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Effect of low glycogen on carbohydrate and energy
metabolism in human muscle during exercise
MARK
K. SPENCER,
Department
ZHEN
of Kinesiology,
YAN,
University
AND ABRAM
of Illinois,
Spencer, Mark K., Zhen Yan, and Abram Katz. Effect
of low glycogen on carbohydrate and energy metabolism in
human muscle during exercise. Am. J. Physiol. 262 (Cell Physiol. 31): C975-C979, 1992.-The
effect of preexercise muscle
glycogen content on the metabolic responses to exercise has
been investigated. Seven men cycled at a work load calculated
to elicit 75% of maximal oxygen uptake [2ll& 17 (SE) W] on
two occasions: 1) to fatigue (37.2 t 5.3 min) and 2) at the same
work load and for the same duration as the first. Biopsies were
obtained from the quadriceps femoris muscle before and after
exercise. Before the first experiment, muscle glycogen was
lowered by exercise and diet, and before the second experiment,
muscle glycogen was elevated. In the low-glycogen condition
(LG), muscle glycogen decreased from 182 ? 15 at rest to 7 &
4 mmol glucosyl units/kg dry wt at fatigue, while in the highglycogen condition (HG), glycogen decreased from 725 & 31 at
rest to 353 t 53 mmol glucosyl units/kg dry wt at the end of
exercise. Hexose monophosphates were not increased after LG
exercise but increased approximately fivefold after HG exercise.
Lactate increased more during HG exercise (LG = 16 & 5, HG
= 61 k 7 mmol/kg dry wt; P 5 O.OOl), whereas IMP increased
more during LG (LG = 2.8 k 0.6, HG = 0.9 & 0.2 mmol/kg dry
wt; P 5 0.05). The increases in the sum of tricarboxylic acid
cycle intermediates (TCAI; citrate + malate + fumarate) and
acetylcarnitine (which is in equilibrium with acetyl CoA) were
significantly greater during HG exercise (P 5 0.05). It is suggested that the increase in IMP during LG exercise reflects
larger increases in free ADP and AMP at the enzymatic site
(AMP deaminase) during the contraction. The larger increases
in ADP and AMP during LG exercise are considered necessary
to activate phosphofructokinase, the TCA cycle, and oxidative
phosphorylation under conditions in which glycolysis does not
provide adequate substrate for formation of acetyl CoA and
TCAI.
glycogenolysis; hexose phosphates; adenine nucleotides; acetylcarnitine; inosine monophosphate; fatigue; lactate; aspartate;
glutamate; alanine; malate; citrate; fumarate
SUBMAXIMAL
EXERCISE
at60-80% of maximal
oxygen uptake (VO 2max),fatigue is associated with a low
muscle glycogen content (4, 8). Recently, we have determined the time course of changes in the metabolic profile
of muscle as well as the effect of glucose ingestion on
muscle metabolism during submaximal exercise to fatigue (14,16). Our results have led to the hypothesis that
adequate glycogen stores attenuate the formation of
AMP and ADP during exercise. As a consequence, activation of AMP deaminase and loss of the adenine nucleotide pool are minimized, and a better balance between
ATP utilization and formation is maintained (14-16).
The sequence of metabolic events that is believed to
occur when carbohydrate stores are depleted during submaximal exercise is depicted in Fig. 1. If the hypothesis
is correct, then one would predict that exercising under
conditions wherein the muscle glycogen store was lowered before the exercise would result in a larger formation
of inosine monophosphate (IMP) and attenuated inDURING
0363-6143/92
$2.00 Copyright
KATZ
Urbana,
Illinois
61801
creases in hexose monophosphates (HMP) and tricarboxylic acid cycle intermediates (TCAI) vs. exercise with
a high muscle glycogen content.
To test this hypothesis, we compared the metabolic
responses of human skeletal muscle to submaximal exercise under conditions in which the preexercise muscle
glycogen contents were low and high.
