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Vol. 83, Issue 6, 1917-1922, December 1997
Zoology Department, Brigham Young University, Provo, Utah 84602
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Hutber, C. Adrian, B. B. Rasmussen, and W. W. Winder.
Endurance training attenuates the decrease in skeletal muscle malonyl-CoA with exercise. J. Appl.
Physiol. 83(6): 1917-1922, 1997.
Muscle
malonyl-CoA has been postulated to regulate fatty acid metabolism by
inhibiting carnitine palmitoyltransferase 1. In nontrained rats,
malonyl-CoA decreases in working muscle during exercise. Endurance
training is known to increase a muscle's reliance on fatty acids as a
substrate. This study was designed to investigate whether the decline
in malonyl-CoA with exercise would be greater in trained than in
nontrained muscle, thereby allowing increased fatty acid oxidation.
After 6-10 wk of endurance training (2 h/day) or treadmill
habituation (5-10 min/day), rats were killed at rest or after
running up a 15% grade at 21 m/min for 5, 20, or 60 min. Training
attenuated the exercise-induced drop in malonyl-CoA and prevented the
exercise-induced increase in the constant for citrate activation of
acetyl-CoA carboxylase in the red quadriceps muscle of rats run for 20 and 60 min. Hence, contrary to expectations, the decrease in
malonyl-CoA was less in trained than in nontrained muscle during a
single bout of prolonged submaximal exercise.
muscle acetyl-CoA carboxylase; carnitine palmitoyltransferase; fatty acid oxidation
INTRODUCTION IN SKELETAL MUSCLE OF RATS, malonyl-CoA decreases in
response to exercise (32, 33) or electrical stimulation (8, 15, 30). In
isolated mitochondria, malonyl-CoA inhibits carnitine palmitoyltransferase 1 (CPT 1), the enzyme responsible for transferring fatty acids to the mitochondria for Endurance training has a significant impact on a muscle's use of
substrate, increasing its reliance on fat at a given absolute intensity
of exercise (3, 4, 14, 16, 17) and possibly also at the same relative
workload (7, 22, 28). The mechanisms by which this is effected are
poorly understood, since the increase in training-induced muscle
mitochondrial volume (9, 12, 13) might be expected to enhance a
muscle's ability to oxidize acetyl-CoA, irrespective of the source. In
light of malonyl-CoA's proposed importance in regulating muscle fatty
acid metabolism, we hypothesized that the reduction in malonyl-CoA
might be larger with exercise in trained than in nontrained muscle and
that training might thus attenuate malonyl-CoA's inhibition of CPT 1, thereby allowing increased fatty acid oxidation. This experiment was
designed to investigate the malonyl-CoA response to exercise in
endurance-trained rats vs. nontrained rats and to determine whether the
kinetic properties of muscle ACC are influenced by the training.
MATERIALS AND METHODS
-oxidation (18, 23, 31). This
decrease in malonyl-CoA is hypothesized to relieve inhibition of CPT 1 and to allow an increased rate of fat oxidation as fatty acids become
available (30, 32, 33). The decline in malonyl-CoA is accompanied by a
decrease in the maximal velocity
(Vmax) of acetyl-CoA carboxylase (ACC), the enzyme that synthesizes malonyl-CoA, and by an increase in ACC's constant for citrate activation
(Ka) (30, 33).
75 and 95°C, respectively, until assayed for
glycogen. A blood sample was withdrawn from the abdominal aorta, an
aliquot was heparinized to collect plasma for determination of free
fatty acids, and a perchloric acid extract was prepared for measurement of glucose and lactate concentrations. Both blood samples were kept at
20°C until the relevant assay was performed.
Muscle and blood assays.
