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(Received for publication, August
15, 1995; and in revised form, October 24, 1995) From the
The effect of increased expression of glycogen phosphorylase on
glucose metabolism in human muscle was examined in primary cultured
fibers transduced with recombinant adenovirus AdCMV-MGP encoding muscle
glycogen phosphorylase. Increments of 20-fold in total enzyme activity
and of 14-fold of the active form of the enzyme were associated with a
30% reduction in basal glycogen levels. Total glycogen synthase
activity was doubled in AdCMV-MGP-transduced cells even though the
activity ratio was decreased. Incubation with forskolin, which
inactivated glycogen synthase and activated glycogen phosphorylase,
induced greater net glycogenolysis in engineered cells. In unstimulated
fibers, lactate production was three times higher in AdCMV-MGP fibers
as compared with controls, despite similar rates of glycogenolysis. In
transduced fibers incubated with 2-deoxyglucose, the level of
2-deoxyglucose 6-phosphate was about 8-fold elevated over the control
even though hexokinase activity was unmodified in AdCMV-MGP fibers.
Overexpression of glycogen phosphorylase also led to enhancement of
[U-
Glycogen phosphorylase is the rate-limiting enzyme of glycogen
breakdown. In muscle, glycogen serves mainly to provide glucose for
energy production during exercise, although it is also consumed in the
resting state. During exercise muscle glycogenolysis is triggered by
the dual control of contractile activity and epinephrine(1) .
These stimuli result in the release of Ca During exercise, glucose uptake
and metabolism are greatly increased in muscle despite low
physiological concentrations of insulin. Indeed, it has been shown that
insulin is not required to mediate glucose uptake during contractions (3, 4) and that contractile activity augments glucose
uptake by muscle even in severely insulin-deficient diabetic
rats(5) . Furthermore, in exercised muscle, glucose uptake and
disposal are enhanced independently of insulin(6) . Insulin
sensitivity of glucose uptake and glycogen synthesis are increased in
exercised muscle, in normal humans and insulin-deficient type I
diabetic patients (7, 8) . The mechanism by which
exercise increases basal and insulin-stimulated muscle glucose uptake
remains to be elucidated. The system accounting for such effects
appears to be located at a post-receptor level, because exercise does
not affect the amount of insulin receptors or insulin-stimulated kinase
activity(9, 10) . Breakdown of glycogen stores (11, 12, 13) or the activation of glycogen
synthase (9) have been suggested as possible mediators of this
phenomenon. On the other hand, even though these studies are consistent
with the fact that glucose uptake is limited by glucose metabolism,
other studies suggest that it is glucose transport that limits glucose
uptake(14, 15) . We have previously shown that
adenoviruses constitute a very efficient vehicle to deliver DNA into
nondividing fused C2C12 myotubes(16) . In this study, we have
used adenoviruses bearing the rabbit muscle glycogen phosphorylase cDNA
to increase the expression of the enzyme in human myotubes in culture.
This approach has allowed us to evaluate the contribution of
phosphorylase to the regulation of glucose metabolism in human muscle
fibers and the repercussion of the stimulation of the glycogenolytic
process. Our data show that human muscle fibers overexpressing glycogen
phosphorylase show a higher capacity for glucose uptake and metabolism
through nonoxidative glycolysis and lipid synthesis. These results may
be related to the physiological mechanism by which muscle glucose
disposal is increased during and after exercise.
Figure 1:
Glycogenolysis in unstimulated and
forskolin-challenged human fibers. Noninfected (squares) or
AdCMV-MGP-transduced fibers (circles) were incubated in the
absence (open symbols) or the presence (closed
symbols) of 100 µM forskolin for the indicated times.
Glycogen content was measured as described under ``Materials and
Methods.'' The results are the means ± S.E. of seven
independent experiments performed in triplicate. prot,
protein.
As expected, in AdCMV-MGP fibers total glycogen
phosphorylase activity (measured in the presence of the activator AMP)
was clearly higher (20-fold over the control) (Table 1), as was
phosphorylase a activity (assayed without AMP), which
increased 14 times. Therefore, in transduced cells, the
-AMP/+AMP activity ratio was significantly lower, suggesting
that a high proportion of the exogenous glycogen phosphorylase was kept
inactive in the basal state (Fig. 2). After incubation of the
cells with forskolin, a time-dependent activation of phosphorylase
could be observed in both control and transduced cells (Fig. 2).
