
obvious that the rate of ATP forma-
tion from both PCr degradation and glycolysis
decreases with the continuation of the intense
contraction. Whether this decrease is caused
directly by the observed reduction in muscle force
generation, i.e. a decreased demand for ATP re-
synthesis or by an insufficient ATP re-synthesis
rate, resulting eventually in decreased capacity to
generate force, cannot be determined from these
studies. It is interesting to note, however, that the
glycogen store in the whole muscle sample is
still
sufficiently abundant to fuel ATP formation, while
the PCr store is practically depleted.
[121.
Energy metabolism
in
type
I
and
type
II
fibres
The quadriceps femoris muscle
of
man
is
com-
posed of two principal fibre types. These have been
characterized as type I (slow contracting, highly
oxidative and fatigue resistant) and type
II
(fast
contracting, highly glycolytic and rapidly fatigued)
fibres. The two fibre types have different maximal
rates of ATP utilization and also different capacities
to produce initial and sustained power output (for
references see [21]). Most of the studies investigat-
ing the functional and biochemical differences
between the two fibre types have been performed
using rat soleus (composed predominantly of type I
fibres) and gastrocnemius (composed predomi-
nantly of type
11
fibres) muscle. Such studies have
demonstrated that the comparatively higher initial
isometric force generating capacity of predomi-
nantly fast-contracting muscle
is
accompanied by a
corresponding high rate of ATP utilization and
glycolysis [22-251. In a study by Faulkner
et
al.
[26], involving the stimulation of bundles of human
skeletal muscle fibres,
it
was estimated that the peak
power output of type I1 fibres could be 3-4 times
higher than that of type I fibres. The authors also
presented evidence demonstrating that the initial
power output of the fast-twitch motor units could
not be sustained for longer than a few seconds after
the initiation of contraction, but was well maintained
in type I motor units. The calculated time-related
force-power in Faulkner's study was very similar to
the change in force measured during electrical
stimulation
of
the knee extensors in man
[
12,271.
In an attempt to relate the energy metabolism
of individual type I or type I1 fibres to the decline in
whole muscle force during stimulation, muscle-
biopsy samples were obtained before and after 10
and 20
s
of
intermittent electrical stimulation (1.6
s
contraction, 1.6
s
rest, at a frequency of 50
Hz)
to the
quadriceps muscle group with open circulation.
After freeze-drying, fragments of individual muscle
fibres
(n
=about
50)
were dissected free from each
biopsy sample. After weighing and characterization,
fibres of each type were analys'ed for single-fibre
PCr and ATP concentrations. The PCr and ATP
concentrations after 10 and 20
s
of stimulation are
shown in Fig. l(a). During the first 10
s
of stimula-
tion, the rate of PCr degradation in type I1 fibres
averaged 5.3 mmol
s-l
kg-' of dry muscle. The
corresponding rate in type I fibres was 3.3 mol
s-'
kg-I of dry muscle. During the period of 10-20
s
stimulation, the rate of PCr degradation in type I1
decreased to 2.1 mmol
s-l
kg-' of dry muscle and
in type I fibres to 2.8 mmol
s-l
kg-I of dry muscle.
At the end of the stimulation period the PCr store in
type
11
fibres was nearly totally depleted. It
is
there-
fore plausible to suggest that continued contraction
beyond 20
s
is
limited to the use of PCr at a rate
349
1991
Biochemical Society Transactions
Fig.
I
PCr and ATP concentrations after
10
s
and
20
s
of stimulation
350
(a)
Whole muscle force
(x)
and single-fibre PCr
(A.
A)
and ATP
(0,
.)
concentrations
at rest and after
10
and
20
s
of intermittent electrical stimulation at
50
Hz.
Open symbols
denote type
I
fibres; closed symbols denote type
II
fibres.
(b)
Glycogenolytic rates in type
I
and type
II
fibres during the
20
s
stimulation period. The open bar denotes type
I
fibres;
the closed bar denotes type
I1
fibres.
I
3
40-
10
.-
-
M
T
E
Y
I
I
P)
0-
0.
Y
0
-0
I0
20
Y
Stimulation time
(5)
corresponding to that eventually formed by mito-
chondrial
ADP
phosphorylation.