Muscles were ground to powder under liquid nitrogen just before
analysis. Neutralized perchloric acid extracts of the muscles were used
for determination of malonyl-CoA (19). Fatty acid synthase for
malonyl-CoA assays was isolated from livers of fasted-refed rats as
described by Linn (see Ref. 32). ACC activities were determined using
ammonium sulfate precipitates from homogenates prepared from the ground
muscles, as previously described (33). Muscle citrate synthase activity
was measured according to Srere (26). Muscle and liver glycogen were
determined by the anthrone method (11). Blood glucose (2) and blood
lactate (10) were determined on neutralized perchloric acid extracts,
and plasma free fatty acids were determined as described by Novak (21).
Values are means ± SE. Statistical differences
(P < 0.05) between treatment groups
were determined using analysis of variance and Fisher's least
significant difference (as a post hoc test) or a
t-test, where appropriate.
RESULTS
Rats assigned to the training group ran with various degrees of
competence. Inasmuch as we were interested in comparing responses of
well-trained rats with nontrained rats, data from rats in the "trained group" that demonstrated <30% increase in red
quadriceps citrate synthase activity (marker of degree of training) are
not included. If data from a "trained" rat were discarded for
this reason, data from the paired nontrained rat killed at the same time point were also eliminated. The citrate synthase activity in the
red portion of the quadriceps muscle was 66.2 ± 2.2 and 39.1 ± 1.7 (SE)
µmol · g
1 · min1
for the trained and nontrained groups, respectively. Malonyl-CoA decreased during the 60 min of running in the nontrained and trained animals (P < 0.05) and was
significantly lower (P < 0.05) in
the nontrained rats at 20 and 60 min of running (Fig.
1).
Table 1 and Fig. 2 show the effect of running on the citrate dependence of ACC that had been precipitated from muscle homogenates with ammonium sulfate. The Vmax was lower for all exercised groups than for the nonexercised group (P < 0.05) in the nontrained and trained animals. The K0.5 for citrate activation tended to increase (P = 0.06) in the nontrained animals by 5 min of running and continued to remain higher (P < 0.05) in rats run for 20 and 60 min than in nonexercised, nontrained animals. Training lowered (P < 0.05) the K0.5 in muscles from rats run for 20 and 60 min and tended to decrease the K0.5 (P = 0.07) in muscles from rats run for 5 min compared with the nontrained rats. The activation constant calculated from the Hill equation (Ka) demonstrated a pattern similar to the K0.5, showing an exercise-induced increase (P < 0.05) in the nontrained rats but not in the trained rats. The Ka values for citrate were significantly lower in the trained than in the nontrained rats after 20 and 60 min of exercise. The difference between the trained and nontrained ACC activity at 0.2 mM citrate, which is in the physiological range, was especially pronounced (Fig. 3). All trained, exercised groups showed significantly greater ACC activity at 0.2 mM citrate than did their nontrained counterparts (P < 0.05).
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Figure 4 shows the change in muscle and
liver glycogen concentration with exercise and due to training. The
glycogen content of the red quadriceps muscle was significantly greater
(P < 0.05) before exercise in the
trained state than in the nontrained state. The rate of utilization of
glycogen in this muscle was similar in trained and nontrained rats: 29 and 32 µmol glucose units/g, respectively. The gastrocnemius muscle
showed less depletion of glycogen with training: 18 and 28 µmol/g for
trained and nontrained groups, respectively.
Liver glycogen utilization in trained rats was markedly different from that in nontrained rats (Fig. 4). In trained rats, liver glycogen was 454 ± 49 and 288 ± 47 µmol glucose units/g at rest and after 60 min of running, respectively. In nontrained rats, corresponding values were 384 ± 28 and 82 ± 22 µmol glucose units/g. Average liver weights for rats killed at these same time points were 12.0 ± 0.4 and 11.7 ± 0.5 g for trained and 12.0 ± 0.5 and 10.2 ± 0.4 g for nontrained rats. The total liver glycogen utilized during the 60-min bout of exercise was 2,079 and 3,772 µmol glucose units for the trained and nontrained rats, respectively. This represents a 45% reduction in the amount of liver glycogen utilized in trained rats compared with the nontrained rats during exercise.