A 1.3-fold increment in the -AMP/+AMP activity ratio was
obtained in control cells, which was already maximal after 20 min of
incubation and had disappeared after 120 min. In contrast, an increment
of about 2-fold was detected in AdCMV-MGP cells, which led to activity
ratio values (around 0.85) equivalent to those measured in control
cells after forskolin challenge, indicating that almost all of the
phosphorylase was in the active form after forskolin treatment.
Figure 2:
Time-dependent effect of forskolin on
glycogen phosphorylase activity ratio. Noninfected (squares)
or AdCMV-MGP-transduced fibers (circles) were incubated in the
absence (open symbols) or the presence (closed
symbols) of 100 µM forskolin for the indicated times.
Glycogen phosphorylase (GP) activity was determined as
described under ``Materials and Methods.'' The results are
the means ± S.E. of seven independent experiments performed in
duplicate.
In
AdCMV-MGP cells, total glycogen synthase activity (assayed in the
presence of 10 mM glucose 6-P) was significantly higher than
that of control cells (about 2-fold increment) (Table 1). In
contrast, the active form (assayed without glucose 6-P) was only
slightly increased. Thus, the -Glc6P/+Glc6P activity ratio
was lower in transduced cells (Fig. 3). Treatment of the cells
with forskolin induced a time-dependent decrease in the
-Glc6P/+Glc6P activity ratio in control and AdCMV-MGP
fibers. The maximal inactivation was reached between 40 and 60 min and
was of similar magnitude (about 50%) for both type of cells. By 120
min, the activity ratio had returned to basal values in control and
transduced fibers.
Figure 3:
Time-dependent effect of forskolin on
glycogen synthase activity ratio. Noninfected (squares) or
AdCMV-MGP-transduced fibers (circles) were incubated in the
absence (open symbols) or the presence (closed
symbols) of 100 µM forskolin for the indicated times.
Glycogen synthase (GS) activity was measured as described
under ``Materials and Methods.'' The results are the means
± S.E. of four independent experiments performed in duplicate. G6P, glucose 6-P.
We examined whether glycogenolysis resulted in
changes in lactate formation. Although control cells showed a very
small accumulation of lactate in the medium during a 120-min
incubation, cells overexpressing myophosphorylase demonstrated a
time-dependent increase in lactate concentration. As shown in Fig. 4, lactate production (calculated as the difference in
lactate concentration) in 2 h was 9.55 µmol/mg protein in
transduced cells and only 2.27 µmol/mg protein in control cells. It
should be mentioned that during this period of time, cellular glycogen
content decreased by 0.21 µmol of glucose/mg of protein in
transduced cells, and a similar decrease (0.18 µmol of glucose/mg
of protein) was observed in control cells (Fig. 1). Therefore,
data suggested that the increase in lactate is larger than can be
accounted for net glycogen breakdown, suggesting an increase in glucose
metabolism.
Figure 4:
Time course of lactate production in human
muscle fibers in culture. Human fibers nontransduced (
Examination of the
Figure 5:
Histochemical staining of lipid content.
