Departments of 1 Physiology and 2 Movement Sciences, University of Maastricht, 6200 MD Maastricht, The Netherlands; and 3 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461
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ABSTRACT |
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GLUT-4 plays a predominant role in glucose
uptake during muscle contraction. In the present study, we have
investigated in mice whether disruption of the GLUT-4 gene affects
isometric and shortening contractile performance of the dorsal flexor
muscle complex in situ. Moreover, we have explored the hypothesis that lack of GLUT-4 enhances muscle fatigability. Isometric performance normalized to muscle mass during a single tetanic contraction did not
differ between wild-type (WT) and GLUT-4-deficient [GLUT-4(/
)] mice. Shortening contractions, however, revealed a significant 1.4-fold
decrease in peak power per unit mass, most likely caused by the
fiber-type transition from fast-glycolytic fibers (IIB) to
fast-oxidative fibers (IIA) in GLUT-4(
/
) dorsal flexors. In
addition, the resting glycogen content was significantly lower (34%)
in the dorsal flexor complex of GLUT-4(
/
) mice than in WT mice.
Moreover, the muscle complex of GLUT-4(
/
) mice showed enhanced
susceptibility to fatigue, which may be related to the decline in the
muscle carbohydrate store. The significant decrease in relative work
output during the steady-state phase of the fatigue protocol suggests
that energy supply via alternative routes is not capable to compensate
fully for the lack of GLUT-4.
skeletal muscle; electrical stimulation
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INTRODUCTION |
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GLUCOSE IS A major
fuel for contracting muscle fibers (6, 20). This substrate
is supplied to the muscle fiber from extra- and intracellular sources,
i.e., blood glucose pool and intracellular glycogen (12,
25). The uptake of glucose by skeletal muscle cells is
facilitated by a family of membrane-associated glucose transporters
(GLUTs; see Refs. 1, 6, and 16).
Basal glucose uptake is mediated via the GLUT-1 isoform, whereas the
bulk of glucose is primarily transported across the sarcolemma by the insulin- and contraction-regulatable glucose transporter GLUT-4 (5, 9, 18, 24, 28, 29). After uptake, glucose is metabolized to generate ATP or is stored as glycogen (2).
During the initial phase of moderate-intensity exercise, skeletal
muscle uses the intracellular glycogen store to meet its energy demand (23). It was recently shown that, during electrical
stimulation, blood-borne glucose also serves as a suitable substrate
during moderate-intensity exercise in mice (27). To enable
detailed studies on the specific role of GLUT-4 in glucose homeostasis in general and in muscle mechanical performance in particular, mice
with the GLUT-4 gene disrupted [GLUT-4(/
)] were generated (17, 36).
Despite the importance of regulatable glucose transporters for muscle
energy metabolism, information on the impact of GLUT-4 deficiency on
muscle contractile behavior is scarce. It was recently reported that
developed isometric tension during in vitro electrical stimulation of
isolated extensor digitorum longus (EDL) muscle did not differ between
wild-type (WT) and GLUT-4(/
) mice (27). Extrapolation
of these findings to the in vivo situation, however, should be done
with caution, since the muscle fibers were studied isolated from their
natural surroundings, and only isometric contractile function was studied.
In the present study, we have investigated whether disruption of the
GLUT-4 gene affects muscular function in situ. To this end, we recently
developed an experimental model to monitor isometric and shortening
parameters of intact mouse skeletal muscle (10, 11). These
parameters include torque development of the dorsal flexors during and
the rate of relaxation after a single isometric tetanic contraction on
the one hand and peak power and optimal and maximal shortening velocity
on the other. Mass of the dorsal flexor complex, its fiber composition,
and the tissue content of high-energy phosphates have been assessed to
establish possible differences in muscle contractile behavior between
WT and GLUT-4(/
) mice. Moreover, we have explored the hypothesis
that lack of GLUT-4 results in enhanced fatigability of the dorsal
flexor complex subjected to a contraction protocol of moderate
intensity. This hypothesis was based on the notion that, under normal
conditions, glucose derived from both blood plasma and intracellular
glycogen is an important fuel for muscles contracting at moderate
intensity (13, 23).
To assess muscle fatigability, the dorsal flexors of the anesthetized mouse were subjected to a series of 150 shortening contractions. The muscle complex was electrically stimulated at 125 Hz for 200 ms every 2,000 ms (tour duty cycle, 1). Moreover, the muscle glycogen content has been measured before and after the contraction protocol.
The present study showed that the dorsal flexors of GLUT-4(/
) mice
are more susceptible to failure. This phenotypic change was associated
with a shift from fast-twitch glycolytic IIB fibers to fast-twitch
oxidative IIA fibers and a substantial decline in resting glycogen
content of the muscle complex under investigation.
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METHODS |
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Animals.
Male GLUT-4(/
) mice, as described by Katz et al. (17),
were used in the present study. Twelve-week-old male littermates (C57Bl/6) served as age-matched controls. Genotyping of the WT and
GLUT-4(
/
) mice was performed via PCR analysis. Briefly, isolation
of mouse tail DNA was performed with the DNeasy tissue kit (Qiagen,
Hilden, Germany) according to the manufacturer's instructions.
