Download Skeletal Muscle Glucose Uptake During Exercise: How is it

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PHYSIOLOGY 20: 260–270, 2005; 10.1152/physiol.00012.2005
Skeletal Muscle Glucose Uptake During
Exercise: How is it Regulated?
Adam J. Rose and Erik A. Richter
The increase in skeletal muscle glucose uptake during exercise results from a coor-
Department of Human Physiology,
Institute of Exercise and Sport Sciences,
Copenhagen Muscle Research Centre,
University of Copenhagen, Copenhagen, Denmark
[email protected]
dinated increase in rates of glucose delivery (higher capillary perfusion), surface
membrane glucose transport, and intracellular substrate flux through glycolysis. The
mechanism behind the movement of GLUT4 to surface membranes and the subsequent increase in transport by muscle contractions is largely unresolved, but it is likely to occur through intracellular signaling involving Ca2+-calmodulin-dependent protein kinase, 5⬘-AMP-activated protein kinase, and possibly protein kinase C.
Leg glucose uptake (mmol⭈min–1)
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Regulation of Skeletal Muscle
Glucose Uptake During Exercise
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FIGURE 1. Leg glucose uptake at rest and during
cycle ergometer leg exercise at different power
outputs
Skeletal muscle glucose uptake increases substantially
during dynamic exercise. The increase is dependent
mainly on exercise intensity but also on exercise duration. Adapted from Wahren et al. (131).
260
higher metabolic stress on active muscle fibers (59,
60) at higher exercise intensities. During exercise,
the major metabolic fate of blood glucose after
entry into skeletal muscle cells is glycolysis (139,
157) and subsequent oxidation (61, 157).
Regular exercise can improve glycemic control
(11, 12). This may be due, in part, to the acute
effects of exercise on glucose metabolism as well as
training-induced adaptations. In individuals with
type II diabetes, a single bout of exercise can
reduce blood glucose concentrations (83) mainly
because the exercise-induced increase in skeletal
muscle glucose uptake is intact (79) even when
insulin action is impaired. Thus the molecular
mechanism resulting in increased muscle glucose
transport during exercise is recognized as a clinically relevant alternative pathway to increase glucose disposal in skeletal muscle in states of insulin
resistance.
There are three sites of regulation of skeletal muscle glucose uptake in vivo: glucose delivery to the
skeletal muscle cells, surface membrane permeability to glucose (i.e., glucose transport), and flux
through intracellular metabolism (FIGURE 2).
Whether one or a combination of these factors is
rate limiting to tissue uptake has proven difficult to
discern. Glucose delivery or supply to a tissue vascular bed is usually expressed as the product of
blood flow and blood glucose concentration.
Because muscle blood flow can increase up to 20fold during intense exercise (4), the increase in
muscle perfusion is of large quantitative importance for the increase in glucose supply (97). In
vitro studies of glucose uptake during electrical
stimulation of perfused rat hindlimb muscles indicate that perfusion is important for the rate of glucose uptake during contractions (52), but whether
perfusion limits glucose uptake under normal exer-
1548-9213/05 8.00 ©2005 Int. Union Physiol. Sci./Am. Physiol. Soc.
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During dynamic exercise, the turnover of ATP in
skeletal muscle increases greatly and is fuelled by
the catabolism of carbohydrates (intramuscular
glycogen, blood glucose) and fatty acids (intramuscular triglycerides, blood lipids). During exercise in
the postabsorptive state, the contribution of blood
glucose to ATP resynthesis is initially relatively
minor, but as exercise continues and muscle glycogen stores are depleted, the contribution of blood
glucose becomes more substantial, reaching ~35%
of leg oxidative metabolism and close to 100% of
muscle carbohydrate metabolism (1, 2, 28, 104,
139). Probably the most influential factor for the
magnitude of increase in muscle glucose uptake
during exercise in the postabsorptive state is exercise intensity, with skeletal muscle glucose uptake
being greater at higher exercise intensities (FIGURE
1; Refs. 104 and 131). This is probably due to a combination of greater fiber recruitment (45) as well as
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Capillary
Interstitium
Myocyte
hexokinase
Glucose
(G)
GLUT
G
P
FIGURE 2. Rate-limiting steps of glucose uptake
by skeletal muscle
Glycolysis
G6P
Glucose diffuses from the capillary to the muscle surface
membranes, is transported across these membranes by
facilitated diffusion, and is irreversibly phosphorylated in
the myocyte, provided that there is a glucose concentration gradient. Each of these steps is tightly coupled and
may be limiting during exercise. Shown below each step
are the main mechanisms of regulation.