Representative phase contrast micrographs (
A remarkable consequence of the overexpression of
phosphorylase is an enhancement of glucose uptake and consumption by
the muscle cell, probably secondary to increased turnover and
utilization of glycogen stores. Consistent with this interpretation, we
found that engineered cells exhibited an enhancement in the production
of lactate that could not be explained solely by net depletion of
glycogen. Although depletion of glycogen was similar in control and
AdCMV-MGP cells, the rate of net lactate production was much higher in
engineered cells, as was the incorporation of radioactivity from Controversy exists regarding whether it is
glucose transport or its intracellular metabolism that limits glucose
utilization by muscle tissue(14, 32) . Our data
provide evidence that it is the intracellular glucose utilization that
limits the rate of glucose uptake. We show that in AdCMV-MGP-transduced
cells, along with the increase in glucose uptake, there is a
stimulation of [U- Our data also show that overexpression of glycogen
phosphorylase induces an increase in total glycogen synthase activity
even though glycogen synthase mRNA levels appear to be unmodified (data
not shown). Even though total glycogen synthase activity is increased,
there is only a small increase in the level of the active form, and
thus the activity ratio is decreased. These results might be related to
previous observations showing that exercise increases the total
activity of both glycogen synthase and glycogen
phosphorylase(34, 35) , conferring to the muscle cells
enhanced capacity for glycogen depletion and resynthesis. Additionally,
Westergaard and colleagues (36) demonstrated in athletes an
elevation of total glycogen synthase activity together with a decrease
in the activity ratio, which is accompanied by no difference in
immunoreactive glycogen synthase. As in this study, it is suggested
that post-translational modifications of the enzyme and not regulation
of gene expression seem to account for modulation of glycogen synthase
activity in muscle. The fact that an increase in glycogen phosphorylase
activity results in an increase in the activity of glycogen synthase
suggests the presence of a local control of glycogen turnover. It seems
that a compensatory mechanism exists that tends to equilibrate the
rates of glycogenolysis and glycogenesis to maintain glycogen turnover
and net glycogen content. The simultaneous existence of both reactions
or glycogen cycling has been clearly demonstrated in
liver(37) . Furthermore, in liver, glycogen turnover is greater
in the fed state than in the fasted state (38) , and thus it
has been suggested that glycogen concentration may exert a regulatory
effect on glycogen turnover. We found that in AdCMV-MGP-treated muscle
cells, there is a compensatory mechanism that up-regulates glycogen
synthase activity following the increase in phosphorylase, despite a
moderate decrease in glycogen content. Therefore, our data suggest the
involvement of local undetermined regulatory factors. It is
concluded that in human skeletal muscle cells, the increase in glycogen
phosphorylase activity is sufficient to up-regulate glycogen metabolism
and to drive the uptake of glucose. Therefore, increased intracellular
metabolism of glucose may be the primary event in the induction of a
higher capacity to take up glucose by skeletal muscle. Our finding may
be related to the exercise-induced enhancement in muscle glucose
transport. Additionally, we show that the increase in glucose
utilization is associated with increased production of lactate and
accumulation of lipid. In summary, it is shown that muscle cells
respond to the increase in the glycogenolytic capacity by increasing
glucose uptake and consumption.
Volume 271,
Number 5,
Issue of February 2, 1996 pp. 2594-2598
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
C]glucose incorporation into glycogen,
lactate, and lipid. Accordingly, determination of lipid cell content
revealed that engineered cells were accumulating lipids. Furthermore, CO
formation from
[U-C]glucose was 1.6-fold higher, whereas CO formation from
[6-C]glucose was unmodified, in AdCMV-MGP
fibers. Our data show that in human skeletal muscle cells in culture,
the increase in glycogen phosphorylase activity is able to up-regulate
glycogen synthase activity indicating the enhancement of glycogen
turnover. We suggest that the increase in glycogen phosphorylase and,
thereby, in glycogen metabolism, is sufficient to enhance glucose
uptake in the muscle cell. Glucose taken up by engineered muscle cells
is essentially disposed of through nonoxidative metabolism and
converted into lactate and lipid.
and an
increase in cyclic AMP, respectively, which in turn lead to the
phosphorylation and activation of glycogen phosphorylase by
phosphorylase kinase(2) .
Human Muscle Primary Cultures
Human muscle
cultures were initiated from satellite cells of muscle biopsies of
patients considered free of muscle disease after all diagnostic studies
were reported. Aneural muscle cultures were established in monolayer
according to the explant re-explantation technique described by Askanas
and Engel in (17) and modified as in (18) . The
cultures were grown in a Dulbecco's modified Eagle's
medium/M-199 medium (proportion, 3:1; Life Technologies, Inc.)
supplemented with 10% fetal bovine serum (Hyclone), 10 µg/ml
insulin (Sigma), 20 mM glutamine (Sigma), 25 ng/ml fibroblast
growth factor (Collaborative Biomedical Products), 10 ng/ml epidermal
growth factor (Collaborative Biomedical Products), and an
antibiotic-antimycotic mixture (Life Technologies, Inc.). Immediately
after myoblast fusion, cells were rinsed with Hanks' balanced
salt solution (Life Technologies, Inc.), and the medium was replaced by
a medium devoid of fibroblast growth factor, epidermal growth factor,
and glutamine. To perform metabolic studies, except where otherwise
stated, cells were switched to a medium devoid of insulin and fetal
serum and including 5 mM glucose 2 h before the beginning of
the experiment. This condition was considered the basal state.