MATERIALS
AND
METHODS
Subjects. Seven healthy men whose mean (range) age, height,
weight, and VO 2maxwere, respectively, 21 yr (20-22), 177 cm
(172-179), 73 kg (64-83), and 4.24 liters/min (3.53-5.07) participated in the study. The subjects were informed of the
possible risks involved before giving voluntary consent. The
experimental protocol was approved by the University of Illinois Institutional Review Board.
Experimental design. Approximately 1 wk before the experiments, VOzmaxwas determined by an incremental cycling test
on an electrically braked (rate independent) cycle ergometer
(Bosch ERG-551, West Germany). Subjects cycled in the upright position at 70 revolutions/min
to fatigue. Fatigue was
considered the point at which pedaling rate could not be maintained 250 revolutions/min.
The peak Vo2 obtained was considered to be Vo2 mBx.
The day before the first experiment, the muscle glycogen
content was reduced by a combination of exercise and diet as
previously described (15). Subjects reported to the laboratory
the next day after an overnight fast, and after they assumed
the supine position, a plastic catheter was placed in an antecubital vein and incisions were made over the lateral aspect of
the quadriceps femoris muscle of both thighs (-35% of the
distance from the superior margin of the patella to the anterior
iliac spine). Subjects then rested for ~15 min, during which
expired gases were collected and heart rate was monitored.
Thereafter, the first blood sample was drawn and muscle biopsy
was obtained (3). Subjects then cycled (70 revolutions/min)
for
2 min at a power output calculated to correspond to 50% Vo2 max
(127 t 9 W); thereafter, the work load was immediately increased to one calculated to elicit 75% V02max (211 k 17 W).
The subjects cycled at this work load to fatigue (37.2 t 5.3
min). Respiratory exchange and heart rate were determined
throughout exercise. A blood sample and biopsy were obtained
at fatigue.
For the following 3 days, subjects performed no exercise and
consumed a diet rich in carbohydrate to increase the muscle
glycogen content to high levels (HG condition) (15). The experimental protocol was then repeated with individual exercise
durations and power outputs being identical to the LG condition. During the LG treatment, the resting biopsy was taken
from the left thigh in five subjects and right thigh in two, and
the postexercise biopsies were taken from the contralateral
thigh at the same level as the resting biopsy. During the HG
treatment, the biopsy order for each subject was reversed (see
Ref. 15). All postexercise biopsies were taken while the subject
was still seated on the ergometer. The time between termination of exercise and freezing of the biopsy averaged 20 * 2 and
17 t 1 s during the LG and HG trials, respectively (P > 0.05).
0 1992 the American
Physiological
Society
c975
C976
GLYCOGEN
AND
TRICARBOXYLIC
Pyruvate
t
Decreased
2-Oxoglutarate
Decreased
Oxaloacetate
Decreased
Decreased
+
Fructose
Decreased
PFK Activity
6-P
Decreased
Glycolysis
I
4
-3
Decreased
Acetyl-CoA
TCAI
Decreased Mitochondrial
NADH Production
Activation of TCA
Cycle and Oxidative
Phosphorylation
+
. Decreased
AT
Production
4-
1
Increased
CYCLE
INTERMEDIATES
RESULTS
Decreased
Carbohydrate
Decreased
ACID
ADP
1
Decreased
PCr
Deaminase
Increased
IMP + NH2
Fig. 1. Scheme proposing the sequence of metabolic events in muscle
during exercise when carbohydrate stores are depleted. See text and
Refs. 14 and 16 for further details.