Blood glucose did not change significantly
(P > 0.05) with exercise in the
nontrained or trained group (Fig. 5). Blood
lactate was significantly lower (P < 0.05) in the trained animals that had been run for 60 min than in their
nontrained counterparts (Fig. 5). Free fatty acids in the plasma
increased (P < 0.05) with exercise
for the nontrained group and tended to increase (P = 0.08) by 60 min of running in the
trained group.
DISCUSSION
This study confirms earlier studies on nontrained rats (32, 33), in which malonyl-CoA has been demonstrated to decrease in working muscle during exercise. To our knowledge, this is the first report demonstrating a decrease in malonyl-CoA in working muscle of endurance-trained rats during a bout of treadmill exercise. We hypothesize that this decrease in malonyl-CoA is important for relieving inhibition of CPT 1 and allowing increased rates of fatty acid oxidation during exercise in trained and nontrained rats.
Previous studies have clearly demonstrated that endurance-trained human
subjects obtain a greater proportion of their energy requirements from
fat oxidation during exercise than do nontrained subjects working at
the same absolute submaximal work rate (6, 14, 16, 17, 29). Trained and
nontrained rats in this study were working at the same absolute work
rate. Although we did not measure oxygen consumption, rats of this
strain have been reported to utilize ~70 ml oxygen/kg body wt when
running at this grade and speed (1). If we assume a maximal
oxygen consumption of 120 ml · kg1 · min1
(1), the nontrained rats were working at ~58% of maximal oxygen consumption. The trained rats were likely working at a level somewhat <58% of maximal oxygen consumption. In
RESULTS, we calculated the total liver
glycogen utilization during the 60-min exercise bout to be 3,772 µmol
glucose units for the nontrained rats and 2,079 µmol glucose units
for the trained rats. The amount of oxygen required to oxidize these
amounts of glycogen completely to carbon dioxide is 506 ml for the
nontrained and 269 ml for the trained rats. If it is assumed the oxygen
cost is 21 ml/min for these rats running at this speed, the total
oxygen cost for 60 min of exercise would be 1,260 ml. Thus the oxygen
requirement for oxidizing glucose derived from liver glycogen in the
nontrained rats represents 40% of the total oxygen cost. The
corresponding value in the trained rats is 21%. The remaining oxygen
is utilized principally to oxidize glucose units derived from muscle
glycogen, glucose produced by gluconeogenesis, and fatty acids. Much of
the gluconeogenic substrate is derived from glycogen. Lactic acid
produced by muscles must ultimately come from muscle or liver glycogen
or from dietary carbohydrate. The difference in the amount of lactate
in the extracellular fluid volume between trained and nontrained rats
represents a relatively minor fraction of the total carbohydrate
derived from liver and muscle glycogen. Although lactate is continually
being produced during exercise, it is also being utilized for
gluconeogenesis in the liver and is oxidized by the active muscle
fibers (27). Because glycogen utilization appears also to be less in
the mixed-fiber muscles of the trained rats, it is logical to conclude
that the deficit in liver and muscle glycogen utilization must be met
principally by fatty acid oxidation.
The purpose of this experiment was to determine whether endurance training alters the malonyl-CoA response to exercise. Malonyl-CoA is an inhibitor of CPT 1, the enzyme responsible for transfer of long-chain fatty acyl-CoA to the mitochondria for oxidation (18, 23). We hypothesized that endurance training would result in a greater decline in muscle malonyl-CoA during submaximal exercise, thereby allowing an increased rate of oxidation of fatty acids as a source of energy. As can be seen from Fig. 1, however, this hypothesis proved to be incorrect. The muscle malonyl-CoA content was significantly higher after 20 and 60 min of exercise in trained rats than in nontrained rats running at the same treadmill speed and grade. We inferred from liver and muscle glycogen data that the rate of carbohydrate utilization was decreased in the trained rats and that increased fat oxidation compensated for the diminished glycogen utilization. These facts together lead us to conclude that the higher rate of fat oxidation during exercise in response to endurance training cannot be attributed to a lower malonyl-CoA content of the trained muscle.