Glycogenesis
TRANSPORT
• Surface membrane
GLUT abundance
• Glucose gradient
• GLUT activity
METABOLISM
• Hexokinase activity
• Substrate flux
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cise conditions is questionable. If flow were to be
limiting during exercise, a decrease in the interstitial glucose concentration would be expected.
However, this is not the case, as skeletal muscle
interstitial glucose concentration is actually higher
when comparing exercising and rested limbs (76).
On the other hand, increasing glucose supply to the
working muscle by raising glucose concentrations
during contractions in vitro (85, 91) or during exercise in vivo (97, 157) increases skeletal muscle glucose uptake during exercise even when insulin levels are prevented from rising (FIGURE 3).
Conversely, during prolonged exercise when blood
glucose concentration decreases, leg glucose
uptake decreases as well (1). It is noteworthy that
within the physiological range of glucose concentrations the relationship between plasma glucose
concentration and glucose uptake in muscle during exercise is almost linear, indicating that
changes in plasma glucose concentrations during
exercise translate almost proportionally to changes
in glucose uptake by muscle (FIGURE 3). Thus,
whereas the increase in muscle blood flow seems
well matched to the metabolic demands of muscle
(4) and does not pose an obvious limitation to glucose uptake in healthy individuals, the blood glucose concentration is an important limiting factor
for glucose uptake during exercise.
Skeletal muscle expresses multiple isoforms of
glucose transporters (93). During exercise the most
important of these is GLUT4, because systemic
(110) and muscle-specific (158) GLUT4 knockout
abolishes contraction-stimulated glucose uptake,
at least when studied in vitro. Several studies suggest that glucose transport is rate limiting for glucose uptake into muscle during exercise. Derave et
al. (32) provided evidence that membrane transport is a limiting step for glucose uptake during
exercise in a study in which the perfused rat
hindlimb preparation was used and the magnitude
of glucose uptake during contractions was altered
by differing initial muscle glycogen concentrations
manipulated by prior exercise and diet. It was
shown that there was a strong positive correlation
between sarcolemmal GLUT4 content and glucose
uptake, at least in muscles that contained primarily fast-twitch fibers (32). Studies of humans also
suggest that glucose transport may be rate limiting
for glucose uptake in skeletal muscle during moderate-intensity exercise, because intramuscular
glucose does not accumulate except perhaps in the
first few minutes of exercise (64, 99), which would
be expected if phosphorylation of glucose was limiting. However, during intense exercise when
glycogenolysis is very rapid and formation of glu1.4
Glucose uptake (mmol⭈kg–1⭈min–1)
SUPPLY
• Perfusion
• Blood glucose
concentration
1.2
1.0
0.8
0.6
0.4
0.2
0
0
4 5
8
10
15
20
25
Glucose concentration (mM)
FIGURE 3. Glucose uptake across the thigh during moderate-intensity, dynamic knee-extensor
exercise performed by humans
Glucose uptake was measured after 30 min of exercise
at each plasma glucose concentration. Plasma insulin
concentration was clamped at basal levels by infusion of
somatostatin and replacement insulin. Values are means
± SE; n = 4. Km was calculated to be 10.5 mM and Vmax
to be 1.67 mmol⭈kg–1⭈min–1. Broken lines illustrate that if
plasma glucose concentration increases from 4 to 8 mM
during exercise, this would result in almost a doubling of
the rate of leg glucose uptake. It should be noted that,
depending on exercise intensity, an increase in plasma
glucose concentration to 8 mM might increase plasma
insulin concentrations under normal conditions when
plasma insulin is not clamped, and it would perhaps
increase leg glucose uptake even further (30). Modified
from Richter (97).