Analytical methods. All biopsies were quick frozen (~2 s after
excision) in the needle by immersion into liquid Freon and
maintained at its melting point (-150°C) with liquid NP. The
biopsies were stored in liquid Nz until preparation for analysis,
at which time they were lyophilized, dissected free of solid
nonmuscle constituents (connective tissue and blood), powdered, and thoroughly mixed. One aliquot of powder was extracted and analyzed for metabolites by enzymatic methods (2,
12) as previously described (16). Reverse-phase high-performance liquid chromatography was used to quantify adenine nucleotides, their catabolites, and NAD’ (17). Except for lactate,
pyruvate, and glucose (due to their extracellular presence),
muscle metabolites were normalized to the mean total creatine
content (sum of phosphocreatine concentration ([PC,]) and
creatine concentration ([Cr])) for the whole material (111.9 &
2.5 mmol/kg dry wt) to correct for variability in solid nonmuscle
constituents between biopsies.
Blood was drawn anaerobically and immediately injected
into ice-cold tubes containing EDTA. The samples were left on
ice for 10 min and centrifuged at 4”C, and the plasma was
aspirated and stored at -80°C until analysis. Plasma was
analyzed for insulin by radioimmunoassay (Diagnostics Products, Los Angeles, CA), free fatty acids, glucose, and lactate, as
previously described (16).
Whole body respiratory exchange was measured by continuous collection of 30-s aliquots of expired air and analyzed for
fractional components of 02 and CO2 (Applied Electrochemistry S-3Al and CD-3A, respectively, Sunnyvale, CA). Ventilation was measured with a turbine transducer gas flowmeter
(Pneumoscan S-300, Sylmar, CA). Heart rate was monitored
by telemetry.
Statistics. Significant differences (P < 0.05) between means
were determined with Student’s t test for paired observations.
Values are reported as means t SE unless otherwise indicated.
Cardiorespiratory. Heart rate and VOW increased progressively during exercise, but the increases were attenuated during HG (Table 1). These results are consistent
with previous observations (X,16) and are probably due
to an increased carbohydrate oxidation (in HG), which
results in a greater caloric yield than fat oxidation (per
liter O2 consumed). Significant differences between
treatments for respiratory exchange and substrate utilization were found at rest and throughout exercise. After
15 min of exercise, the percent VOzrnax was 76.9 t 2.7
during HG and 81.9 t 3.3 during LG.
A&s& metabolites. The exercise and diet manipulations yielded the expected differences in the muscle
glycogen contents at rest during LG and HG (Table 2)
(15). HMPs were higher and net glycogenolysis was more
than doubled during HG exercise. Exercise during LG
resulted in virtually complete degradation of glycogen.
Glycogen was not measurable in the biopsies at fatigue
in four subjects, and the highest value in the remaining
subjects was only 23 mmol glucosyl units/kg dry wt.
Lactate content was approximately fourfold higher after
exercise in the HG group. The higher glycogenolytic rate
and lactate content in muscle indicate that glycolysis
was higher during HG exercise. Glutamate decreased
during exercise in similar fashion in both treatments,
while aspartate increased approximately threefold during
LG but was not changed after HG exercise.
Free carnitine decreased and acetylcarnitine increased
during exercise under both conditions (Table 3). However, acetylcarnitine was significantly increased in the
LG resting condition, which is probably due to increased
fat oxidation (7). The increase in acetylcarnitine from
rest to end of exercise was significantly higher with HG
(13.3 t 0.9 vs. 4.9 t 2.7 mmol/kg dry wt; P 5 0.05).
While fumarate and malate were similar at rest, citrate
was ~50% higher at rest with LG, which can also be
attributed to increased fatty acid oxidation (6). TCAI
Table 1. Cardiorespiratory
and during
variables
at rest
exercise
Duration of Exercise, min
Rest
Heart rate, beats/min
Low glycogen
High glycogen
VO2, l/min
Low glycogen
High glycogen
RER
Low glycogen
High glycogen
Carbohydrate oxidation,
g/min
Low glycogen
High glycogen
Fat oxidation, g/min
Low glycogen
High glycogen
69k4
64k3
End of
exercise
15
17824
171k2
192t3
181*2t
0.30~0.01
0.29t0.01
3.49t0.26
3.27k0.237
3.77t0.21
3.39+0.21$
0.70~0.03
0.81kO.O3*
0.83t0.01
0.94*0.01$
0.81t0.01
0.90+0.02t
0.03zk0.01
0.10~0.04’
1.67kO. 16
3.13k0.367
1.50&O. 15
2.67k0.45t
0.14zk0.01
0.07+0.01t
1.02kO.09
0.31+0.08t
1.23t0.05
0.56+0.10t
Values are means t SE from 5 to 7 subjects. RER,
exchange ratio (VCO~/VO,). End of exercise was 37.2t5.3
0.05; t P 5 0.01; $ P 5 0.001 vs. low glycogen.