The glycogen content of single fibres obtained
from the same muscle-biopsy samples was also
determined and the glycogenolytic rates of the two
fibre types were estimated (Fig.
lb).
The very high
glycogenolytic rate of 6.3 mmol
s-l
kg-I
of
dry
muscle in type I1 fibres contrasted with the negli-
gible rate
of
0.6 mmol
s-'
kg-I of dry muscle in
type
I
fibres. This finding is in agreement with
animal studies demonstrating a very high capability
for anaerobic energy supply via glycogenolysis in
type IIa and IIb skeletal muscle fibres
[28].
Recent
histochemical studies of human skeletal muscle,
obtained after repeated bouts of short-term maxi-
mal exercise (about
200%
Vo,,,,x,),
suggest that the
glycogen degradation rate
is
higher in type
I1
fibres
compared with type I fibres during this type of
exercise
[29].
The measurements made, however,
gave only a semiquantitative estimation of the rate
of
glycogen degradation.
In an attempt to study the glycogenolytic
mechanism
of
the
two
fibre types further, we stimu-
lated both legs of five subjects intermittently at a
frequency of
50
Hz
for a total stimulation time of
30
s,
with blood flow intact. One leg was stimulated
without simultaneous adrenaline infusion and the
remaining leg
was
stimulated with continuous infu-
sion of adrenalin
(0.14
pg of adrenalin min-l kg-'
body
wt.).
A
further study using the same stimula-
tion protocol was undertaken, but on this occasion
Fig.
2
The glycogenolytic rate in type
II
fibres
is
unchanged
by adrenaline infusion and only slightly increased by
occlusion of blood flow during the contraction
Glycogenolytic rates in type
I
(0)
and type
II
(.)
fibres during
30
s
of intermittent electrical stimulation at
50
Hz.
Two experi-
ments were performed, one without and with adrenaline
infusion in the same subjects and the other with circulation
(circ.) occluded in
a
separate group of subjects.
10-
T
Open circ. Open circ.
+
Occluded circ.
adrenaline
blood flow to the leg was occluded. The occlusion
was initiated 30
s
before the start of the stimulation
and continued during the stimulation period. The
results are shown in Fig.
2.
The glycogenolytic rate
in type I1 fibres was unchanged by adrenaline infu-
sion and was only marginally increased by occlu-
sion of the blood flow during the contraction. This
finding could be interpreted to mean that the rate of
glycogenolysis
is
already close to maximum in type
Volume
19
Biochemistry
of
Exercise
II
fibres during stimulation when circulation
is
intact, and thus it
is
not possible to increase the rate
markedly by adrenaline infusion or ischaemia. This
suggestion is supported by the finding that the rate
of glycogenolysis recorded in these fibres was close
to the apparent
V,,,
of phosphorylase measured in
type I1 fibres
[
301.
In type I fibres, however, both-adrenaline infu-
sion and ischaemia increased the glycogenolytic
rate above the extremely low rate recorded during
stimulation with circulation intact and without
adrenaline infusion
(0.15
pg min-' kg-I). The
glycogenolytic rate during contraction in type I
fibres was increased 6-fold by adrenaline infusion
and
11-fold
by ischaemia. Even during ischaemic
stimulation, however, the rate was still only half of
that observed in type I1 fibres, but is in good agree-
ment with the estimated maximal activity of the
phosphorylase in type I human fibres
[
301.
It is generally accepted that the primary
determinant of the glycogenolytic rate during
contraction
is
the degree of transformation of in-
active phosphorylase
b
to the active
a
form. How-
ever,
it
has also been demonstrated that the activity
of phosphorylase
a,
and thereby the rate of glyco-
genolysis,
is
also dependent upon the availability of
inorganic phosphate (Pi) and AMP
[31-331.
Addi-
tionally, a high accumulation of IMP will result in
the activation of phosphorylase
b
[
341.
The most potent allosteric activator of phos-
phorylase
a
is
AMP
[31],
the concentration of
which
is
dependent on the rate of ADP formation in
relation to its rate of re-phosphorylation. It has been
recently demonstrated
[33],
that the glycogenolytic
rate of skeletal muscle is directly related to the
intensity of the contraction and thus to the rate of
ATP turnover. In this particular study, the muscle
was stimulated electrically with frequencies from
15
Hz
to
50
Hz
and the mole fraction of phosphorylase
a
was kept at
85-90%
of
total by continuous
adrenaline infusion. The glycogenolytic rate varied
from
0.5
to
3.5
mmol kg-' min-'. It was suggested
that as the availability of free AMP probably
increased with the increased ATP turnover rate, the
free AMP concentration of the muscle was control-
ling the glycogenolytic activity of phosphorylase
a.