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PHYSIOLOGY • Volume 20 • August 2005 • www.physiologyonline.org
and hence expression, skeletal muscle glucose
uptake is normal (79), perhaps because perfusion
(79, 135) and GLUT4 translocation (65) during
exercise are not impaired. Lastly, there is very little
direct evidence that skeletal muscle HK activity is
altered by acute contractile activity or exercise in
mammals (133), and there are no studies that have
directly examined the relationship between possible acute changes in HK activity and glucose
uptake with exercise. However, the apparent lack of
fine control of HK activity during exercise may very
well be the reason that HK can limit glucose uptake
in some circumstances. Overall, the role of HK in
regulation of glucose uptake during exercise in
humans is ambiguous and probably only limiting
to glucose uptake during intense exercise when
G6P accumulates and inhibits HK activity.
In summary, glucose supply, transport, and
phosphorylation are important regulatory steps of
skeletal muscle glucose uptake during exercise
(FIGURE 2). Whether one or a combination of these
factors is rate limiting to glucose uptake in the
intact mammal has proven difficult to discern,
because all steps are likely to be closely coupled to
the metabolic state of the muscle fiber as well as
the percentage of fibers recruited. It may be that
oxidative muscles rely more on glucose supply
(perfusion) and phosphorylation by HK (41, 77),
with glycolytic muscles probably relying more on
glucose transport (32, 108). From a hypothetical
perspective, it is also likely that even within the
same muscle fiber the limiting step for glucose
uptake varies depending on a variety of factors,
including the intensity and duration of exercise
and muscle glycogen and interstitial glucose concentrations.
Given that there is little known about the regulation of HK activity by acute exercise (133) and that
there are several recent reviews on the regulation
and putative molecular events leading to hyperemia (25) and greater microvascular flow (95) and
thus substrate supply in skeletal muscle with exercise, the following section focuses on the regulation
of membrane glucose transport by exercise/contraction.
Regulation of Skeletal Muscle
Glucose Transport by
Exercise/Contraction
The molecular events involved in stimulating
GLUT4 movement within muscle cells are complex
(18, 134). There is evidence that there are distinct
contraction and insulin-responsive GLUT4 vesicle
“pools” in skeletal muscle (26, 35, 74, 92) and that
the molecular signals that trigger increased glucose
transport and surface membrane GLUT4 are different when comparing insulin and contraction stim-
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cose-6-phosphate (G6P) is pronounced, the ensuing inhibition of hexokinase (HK) may make glucose phosphorylation, rather than transport, limiting (63, 69).
Skeletal muscle glucose transport follows
Michaelis-Menten kinetics, and most studies show
that exercise increases the Vmax of glucose transport
without affecting Km (66, 122, 157), suggesting that
the number but not affinity for glucose of individual transporters is higher with exercise. Even so, a
study in perfused rat hindlimb demonstrated both
a contraction-induced increase in Vmax and a
decrease in Km for glucose transport (91) that was
subsequently supported by data obtained in isolated plasma membrane vesicles from rat muscle (90).
These data indicate that the activity of each glucose
transporter may increase with contractions. Similar
to the action of insulin, it has been demonstrated
that muscle contractions increase the sarcolemmal
and transverse-tubular content of GLUT4 (FIGURE
4) using several different methods and models (34,
35, 36, 46, 70, 74, 75, 92, 108, 109, 126), thereby
enhancing the facilitated diffusion of glucose into
the muscle cells. The increased GLUT4 abundance
in the transverse tubules is hypothesized to
account for a substantial proportion of the overall
increase in skeletal muscle glucose transport,
allowing delivery of glucose deep into the
myoplasm (33).
Recent studies using genetic manipulation to
alter the expression of proteins involved in glucose
transport and metabolism have shed some light on
the possible limiting steps in glucose uptake during
exercise. Wasserman and colleagues have demonstrated that neither GLUT4 overexpression nor partial knockout alter exercise-stimulated increases in
skeletal muscle glucose uptake in vivo (40, 42),
indicating that the increase in surface membrane
GLUT4 is a permissive step in glucose uptake
under normal conditions or that only a percentage
of the total GLUT4 pool is required for the increase
in surface membrane permeability with exercise.