respiratory
min. * P 5
GLYCOGEN
AND
TRICARBOXYLIC
ACID
CYCLE
c977
INTERMEDIATES
Table 2. Muscle contents of glycogen, glycolytic
intermediates,
and amino acids
Rest
Glycogen
Glucose
Intracellular
glucose
Glucose- 1 -P
Glucose-6-P
Fructose-6-P
Pyruvate
Lactate
Alanine
Glutamate
Aspartate
r--*1
Exercise
Low
glycogen
High
glycogen
Low
glycogen
High
glycogen
182*15
2.1t0.2
0.7OkO.17
725&31*
2.OkO.l
0.34*0.09*
7*4
1.620.2
-0.29kO.34
353+53$
9.7*1.2$
6.95*1.17?
0.08tO.03
0.77t0.19
0.19&0.04
0.05~0.01
3.4kl.l
5.2tl.l
15.4kO.7
1.4kO.l
0.07tO.01
0.78kO.05
0.17&0.01
0.1 lt0.02
4.5tl.O
10.0+1.0t
13.6kO.9
1.2t0.2
0.07~0.01
0.49kO.13
0.08t0.02
0.27t0.06
17.Ok6.2
8.7tl.7
3.8kO.3
4.3t0.8
0.24&0.03$
4.11*0.45$
0.82&0.09$
0.4320.06
60.8+6.5$
14.2kl.57
3.8k0.2
1.5kO.3"
Values are means of:SE from 6 or 7 subjects (except glycogen at rest
in low glycogen treatment; n = 4) and are given in mmol/kg dry wt,
except glycogen which is given in mmol glucosyl units/kg dry wt.
Glucose-6-P, glucose-6-phosphate.
Intracellular
glucose is calculated
from total muscle glucose minus extracellular glucose, assuming 0.3 1
of extracellular water/kg dry wt at rest and 0.52 after exercise, and the
plasma glucose concentration at the time of biopsy reflects the glucose
concentration
in the extracellular space (9). * P 5 0.05; t P 5 0.01;
$ P 5 0.001 vs. low glycogen.
Low Glycogen
High Glycogen
Fig. 2. Change in the sum of tricarboxylic
acid cycle intermediates
(TCAI; malate + citrate + fumarate) during exercise (i.e., exercise rest value). Values are means ,t SE for 7 subjects. *:P (: 0.05.
Table 4. Muscle contents of high-energy
purine
nucleotide
catabolites,
Rest
Low
glycogen
Table 3. Contents of carnitines
acid cycle intermediates
and tricarboxylic
in muscle
Rest
Total carnitine
Carnitine
Acetylcarnitine
Citrate
Exercise
Low
glycogen
High
glycogen
Low
glycogen
High
glycogen
18.0&l.&
15.2zk2.2
2.8zkO.7
0.49kO.05
0.07t0.01
0.2920.02
18.3kl.4
18.ltl.3
0.2-I-0.q
0.33kO.03"
0.06t0.01
0.24t0.04
15.2kl.2
7.6tl.9
7.7k2.4
0.62kO.09
0.58t0.10
2.11t0.28
16.8kl.2
3.3t0.4
13.5kO.9
0.69kO.09
0.73t0.07
2.5lt0.14
Fumarate
Malate
Values are means * SE from 7 subjects and are given in mmol/kg
dry wt. Total carnitine was calculated from Zcarnitine + acetylcarnitine. * P 5 0.05; t P 5 0.01 vs. low glycogen.