During the present series of experiments
it
is
probable that the transformation of phosphorylase
b
to
a
was complete in type I1 fibres, as no further
increase in glycogenolytic rate was observed in
these fibres after adrenaline infusion. As fast-twitch
muscles are known to have a high rate of ATP turn-
over
[21,
221
and a high capacity to generate AMP
[35],
it
is
also
probable that the rapid rate of glyco-
genolysis recorded in these fibres is attributable to a
free AMP-induced activation of phosphorylase
a.
This is supported by the findings that the decline in
ATP in type
11
fibres was close to
5
mmol kg-'
when circulation was open and was in excess of
10
mmol kg-I when circulation was occluded. The
decrease in ATP during intense contraction has
been shown to result in a stoichiometric rise in IMP
formed from the accumulation of free AMP.
The lower ATP turnover rate of type I fibres,
together with the oxidative re-synthesis of formed
ADP, explains the observed low rate of glycogeno-
lysis in these fibres with open circulation. It
is
logi-
cal also that the increased rate of glycogenolysis
observed in these fibres following adrenaline infu-
sion was attributable to an increased degree of
phosphorylase transformation. When the blood
flow was occluded, the oxidative re-synthesis
of
ADP was inhibited resulting in an increase in ADP
availability as substrate for adenylate kinase. It is
postulated that the resulting increased formation of
free AMP was
of
a sufficient quantity to activate
phosphorylase
a.
The marked decrease in ATP in
type I fibres during occlusion (about
6
mmol kg-')
supports this suggestion. Furthermore, the recently
reported
[36]
increase in calculated free AMP in
ischaemic slow-twitch rat muscle was of a sufficient
magnitude (about
5
pmol
1-
of intracellular water)
to support the above hypothesis. In accordance,
it
is
also probable that the slightly higher rate of glyco-
genolysis observed in type I1 fibres during occlu-
sion can be attributed to the activation of
phosphorylase
a
in type IIa fibres via an ischaemia-
induced increase in the availability of free AMP.
A
marked increase in free AMP available has been
reported in contracting oxidative fast-twitch skeletal
muscle after the onset of occlusion
[35].
The rapid
decrease in PCr in both fibre types suggests that the
availability of
Pi
is not a limitation to glycogen phos-
phorylation.
Possible relationship between energy
metabolism and fatigue
Force generation (measured as power output
during cycling or as contraction force during elec-
trical stimulation) showed a similar pattern of
change during the
30
s
work periods in the studies
outlined in Table
1.
In all studies, the force had
decreased by about
40%
after
30
s
of work, but the
shape of the force decay curve varied with the type
of exercise performed. The force generation during
the initial
20
s
of electrical stimulation in the
present series
of
studies is shown in Fig.
1.
Parallel
with the decreasing force generation
is
a decrease in
35
I
1991
Biochemical Society Transactions
352
anaerobic
ATP
provision both from PCr degrada-
tion and from glycolysis (Table
1).
The fastest drop
in energy provision
is
from the PCr store, which
during the first second of contraction apparently
compensates for the short delay in glycolytic ATP
production. This
is
especially the case in type
11
fibres, where after
10
s
of contraction
70%
of the
PCr store is utilized and after
20
s
the store is near
depletion. At this point it would appear that glyco-
genolysis-glycolysis has already reached maximal
activity in type
I1
fibres, and thus cannot increase
further in spite of an abundant availability of glyco-
gen. There
is,
therefore, apparently no mechanism
by which the type
I1
fibres can increase their glyco-
lytic ATP re-synthesis rate to compensate for the
lack of available PCr. Taken together, this means
that
if
the force had been kept constant an im-
balance between ATP utilization and ATP re-
synthesis would have occurred. This imbalance
could consequently be the reason for the decreased
force production, i.e. a fatigue mechanism in this
type of intense exercise.