Further work by Wasserman and colleagues using
mice with skeletal muscle HKII overexpression or
partial knockout implicate an important role for
HKII in the regulation of glucose uptake by working
murine muscle in vivo (40, 41, 42, 48). However,
when mice with a partial knockout of skeletal muscle HKII were exercised, there was a limitation to
glucose uptake only in the oxidative skeletal muscles during exercise and no discernable effect in
muscles of a mixed fiber type (41). Given that
human vastus lateralis (the muscle typically sampled for biochemical measures, representative of
leg glucose uptake) is of a heterogeneous fiber population (116), it is difficult to extend these findings
to humans. Furthermore, in individuals with type II
diabetes who have lower maximal HKII activity (88)
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Signaling mechanisms involved in
contraction-stimulated glucose transport
Although the signaling mechanisms that are
involved in insulin-stimulated glucose transport
are still partly unresolved (134), even less is known
about the molecular mechanisms responsible for
the increase in glucose transport and GLUT4
translocation during muscle contraction (FIGURE
4). It is generally accepted that the underlying signals occur independently of humoral factors and
arise from local factors within the contracting
skeletal muscle (97). Indeed, it has been demon-
strated numerous times that contraction of skeletal
muscle ex vivo results in higher glucose transport
compared with basal conditions. Furthermore, the
use of these reductionist models such as the perfused hindlimb and incubated muscle techniques
allow greater insight into the regulation of glucose
transport, because glucose supply can be precisely
controlled (10, 142).
Role of Ca2+ signaling
The transient “spikes” in intracellular Ca2+ that
occur with muscle contractions have for more than
30 years been hypothesized to be involved in contraction-stimulated glucose transport (56). Since
the intracellular Ca2+ level is related to the activity
of the motor nerves, signaling directly influenced
by Ca2+ can be considered as feedforward regulation. The original studies were performed in frog
sartorius muscle incubated with caffeine, which
releases Ca2+ from the sarcoplasmic reticulum. In
rat epitrochlearis muscle, raising intracellular Ca2+
by treatment with caffeine in vitro also increases
glucose transport (125, 154). In contrast, other in
vitro studies have shown no effect of Ca2+
ionophores on basal skeletal muscle glucose transport, with an inhibition of insulin-stimulated glucose transport (68, 72). The discrepancies between
these findings are difficult to explain but may relate
to the magnitude and duration of the increase in
cytosolic Ca2+ (72). Importantly, at the concentra-
Glucose
Exercise
contraction
GLUT4
Sarcolemma
hexokinase
?
P
G6P
AS160?
catabolism
Vesicle
?
ADP
ATP
?
AMPK
AMP
Pi
PKB
PKC
NOS
Myofibrils
Contraction/
exercise
GLUT4
CaMK
CaM
Ca2+
T-tubule
T-tubule
Sarcoplasmic
reticulum
FIGURE 4. Putative regulation of glucose uptake
and GLUT4 “translocation” in skeletal muscle
during exercise/contractions
The higher glucose transport with exercise mainly occurs
due to higher amounts of glucose transport protein
GLUT4 in surface membranes, more specifically the sarcolemma and transverse tubules (T-tubules). The mechanisms behind this are unclear but may involve several
kinases that sense and transduce signals relating to
changes in the intracellular environment during contractions (i.e., higher Ca2+, AMP concentrations) to other
undefined proteins involved in GLUT4 movement and
insertion into membranes. Question marks refer to
unidentified signaling and structural molecules that are
involved in this process. G6P, glucose-6-phosphate;
AS160, Akt substrate of 160 kDa; AMPK, 5⬘-AMP-activated protein kinase; CaM, calmodulin; CaMK, Ca2+-CaM
dependent protein kinase; PKB, protein kinase B (also
known as Akt); PKC, protein kinase C; NOS, nitric oxide
synthase.
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ulation (58, 73, 75, 151). Indeed, insulin, but not
contractions, results in changes in distribution of
the rab4 protein (118) and contractions, but not
insulin, alter the distribution of the transferrin
receptor (74). Even so, there are likely to be similarities between the two stimuli, as both exercise and
insulin probably recruit GLUT4 vesicles that contain vesicle-associated membrane protein-2 (70,
94) and insulin-responsive aminopeptidase (26) as
well as stimulate higher sarcolemmal content of
GTP-binding proteins (36). Although it is not
known whether the higher surface membrane
GLUT4 with contraction results from a slower
endocytosis or faster exocytosis of GLUT4 vesicles
in intact mammalian skeletal muscle, insights from
work with cultured cardiomyocytes suggest the latter (152).