Experiments were performed using muscle cultures established from the
muscle biopsies of seven different patients.Construction of Recombinant Adenovirus AdCMV-MGP and Cell
Infection
The construction of AdCMV-MGP, which contains an
expression unit consisting of the cytomegalovirus promoter, a
2.56-kilobase fragment of the rabbit muscle glycogen phosphorylase cDNA
including the entire coding region(19) , and a fragment of the
SV40 genome, which includes the polyadenylation signal, has been
previously described(20) . The recombinant viruses were
amplified in 293 cells (21) and viral stocks of 5-50
10
plaque-forming units/ml were prepared in 10%
fetal bovine serum:Dulbecco's modified Eagle's medium. Gene
delivery into primary cultured human muscle fibers was performed by
exposing 14-day-old fibers, induced to fuse by removal of growth
factors, for 1 h to AdCMV-MGP at a multiplicity of infection of 10. An
equivalent dose of AdCMV-
Gal (22) was shown to transduce
95 ± 2% of the cells. (
)All studies with
AdCMV-MGP-transduced fibers were performed 7 days after infection.Enzyme Activity Assays
To measure enzyme
activities, extracts were prepared by scraping cell monolayers in a
buffer consisting of 10 mM Tris-HCl (pH 7.0), 150 mM KF, 15 mM EDTA, 15 mM 2-mercaptoethanol, 10
µg/ml leupeptin, 1 mM benzamidine, and 1 mM phenylmethylsulfonyl fluoride and by subsequent sonication.
Homogenates were centrifuged at 10,000 g for 15 min,
and the resulting supernatants were used for the determination of
enzyme activities. Protein concentration was measured as described by
Bradford (23) using the Bio-Rad protein assay reagent.
Glycogen phosphorylase activity was determined by the incorporation of
[U-C]glucose 1-phosphate into glycogen in the
absence or the presence of the allosteric activator AMP (5 mM) (24) . Glycogen synthase activity was measured in the absence
or the presence of 10 mM glucose 6-P ()(25) . Hexokinase activity was measured as
described in (26) .Measurement of
Cells were incubated in Dulbecco's modified
Eagle's medium containing 10 or 20 mM [U-C-Glucose
DisposalC]glucose (0.1 µCi/µmol) (DuPont
NEN). To measure the rate of glycogen synthesis, cell monolayers were
scraped into 30% KOH. The homogenates were boiled for 15 min and
centrifuged (5,000 g, 15 min). Supernatants were
spotted onto Whatman 31ET paper, and glycogen was precipitated by
immersing the papers in ice-cold 66% ethanol. After two additional
washes, papers were dried and counted for radioactivity. To measure
lipid content, cells were scraped into 5 mM Tris-HCl (pH 7.0)
containing 0.9% NaCl. Lipids were extracted with 1 volume of
chloroform:methanol (2:1). The aqueous phase was re-extracted under the
same conditions, and organic phases were combined and counted for total C-lipid content. Alternatively, the organic phase was
evaporated to dryness under a nitrogen flow. The residue was saponified
using 1 M KOH in 95% methanol for 2 h at 50 °C. After
saponification, lipids were extracted with chloroform twice, and
organic (total lipid fatty acid) and aqueous (total lipid glycerol)
phases were counted separately. To determine CO production, a piece of filter paper was suspended on the interior
face of the dish lid soaked with 0.15 ml of -phenylethylamine. At
the end of the incubation, 0.5 ml of 10% HClO
were added to
the incubation medium (2 ml), and the plates were sealed with plastic
wrap and incubated at room temperature for 45 min. The filter papers
were finally counted for radioactivity. Detection of the presence of C-lactate was performed by applying aliquots of the
incubation medium to columns of Dowex AG1x8 (formate form, Bio-Rad) to
separate lactate from radioactive glucose.Metabolite Determinations
For the measurement of
glycogen content, cell monolayers were scraped and treated as described
above. Dried papers containing precipitated glycogen were incubated for
90 min at 37 °C in 0.4 M acetate buffer (pH 4.8) with 25
units/ml of 
-amyloglucosidase (Sigma). Glucose released from
glycogen was measured enzymatically in a Cobas-Bio autoanalyzer with a
GlucoQuant kit (Boehringer Mannheim). Glucose 6-phosphate and
2-deoxyglucose 6-phosphate intracellular concentrations were measured
enzymatically in neutralized HClO extracts(27) . L-Lactate concentrations were measured enzymatically in the
incubation medium(28) . Lipid content was determined by Oil Red
O histochemical staining after fixing cells in Baker's Formal
(10% formaldehyde, 10 mg/ml CaCl). The fixed cultures were
then rinsed with water and incubated in 100% propylene glycol.