Conclusion
The initial high force generation during near-
maximal contraction force seems to rely mainly on
type
I1
fibre contraction, utilizing both PCr degrada-
tion and glycolysis for ATP re-synthesis. The rapid
utilization of PCr limits the ATP provision from
this store after
10
s
of stimulation. The glycogeno-
lysis-glycolysis pathway is working at a maximum
rate already within the first second and cannot be
increased to compensate for the falling rate of ATP
re-synthesis from PCr. Type
I
fibres show a very
low glycogenolytic rate, but also in these fibres the
PCr store is rapidly utilized. The large difference in
glycogenolysis-glycolysis
rate between the two
fibre types depends both on differences in total
phosphorylase activity and on differences in ATP
turnover rates, which probably determine the
glycogenolytic activity of phosphorylase. This regu-
lation
is
suggested to be mediated via the sarco-
plasmic concentration of free AMP. The free
AMP
concentration
is
itself determined by the rate
of
ADP
formation and re-phosphorylation and also by
the activity of AMP deaminase, which
is
known
to
be high in type
I1
fibres and activated by acidosis.
The increasing acidosis during intense contraction
could thus partly explain the observed fall in the
glycogenolytic rate of these fibres resulting from a
decreased AMP activation of phosphorylase
a.
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Control of energetic processes in contracting human skeletal muscle
Kent
Sahlin
Department
of
Clinical Physiology, Karolinska Institute, Huddinge University Hospital,
S-
I41
86
Huddinge, Sweden
Introduction
Skeletal muscle is unique in its ability to switch
rapidly from a low- to a high-energy turnover, and
this necessitates an intricate system for control of
the flux through the energetic pathways.
The ultimate process for ATP formation in
aerobic cells is the oxidation of different substrates
with
O2
being the final electron acceptor. For a
limited period of time ATP can also be produced
through non-oxygen requiring processes [i.e. for-
mation of lactate and breakdown of phospho-
creatine (PCr)]. The maximal rate at which ATP
can be formed by the anaerobic processes is at least
two
times higher than ATP formation by oxidative
phosphorylation. However, the amount of energy
that can be formed is restricted by the cellular con-
tent of PCr and by feedback inhibition of glycolysis
by
H+,
which is formed stoichiometrically with
lactate. Formation of ATP through the anaerobic
processes is therefore of great importance during
short bursts of high-intensity exercise or during
ischaemic conditions, but negligible in terms of
energy equivalents during sustained exercise.
The present paper will discuss some general
aspects of how the energetic processes are con-
trolled in skeletal muscle during exercise. Special
emphasis will be placed on the role of adenine
nucleotides and
0,
availability.
Abbreviations used:
PCr,
phosphocreatine; Cr, creatine;
CK, creatine kinase; AK, adenylate kinase; PFK,
phosphofructokinase; IMP, inosine monophosphate.
A
critical note on the calculation of
ADP
from the creatine kinase
equilibrium
The concentrations of the adenine nucleotides have
a major influence on the energetic processes, the
control being exerted both through allosteric and
substrate/product effects. Evidence has been pre-
sented
[
1,
21
that changes in the PCr/creatine (Cr)
ratio in skeletal muscle are not associated with simi-
lar changes in the ATP/ADP ratio and it was sug-
gested that the adenine nucleotides are functionally
compartmentalized in the cell
[l,
21.
From these
studies and others, it was concluded that a large
part
(>
90%)
of the cellular content of
ADP
and
AMP is bound to proteins or otherwise sequestered
in the cell
[3,
41.
The major binding sites for
ADP
are considered to be actin and myosin, but since
brain tissue and liver exhibit a similar degree of
functional compartmentation, it was suggested that
part of the inactive
ADP
was located within the
mitochondria
[4].
Extraction of muscle tissue with
ethanol/citrate and perchloric acid has shown that
the proportion of ADP bound to proteins
is
about
50%
of
the total cellular
ADP
content
[S].
Post-
mortem changes in the adenine nucleotides suggest
a similar amount
of
ADP bound to proteins
[6].
The fractions of ADP and AMP which are not
bound or otherwise sequestered (i.e. ADP,, and
AMP,,,) are the metabolically active forms and are
conventionally calculated from the mass-action
ratios of the creatine kinase (CK) and the adenylate
kinase
(AK)
reactions:
353
1991