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PHYSIOLOGY • Volume 20 • August 2005 • www.physiologyonline.org
tional CaMK isoforms such as CaMKI cannot be
ruled out. Indeed, CaMKI is expressed in skeletal
muscle (3), whereas CaMKIV is not (3, 105).
However, the observation that insulin stimulation
of glucose transport is also partially inhibited by
KN62 (16, 148) suggests that insulin action is partially dependent on CaMK but also raises the possibility that KN62 inhibits glucose transport nonspecifically. Clearly, further study is required to
clarify this issue.
Nitric oxide synthase (NOS) is also activated by
Ca2+-bound CaM (12). NOS is expressed in skeletal
muscle cells, and there is evidence from rodent
studies that NOS activity (101) and nitric oxide production (5) are increased during exercise. There is
equivocal evidence regarding the involvement of
NOS in contraction-stimulated glucose transport
in skeletal muscle of rats, with some studies indicating no effect (37, 54, 107) and other studies
showing a reduction (6, 102, 121) in muscles treated with NOS inhibitors. Inhibition of NOS leads to
reduced glucose uptake without affecting total
blood flow across the working limb of humans in
vivo (13, 67). This does not rule out an effect of NOS
inhibition on glucose supply, as the inhibitor used
in these studies probably affects endothelial NOS,
and nitric oxide is believed to be involved in
increasing nutritive microvascular flow with exercise/contraction (95). As changes in nutritive flow
can occur in the absence of changes in total flow
(129), the effect of NOS inhibition on glucose
uptake in humans might be explained by regulation of nutritive flow rather than membrane transport, although this remains to be established.
Signaling related to metabolic status of
muscle
Early studies observed an inverse relationship
between the phosphocreatine concentration and
glucose uptake by contracting muscle (63, 132),
suggesting a role for signals that sense metabolic
stress in contraction-stimulated glucose transport.
This may be regarded as feedback regulation of glucose transport. In an attempt to address this issue,
Ihlemann et al. (59, 60) employed a model in which
the force development was manipulated while the
stimulation frequency and muscle fiber recruitment were kept constant to alter metabolic stress,
presumably without disturbing Ca2+ signaling.
There was a positive relationship between force
development and skeletal muscle glucose uptake
in both slow-twitch and fast-twitch muscles (59,
60). Thus an energy-sensing signaling system is
likely to be involved in stimulating glucose transport with contractions. Indeed, 5⬘-AMP-activated
protein kinase (AMPK) may be the enzyme that fulfils this role. AMPK is a multifunctional
serine/threonine protein kinase that acts as an
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tions used, none of these agents alter muscle force
development or the concentration of high-energy
phosphate compounds (72, 154), both of which are
believed to be important factors in regulating
skeletal muscle glucose transport (see below).
Other studies have sought to resolve the role of
Ca2+ by examining Ca2+-activated enzymes.
Conventional isoforms of protein kinase C (PKC)
are activated in response to increases in cellular
Ca2+ and diacylglycerol (DAG) (87). In rats, skeletal
muscle PKC activity, as determined by translocation of PKC to a membrane fraction, is higher with
exercise/contractions (24, 98), but this finding
could not be replicated in humans (106).
Furthermore, chronic downregulation (23) as well
as chemical inhibition (58, 143) of conventional
and novel PKC isoforms results in reduced contraction-stimulated glucose transport. However, the
effect of inhibition of DAG-sensitive PKC by the
microbial agent calphostin C was much more pronounced in fast-twitch than in slow-twitch muscles
(143), a finding that is not surprising given that artificial activation of DAG-sensitive PKCs by phorbol
esters results in increased glucose transport in rat
fast-twitch but not slow-twitch muscles (150).
Thus, although there are some studies that suggest
that the conventional and novel PKC isoforms may
be involved in contraction-induced glucose
uptake, it is clear that more definitive studies are
required to resolve the role of these enzymes in this
process.
Another ubiquitously expressed Ca2+-sensing
protein is calmodulin (CaM). Studies using CaM
inhibitors show reductions in contraction-stimulated glucose transport, perhaps because CaM
inhibition leads to reduced tension development
(58), a result likely due to the role of CaM in many
signaling processes in skeletal muscle, including
excitation-contraction coupling (124, 130).