Monolayers were finally stained with Oil Red O, mounted in
glycerol:phosphate-buffered saline (9:1) and photographed under light
microscopy. Lipid content was quantified by extraction and gravimetry
according to the technique described by Folch et al.(29) and using a balance with 0.001 mg of reproducibility.
Glycogen Metabolism and Lactate Production
In
the basal condition, glycogen content in AdCMV-MGP transduced cells was
70% lower than in untransduced cells (Fig. 1). When cells were
stimulated to mobilize glycogen by incubation with forskolin, glycogen
was degraded in transduced cells to undetectable levels upon 120 min of
incubation.
) or
transduced with AdCMV-MGP (
) viruses preincubated as described
under ``Materials and Methods'' were incubated with 10 mM glucose. Lactate accumulated in the medium was measured at the
times indicated. The results are the means ± S.E. of four
independent experiments performed in triplicate. prot.,
protein.
Stimulation of the Utilization of
The rate of
[U-C-GlucoseC]glucose utilization and conversion into
glycogen, lactate, CO, or lipids was determined in cells
overexpressing glycogen phosphorylase (Table 2). AdCMV-MGP fibers
exhibited a marked elevation (1.6-fold increment) in the incorporation
of [U-C]glucose into glycogen. The increase in
labeled glycogen, which is not associated with net increase in glycogen
content, may be due to an elevation of glycogen turnover. The
conversion of [U-C]glucose into lactate was also
enhanced in cells overexpressing glycogen phosphorylase. After 120 min
of incubation, the incorporation of [U-C]glucose
into lactate was 4.5-fold higher in transduced cells than in control
cells. Incorporation of [U-C]glucose into total
lipids was also analyzed. Increases of about 4.5-fold in the percentage
of C present in total lipid were observed in transduced
myofibers compared with controls. When the distribution of
radioactivity between the glycerol moiety and the fatty acid pool was
determined, we found that as previously shown(30) , in muscle
cells most of the radioactivity is present in the glycerol moiety (95%)
rather than in the fatty acid fraction. The incorporation of C into both fractions was higher in AdCMV-MGP muscle cells
with similar increases (about 3-fold) in labeling of each fraction.
CO production revealed
that in cells that had been exposed to AdCMV-MGP viruses, CO release was elevated 1.6-fold over the
controls. CO production from
[U-C]glucose mainly reflects CO derived from the decarboxylation of glucose in the pentose
phosphate pathway and in the pyruvate dehydrogenase step in the pathway
of fatty acid synthesis. Because lipid synthesis was stimulated in
these cells, we used [6-C]glucose to determine
whether the overexpression of myophosphorylase also stimulated glucose
oxidation. We found that there was no difference in the CO production from
[6-C]glucose in AdCMV-MGP-transduced myofibers
compared with control cells. Therefore, the observed increase in CO released from
[U-C]glucose was essentially due to lipid
synthesis.Glucose Uptake and Phosphorylation
The effect of
phosphorylase dosage on the uptake and phosphorylation of the
nonmetabolizable glucose analogue 2-deoxyglucose was studied (Table 3). 2-Deoxyglucose is transported into the muscle cell and
at low doses almost entirely phosphorylated. In AdCMV-MGP-transduced
cells incubated with 2-deoxyglucose, hexose 6-P intracellular
concentration was enhanced by about 7.7-fold after 60 min of incubation
with 10 mM 2-dexoyglucose, meaning that uptake of glucose was
activated. Glucose 6-P levels, in cells preincubated for 2 h in the
absence of 2-deoxyglucose or glucose, were slightly higher in
engineered cells (Table 3). Higher glucose 6-P levels were
observed in cells overexpressing glycogen phosphorylase (74.3 ±
4.1 nmol/g protein) with respect to control cells (33.2 ± 2.7
nmol/g protein) when fibers were continuously incubated in the presence
of 30 mM glucose and 1 µM insulin. The increases
in the hexose 6-P levels cannot be attributed to the rise in hexokinase
activity, because this activity was unmodified in cells overexpressing
phosphorylase (Table 1).