The mechanism of the training-induced enhancement of fatty acid oxidation during submaximal exercise may thus be related more closely to the increase in muscle mitochondrial oxidative enzymes (12, 13, 20, 25) or perhaps to increased availability of long-chain acyl-CoA to mitochondria of the working muscle. In the present study we noted an ~70% increase in citrate synthase in the red region of the quadriceps muscle in response to the training program. Previous studies have clearly demonstrated that endurance training induces an increase in palmitoyl-CoA synthase, an increase in total CPT, and an increase in capacity of mitochondrial preparations to oxidize fatty acids (20). With this increase in mitochondria, the fatty acid oxidation rate at any fixed malonyl-CoA concentration would be expected to be higher in the trained than in the nontrained muscle, all other regulatory factors being equal. With the malonyl-CoA concentration higher in the trained than in the nontrained muscle during exercise, it is more difficult to predict the effect on the rate of fatty acid oxidation. It depends somewhat on the nature of the malonyl-CoA inhibition curve (plot of malonyl-CoA vs. CPT 1 activity) in trained vs. nontrained rats. Inasmuch as we do not know the characteristics of this inhibition curve under in vivo conditions in working muscle, we cannot come to any certain conclusion regarding the effect of the higher malonyl-CoA in the trained rats. Possible differences between trained and nontrained rats in compartmentalization of the total muscle malonyl-CoA must also be considered. It is conceivable that in the trained muscle a greater proportion of the total muscle malonyl-CoA is bound to protein or is not in the compartment exposed to the malonyl-CoA-sensitive site of CPT 1. If, for example, a fraction of the total malonyl-CoA is located inside the mitochondria, the trained muscle, having more mitochondria than nontrained muscle, would be expected to have lower free cytosolic malonyl-CoA concentrations, given the same total muscle malonyl-CoA content.
Previous studies have provided information regarding the mechanism of
the decline in muscle malonyl-CoA during exercise. Purified muscle ACC
can be phosphorylated in vitro by AMP-activated protein kinase (AMPK)
and by adenosine 3
,5-cyclic monophosphate-dependent protein kinase (PKA) (33, 34). Phosphorylation by PKA has no detectable
effect on the activity of muscle ACC. Phosphorylation by AMPK results
in an increase in
Ka for citrate
and increases in the Michaelis constants for the
substrates acetyl-CoA, ATP, and bicarbonate. The net effect of these
changes in kinetic properties is a decrease in the activity of ACC
(i.e., lower rate of malonyl-CoA synthesis), particularly at citrate
concentrations found in the muscle. Within 5 min of the beginning of
treadmill exercise, AMPK activity increases and ACC activity decreases
concurrently with the decline in malonyl-CoA content of the working
muscle of rats (33). In situ stimulation of rat gastrocnemius muscle at
a frequency of 1/s causes an increase in estimated free AMP, a decrease
in ACC, and a decrease in malonyl-CoA (14). The postulated sequence of
events is as follows: 1) The
increase in 5-AMP associated with muscle contraction activates
AMPK kinase. It is also conceivable that the rise in free calcium
associated with contraction may activate a calcium/calmodulin-dependent
kinase. 2) AMPK kinase phosphorylates and activates AMPK. The rise in 5-AMP also
allosterically activates AMPK. 3)
AMPK phosphorylates and inactivates ACC.
4) The consequent decrease in
malonyl-CoA relieves inhibition of CPT 1 and allows an increased rate
of fatty acid oxidation as fatty acids become available (33).
Previous studies have demonstrated less increase in 5-AMP during
contraction in endurance-trained than in nontrained muscle in rats (7,
9). This may be the reason for the attenuation of the decline in muscle
ACC activity during exercise in the endurance-trained rats of the
present study. With a lower 5-AMP concentration in the trained
muscle, we would expect less activation of AMPK. With less
phosphorylation of ACC by AMPK, the
Ka for citrate
would be expected to be lower. At physiological citrate concentrations, this means that malonyl-CoA would be synthesized at a more rapid rate
in the trained muscle. The results on ACC activity at 0.2 mM citrate
and muscle malonyl-CoA appear to be consistent with this
interpretation.