However, specific inhibition by KN62/93 of the
multifunctional kinases that are activated by Ca2+bound CaM (i.e., CaMKI, -II, -IV) (29, 53) leads to
partial reduction in contraction-stimulated glucose transport in epitroclearis (151) and complete
abolition in soleus (149) muscles of rats in vitro.
This inhibitor also reduces contraction-stimulated
glucose transport in murine soleus and extensor
digitorum longus muscles, without affecting tension development in this model (T. E. Jensen, A. J.
Rose, J. F. P. Wojtaszewski, and E. A. Richter, unpublished observations). Importantly, CaMKII activity
is increased in contracting skeletal muscle of
humans (105) and rodents (A. J. Rose, T. E. Jensen,
and E. A. Richter, unpublished observations) during exercise/contraction, and KN62/93 impairs the
activation of CaMKII by contractions in vitro (151).
However, although CaMKII is the likely target of
KN62/93, the involvement of the other multifunc-
REVIEWS
Role of insulin-signaling intermediates
Insulin and muscle contractions both increase
muscle glucose transport, and an obvious question
to propose is whether proteins involved in signaling to insulin-stimulated glucose transport are
involved in contraction signaling to glucose transport. It has been shown that exercise or muscle
contraction does not increase tyrosine phosphorylation of the insulin receptor or insulin receptor
substrate proteins (47, 57). With respect to phosphatidylinositol 3-kinase (PI3K), studies using
incubated muscle (73, 75, 153) show that inhibition
of PI3K does not influence contraction-stimulated
glucose transport, a result not surprising given that
skeletal muscle PI3K activity is not higher with
exercise/contraction (47, 120, 136, 140, 141, 156), at
least for those isoforms examined. However, in the
perfused rat hindlimb, the PI3K inhibitor wortmannin was shown to inhibit contraction-induced
muscle glucose uptake (140, 142). The discrepancies between ex vivo (73, 75, 153) and perfused
hindlimb (140, 142) studies examining the effect of
wortmannin on contraction-stimulated glucose
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important sensor of cellular energy charge, as
reflected by the ratios of AMP/ATP and
creatine/phosphocreatine (49). AMPK activity is
higher in skeletal muscle during exercise/contraction (21, 31, 43, 62, 83, 128, 145, 146). Furthermore,
the magnitude of activation of AMPK is dependent
on exercise intensity (22, 145), which may relate to
the higher metabolic stress of recruited fibers, particularly in fast-twitch muscles (31, 60). Because
activation of AMPK in resting muscle by the drug
5⬘-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR) increases glucose transport/uptake
(9, 50, 80), it would seem logical to ascribe a role for
AMPK in contraction-stimulated glucose transport.
However, experiments with genetically manipulated mice with knockout of catalytic (62) or regulatory (7) AMPK subunits or overexpression of functionally inactive AMPK (44, 82) in skeletal muscles
have yielded conflicting results as to whether or not
AMPK is involved in contraction-stimulated glucose transport. The studies that have reduced
AMPK activity only partially (7, 44, 62) have failed
to demonstrate an effect of manipulation of AMPK
on contraction-stimulated glucose transport
despite the evidence that the knockout completely
abolished the effect of AICAR on glucose transport
in resting muscle (7, 62). On the other hand, in the
study by Mu et al. (82) in which the muscles apparently were without any AMPK enzymatic activity, a
30–40% reduction in contraction-stimulated glucose transport in fast- and slow-twitch muscles was
observed. However, later studies on these mice
revealed that there were differences in force development during repeated contractions (81), a factor
that could explain the lower contraction-stimulated glucose transport (59, 60). In addition, using the
perfused rat hindlimb, a dissociation between
AMPK activity and glucose uptake was observed in
slow-twitch but not in fast-twitch muscle, pointing
to a differing role of AMPK in different muscle fiber
types (31). It was demonstrated (31) that AMPK
activity during contractions of fast-twitch muscle
was reciprocally related to muscle glycogen content, a finding that has been replicated in humans
during exercise (103, 145). Thus, although AMPK is
an attractive candidate for signaling in contraction-stimulated muscle glucose uptake, the available evidence pro and con at this time does not
lead to a clear conclusion regarding its role. At the
very least, there does not appear to be a simple
“dose-response” relationship between AMPK activity and glucose transport during contractions.