Effect on Lipid Accumulation
Because incorporation
of C-glucose into lipid suggested that muscle lipogenesis
was stimulated in cells overexpressing glycogen phosphorylase, it was
determined whether these cells presented accumulation of lipids. As
shown in Fig. 5, AdCMV-MGP-transduced cells showed intense
staining for lipids, whereas control cells were virtually negative.
Quantification of total lipid content by gravimetry showed that
engineered cells had 516 ± 21 µg of lipid/mg of protein with
respect to 292 ± 17 µg of lipid/mg of protein in controls.
100) of Oil Red O
stained cultured human fibers untransduced (A) or transduced
with AdCMV-MGP (B) 7 days after
infection.
C-glucose into lactate. Because the incorporation of C-glucose into glycogen was also increased in engineered
cells, one possible explanation for the increase in lactate production
is that glycogen turnover is stimulated, leading to an increase in
glucose conversion into glycogen and its subsequent degradation to
lactate. Moreover, AdCMV-MGP-transduced cells showed an enhanced
accumulation of the phosphorylated metabolite of 2-deoxyglucose, a
glucose analog that is not metabolized beyond its 6-phosphorylated
form. The increase in 2-deoxyglucose 6-P concentration found in
engineered cells seems to reflect their elevated capacity to transport
glucose, because hexokinase activity is unchanged by overexpression of
phosphorylase. Our results may be relevant to the increase in glucose
uptake and metabolism observed during exercise. It has been long
hypothesized that exercise stimulation of glucose transport is related
to the lowering of muscle glycogen stores. In vivo, exercise
activates glycogen phosphorylase by a dual control of epinephrine and
contractile activity, and both stimulating events have been associated
to the enhancement of glucose uptake. In isolated muscles it has been
observed that a bout of glycogen-depleting exercise increases basal
glucose transport(4, 31) . In addition, in rats
injected with epinephrine, which activates phosphorylase and reduces
glycogen stores independent of exercise, basal glucose transport
activity is increased (13) . We demonstrate that cultured human
muscle fibers with higher levels of glycogen phosphorylase activity
show an enhanced capacity for glucose uptake and consumption, despite
having a relatively unaltered rate of glycogen depletion and unmodified
hexokinase activity.C]glucose conversion into
lactate, lipids, and glycogen. We propose that the influx of glucose
triggered by the overexpression of phosphorylase increases glucose
disposal to lactate and lipid. Accordingly, we found that the
concentration of the intermediate metabolite glucose 6-P is increased
in engineered cells (as described under ``Results''). The
reverse situation has been observed in muscle fibers from
myophosphorylase-deficient patients (McArdle's disease) in which
the levels of intermediate glycolytic metabolites such as glucose 6-P
are depleted(33) . Moreover, our results suggest that the
moderate increase in CO observed from
[U-C]glucose is due to the pentose pathway or
the pyruvate dehydrogenase step rather than to the oxidation of glucose
in the Krebs cycle. Therefore, the glucose taken up by AdCMV-MGP muscle
cells appears to be essentially consumed through nonoxidative
metabolism.
))
We thank Dr. I. Illa and Dr. E.
Càceres (Hospital de Sant Pau i de la Santa Creu,
Barcelona, Spain) and Dr. Gomis (Hospital
Clínic Provincial, Barcelona, Spain) for
providing the muscle biopsies. We thank Dr. V. Askanas and J. McFerrin
for inestimable aid in the establishment of the muscle cultures and
Raquel Díez for skilled technical
assistance. We thank Dr. Loranne Agius and Dr. Christopher B. Newgard
for helpful discussion of the manuscript.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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