The Vmax for
muscle ACC activity is also decreased during exercise. The fact that
the exercise-induced increase in
Ka for citrate
was attenuated in the endurance-trained rats but the exercise-induced decrease in Vmax
was not implies that changes in these two kinetic characteristics of
muscle ACC may be controlled by different kinases. It is clear from
previous studies that
Ka is definitely
increased by phosphorylation of muscle ACC by AMPK at one or more
phosphorylation sites (33, 34). It is possible that the
Vmax of ACC may
be controlled by phosphorylation by a calcium/calmodulin kinase at another site. The rise in sarcoplasmic free calcium would be expected to be similar in trained and nontrained rats, but the increase in
5-AMP would be predicted to be less in the trained rats. A second calcium/calmodulin-sensitive ACC kinase has not been identified.
As noted in MATERIALS AND METHODS, it was necessary to restrict food intake of the nontrained rats to maintain body weights near those of the training rats. During the final exercise test, it is essential that body weights be similar to have rats in each treatment group running at the same submaximal work rate. It is possible that this chronic food restriction resulted in adaptations that would accentuate the malonyl-CoA response to exercise in the nontrained rats. We have, however, observed similar decreases in malonyl-CoA in red quadriceps of nontrained rats that were not food restricted (33). These rats were larger but were run at the same speed and grade for up to 30 min.
In summary, endurance training led to an attenuation of the fall in muscle malonyl-CoA and to attenuation of the increase in Ka for citrate of muscle ACC during submaximal bouts of treadmill exercise in rats. Liver and gastrocnemius muscle glycogen utilization during exercise was also less in trained than in nontrained rats during 1 h of treadmill exercise. We conclude that the decrease in carbohydrate utilization (with likely increased fat utilization) in trained rats during exercise is not due to a lower muscle malonyl-CoA and is more likely due to the previously reported increase in the capacity of muscle to oxidize fatty acids.
ACKNOWLEDGEMENTS
The authors are grateful to Hillary Hatt, Emily Kurth, and Arlin R. Peterson for technical assistance.
FOOTNOTES
Address for reprint requests: W. W. Winder, 545 WIDB, Zoology Dept., Brigham Young University, Provo, UT 84602.
Received 14 May 1997; accepted in final form 22 July 1997.
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 J. N. Nielsen, K. J. W. Mustard, D. A. Graham, H. Yu, C. S. MacDonald, H. Pilegaard, L. J. Goodyear, D. G. Hardie, E. A. Richter, and J. F. P. Wojtaszewski 5'-AMP-activated protein kinase activity and subunit expression in exercise-trained human skeletal muscle J Appl Physiol, February 1, 2003; 94(2): 631 - 641. [Abstract] [Full Text] [PDF]
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P. E. Durante, K. J. Mustard, S.-H. Park, W. W. Winder, and D. G. Hardie Effects of endurance training on activity and expression of AMP-activated protein kinase isoforms in rat muscles Am J Physiol Endocrinol Metab, July 1, 2002; 283(1): E178 - E186. [Abstract] [Full Text] [PDF]
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E. C. Starritt, R. A. Howlett, G. J. F. Heigenhauser, and L. L. Spriet Sensitivity of CPT I to malonyl-CoA in trained and untrained human skeletal muscle Am J Physiol Endocrinol Metab, March 1, 2000; 278(3): E462 - E468. [Abstract] [Full Text] [PDF]
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L. P. Turcotte, J. R. Swenberger, M. Z. Tucker, and A. J. Yee Training-induced elevation in FABPPM is associated with increased palmitate use in contracting muscle J Appl Physiol, July 1, 1999; 87(1): 285 - 293. [Abstract] [Full Text] [PDF]
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