(citrate, fumarate, and malate) increased during exercise
in both treatments and, although not statistically significant, demonstrated a trend to be higher after exercise
with HG. However, when accounting for the higher resting citrate level, the increase in the sum of TCAI during
exercise was greater with HG (P 5 0.05) (Fig. 2). The
contents of TCAI after LG exercise are similar to those
observed after performing a similar exercise bout to
fatigue with a normal initial muscle glycogen content
(445 mmol glucosyl units/kg dry wt) (14). Exercise during
LG resulted in a lower ATP content (Table 4) and higher
contents of IMP and xanthine compared with HG, which
are consistent with previous findings (13-S).
Plasma metabolites. Plasma glucose and insulin concentrations were higher both before and after exercise
with HG (Table 5). The decrease in glucose was significantly greater with the LG treatment. Both before and
after exercise, the lactate concentration in plasma was
greater with the HG treatment. The free fatty acid concentration in plasma was higher before and after exercise
during the LG treatment.
PCr + creatine
PCr
ATP
ADP
AMP
IMP
Adenosine
Inosine
Hypoxanthine
Xanthine
NAD+
112.8k5.6
78.7k2.9
22.2kl.O
3.2kO.l
0.08~0.01
0.10~0.01
co.01
0.09~0.01
0.08t0.01
0.14*0.03
2.220.1
phosphates,
and NAD+
Exercise
High
glycogen
Low
glycogen
High
glycogen
108.5t2.3
116.7t5.7
108.4zk5.7
73.6k2.9
23.5tl.8
20.9t2.5
22.2r40.7
17.9kO.9
20.6&1.1*
3.2kO.l
3.420.1
3.520.1
0.103r0.01
0.14~0.01
0.11+0.02
0.09t0.01
2.82t0.63
0.89t0.20"
0.01~0.00
0.02*0.00
0.02,t0.01
0.12z!zO.O3 0.27zkO.04 0.2OzkO.03
0.06+0.01
0.17t0.03
0.12kO.03
0.11t0.02
0.38t0.06
0.19t0.04'
2.4tO.l
2.0tO.l
2.lkO.l
Values are means & SE from 6 or 7 subjects and are given in mmol/
kg dry wt. PCr, phosphocreatine. * P 5 0.05 vs. low glycogen.
Table 5. Plasma variables at rest and after exercise
Rest
Low
glycogen
Glucose
Insulin
Lactate
Free fatty acids
4.71t0.11
6tl
0.74t0.04
0.80t0.10
Exercise
High
glycogen
Low
glycogen
High
glycogen
5.55+0.11$
12t3*
0.96t0.07*
0.35+0.05t
3.54t0.30
3tl
5.33t0.80
0.78kO.10
5.22ko.lot
6tl”
8.05kO.50$
0.25-+0.04$
Values are means & SE from 7 subjects and are given in mM except
for insulin which is in pU/ml. * P 5 0.05; t P s 0.01; $ P 5 0.001 vs.
low glycogen.
DISCUSSION
Carbohydrate
availability
and TCAI. A major finding
in this study was that LG attenuated the increase in
TCAI during submaximal exercise, which is consistent
with the hypothesis presented in Fig. 1. The lower contents of HMP and higher contents of IMP during LG
exercise are also consistent with the hypothesis (the low
HMP contents necessitate increases in ADP and AMP
which will activate phosphofructokinase as well as AMP
deaminase). In our previous studies we were not able to
C978
GLYCOGEN
AND
TRICARBOXYLIC
detect significant differences in the acetylcarnitine content, which is in near equilibrium with acetyl CoA (5),
in muscle between high vs. low carbohydrate conditions
during exercise. Therefore, we limited our explanation of
the role of glycolysis to producing pyruvate for anaplerosis (via alanine aminotransferase and/or pyruvate carboxylase), thereby providing adequate levels of TCAI for
mitochondrial NADH production (14, 16). However, in
our previous studies we did not completely deplete the
muscle glycogen store as was accomplished in the present
study. Based on the current data, we must now also
consider that the lower contents of acetyl CoA during
LG exercise may have compromised mitochondrial
NADH production, thereby triggering the compensatory
increases in the free concentrations of ADP and AMP
in the immediate vicinity of phosphofructokinase, AMP
deaminase, and mitochondrial
dehydrogenases during
the contraction (see Fig. 1) (14, 16).