“...there does not appear to be a simple
‘dose-response’ relationship between
AMPK activity and glucose transport
during contractions.”
transport may possibly be explained by factors not
present in the incubated muscle preparation, such
as nerve-derived agents. Indeed, stimulation of
neuregulin receptors increases skeletal muscle glucose transport in a PI3K-dependent wortmanninsensitive manner (19, 123), and given that neuregulin receptor tyrosine phosphorylation is higher
with nerve-induced contractions (71), this factor
may explain differences in wortmannin sensitivity
on contraction-stimulated glucose transport
between the two models used.
Some (111, 112, 114, 126, 127, 136) but not all (15,
78, 138, 147) studies demonstrate that skeletal
muscle protein kinase B (PKB; also known as Akt)
activity/phosphorylation is higher during exercise/contractions. It was recently shown that the
Ser/Thr phosphorylation of the PKB/Akt substrate
of 160 kDa (AS160) that is involved in GLUT4
translocation and perhaps glucose transport with
insulin in adipocytes (117, 155) is increased by contractions in rodent skeletal muscle (17). However,
both PKB and AS160 are unlikely to be involved in
contraction-stimulated glucose uptake, as their
activation/phosphorylation with contraction is
inhibitable by the drug wortmannin (17, 114),
whereas typically contraction-stimulated glucose
transport in incubated muscle is not (see above).
Indeed, a preliminary report has demonstrated no
effect of PKB-␤ knockout on contraction-stimulated glucose uptake in soleus muscle of mice (115).
Atypical PKC (aPKC) isoforms are activated by
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REVIEWS
port, but this is presently unresolved. Furthermore,
there are very few defined substrates that may act
downstream of these activated kinases. However, it
has been hypothesized that, because insulin and
contraction signaling both ultimately result in
GLUT4 translocation, there may be convergent signaling intermediates (27). Indeed, aPKC activity is
higher with insulin and exercise/contraction stimulation, and this signaling intermediate, as well as
other yet-undefined participants, may represent
the putative convergent steps toward signaling to
glucose transport. Knowledge of these signaling
mechanisms is important, as exercise can increase
skeletal muscle glucose uptake and GLUT4 translocation normally in individuals with type II diabetes.
Thus the exercise-stimulated molecular mechanism resulting in increased muscle glucose transport may be important as an alternative pathway to
increase glucose disposal in skeletal muscle in
states of insulin resistance. In fact, drugs such as
metformin and rosiglitazone that can activate
skeletal muscle AMPK (39, 84) are widely used to
treat type II diabetes. Summary and Perspectives
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The increase in skeletal muscle glucose uptake during exercise probably results from a coordinated
increase in rates of glucose delivery (higher capillary perfusion), surface membrane transport, and
intracellular substrate flux through glycolysis.
Despite considerable research, relatively little is
known about how exercise/contraction regulates
skeletal muscle glucose transport (FIGURE 4).
Although there is evidence linking activation of
CaMK isoforms and AMPK in this process, the evidence is presently not clear cut. The signaling
through CaMK isoforms is probably related to the
motor nerve activity and could be regarded as a
feedforward level of regulation. On the other hand,
AMPK is activated when the energy status of the
muscle is decreased, and hence its activation can
be regarded as a feedback level of regulation. PKC,
NOS, or PKB/Akt isoforms may also be involved in
regulation of contraction-induced glucose trans266
PHYSIOLOGY • Volume 20 • August 2005 • www.physiologyonline.org
We would like to thank Jørgen F. P. Wojtaszewski,
Sebastian Beck Jørgensen, and Thomas E. Jensen for
their careful and critical review of the manuscript before
submission.
A. J. Rose is supported by an Integrated Project funded
by the European Union (contract number LSHM-CT-2004005272) and by a postdoctoral fellowship from the
Carlsberg Foundation. The Copenhagen Muscle Research
Centre, the Danish Medical Research Council, the Danish
Natural Science Research Council, The Novo-Nordisk
Research Foundation, and the Danish Diabetes
Association are gratefully acknowledged for supporting
cited studies by the authors.
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