According to our hypothesis (see the introduction),
one would have expected the absolute level of TCAI in
muscle to be lower after LG vs. HG exercise. Although
this was the case (3.32 t 0.39 after LG vs. 3.93 & 0.16
mmol/kg dry wt after HG exercise), the difference was
not statistically significant. It is noteworthy that in a
recent study that employed the same experimental design
as in the present study, with the exception that the
exercise intensity was -95% VOWmaxjalthough we showed
the expected differences in HMP and IMP, there was
also no significant difference in TCAI between LG and
HG after exercise (15). In this situation, however, the
exercise can only be sustained for ~5 min, and there is
no measurable decrease in glycolysis during LG vs. HG
exercise. Consistent with the findings during short-term
exercise is the present finding that the postexercise TCAI
value after HG exercise was similar to that after LG
exercise in those subjects who cycled for the shortest
durations. However, the TCAI value after HG exercise
was clearly higher than after LG exercise, in those subjects who cycled for the longest durations. Thus in those
subjects who cycled for ~40 min (n = 4), the TCAI value
after LG exercise was 4.04 t 0.35 vs. 4.00 t 0.28 mmol/
kg dry wt during HG, whereas in those subjects who
cycled for >4O min (n = 3), the TCAI value after LG was
2.35 t 0.15 vs. 3.85 $- 0.13 mmol/kg dry wt after HG.
This differential response of TCAI to exercise is apparent
even though all subjects were virtually glycogen depleted.
These data are in agreement with the idea that low levels
of TCAI become apparent only during the latter stage of
prolonged exercise (14) and that administration of exogenous carbohydrate will attenuate the decrease in
TCAI during the latter part of exercise rather than
enhance the formation of TCAI during the initial stage
of exercise (16).
Aspartate and glycogen. It might be argued that the
difference in aspartate between LG and HG after exercise
may indicate that LG, in addition to accelerating AMP
deamination (15), also inhibits the reamination of IMP
to AMP (via adenylosuccinate synthase and lyase), possibly because of the higher IMP levels which can inhibit
adenylosuccinate synthase (1). Consequently, the lower
levels of TCAI after LG exercise mav be due to dimin-
ACID
CYCLE
INTERMEDIATES
ished anaplerosis via the purine nucleotide cycle (ll),
rather than lower flux through alanine aminotransferase
(yielding %oxoglutarate) or pyruvate carboxylase (yielding oxaloacetate) (Fig. 1). However, in a recent study, we
showed that administration of exogenous carbohydrate
during prolonged submaximal exercise (-70% VOWmax)
attenuated the increase in IMP and maintained higher
levels of TCAI but did not affect the increase in aspartate
(16). Therefore, the suggestion that the high aspartate
content in muscle after LG exercise is indicative of an
attenuation of IMP reamination and formation of fumarate is not tenable. The significance of the higher
aspartate values after LG exercise is not clear, but it may
be related to a greater protein utilization when the muscle
glycogen content reaches exceedingly low levels (10).
We are grateful to Nancy Cain-Adams, Maria Hilbring, Margaret
Williams, and Scott Roecker for technical assistance.
Address for reprint requests: A. Katz, Dept. of Clinical Physiology,
Karolinska Institute, Karolinska Hospital, Box 60500, S-104 01 Stockholm, Sweden.
Received 5 April
1991; accepted in final form 29 November
1991.
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GLYCOGEN
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c979
INTERMEDIATES
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