Surgical procedure. During the measurements of contractile properties, the animals were anesthetized with Halothane (Fluothane; Zeneca, Ridderkerk, The Netherlands), supplied in O2 and N2O (3:1, 1.5-2.0%) via a facemask through a flowmeter system (4.0 l/min; Medec, Montvalle, NJ). All experimental procedures were approved by the Institutional Animal Care and Use Committee of the University Maastricht and complied with the principles of laboratory animal care.
The anesthetized mice were positioned on a thermostatic platform (38.5 ± 0.1°C). After the skin was depilated locally, a small incision in the lateral part of the knee was made to expose the peroneal nerve. A bipolar platinum electrode was carefully attached to the nerve to electrically stimulate the dorsal muscle complex (tibialis anterior muscle and EDL muscle) via a pulse generator (HSE 215/IZ). The position of the electrode was changed if a current of >1.0 mA was needed to obtain supramaximal muscle contraction. The electrode was attached to the skin with cyanoacrylate glue to prevent electrode displacement during the experimental period.Experimental model.
For proper determination of isometric contractile properties of the
intact dorsal flexor complex, the anesthetized mouse was attached to
the measurement device via the hip and foot, as previously described in
detail (11). Supramaximal stimulation current, required
for full recruitment of the fibers of the muscle complex under
investigation, was first assessed using between three and five
isometric double-twitch contractions (5-ms interval) with increasing current. Resting periods between the double twitches were 60 s. Optimal muscle length at optimal ankle angle was
determined using nine double-twitch contractions at ankle angles
between 30° dorsal flexion and 30° plantar flexion. All
measurements were determined at optimal (isometric contractions) or
around (shortening contractions) optimal ankle angle. Maximal tetanic
torque was determined during a 150-ms pulse train (125-Hz stimulation
frequency). Torque signals were digitized and analyzed for maximal
tetanic torque and half-relaxation time. Maximal torque was determined from the filtered torque signals (11 point moving-average filter). The
half-relaxation time, i.e., the time taken for torque to decline from
50 to 25% of its maximal value (7), was determined from the unfiltered torque signals. Thereafter, the isometric measurement device was replaced by the mouse ergometer, i.e., the device
appropriate for measuring the characteristics of the skeletal muscle
during shortening contractions (10). During this
procedure, the optimal ankle angle was maintained. Shortening velocity
was adjusted stepwise via variation in angular stroke and rotation
frequency as indicated in Table 1.
Stimulation frequency was adjusted to angular velocity (26).
|
Fatigue protocol. After a 10-min recovery period after the determination of basal isometric and shortening properties, dorsal flexors were subjected to a series of 150 shortening contractions. The muscle complex was electrically stimulated at 125 Hz for 200 ms every 2,000 ms (tour duty cycle, 1), at 1 Hz angular frequency with a 20° stroke. In this way, electrically stimulated and nonstimulated strokes alternated.
The torque output measured during electrical stimulation equals the sum of frictional torque, inertial torque, passive muscle torque, and the active muscle torque. The active torque of the muscle contraction was calculated by subtraction of the torque measured during a nonstimulated stroke (frictional torque, inertial torque, and passive torque) from the torque signal measured in a stimulated stroke (total torque). Absolute work output of the individual shortening contractions was calculated by integrating active torque over angle. Specific work is defined as absolute work per unit dorsal flexor muscle mass. Relative work during the course of the fatigue protocol is work normalized to work output during the first contraction of the series.Tissue sampling.
A subset of mice was used to determine glycogen content in the dorsal
flexor complex after the 150 shortening contractions. The muscle
complex of the nonstimulated contralateral leg was used as a control.
These contralateral muscles were also used for analysis of resting
high-energy phosphate levels. A second set of contralateral muscles was
frozen in melting isopentane for light microscopic analysis, i.e.,
myosin ATPase staining and determination of the cross-sectional areas
of the muscle fibers. The tissue samples were stored at 80°C until analysis.
Biochemical and histochemical assays.
Before glycogen and high-energy phosphate analysis, muscle complexes
were freeze-dried overnight at 30°C. High-energy phosphates and
related compounds were assessed by HPLC (31, 33). Glycogen content was measured fluorimetrically in HCl extracts of the dorsal flexors and was expressed as micromole glycosyl unit per gram dry
weight (19). For fiber-type distribution and fiber
diameter analysis, the midbelly regions of the dorsal flexor complex
were frozen in melting isopentane. Frozen dorsal flexors were
cryosectioned (10 µm) at
20°C, thaw-mounted on glass slides, and
air-dried until analysis for myosin ATPase staining (4)
and fiber diameter measurements.
Statistics.
Data are expressed as means and SD. Differences in mechanical
parameters, high-energy phosphates, and glycogen content and fiber
characteristics between GLUT-4(/
) mice and WT were analyzed using
the nonparametric Mann-Whitney U-test. Differences in work output at individual times during the fatigue protocol were analyzed using repeated-measures ANOVA with Scheffé's post hoc analyses to identify differences between GLUT-4(
/
) and WT mice. Increased fatigability in GLUT-4(
/
) mice was tested as the difference in mean
relative work output over the last 40 contractions of the fatigue
protocol by a one-sided Mann-Whitney U-test. Differences were considered significant at P < 0.05. SPSS 9.0 (SPSS Benelux, Gorinchem, The Netherlands) was used for statistical analyses.
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RESULTS |
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The values of body, heart, and dorsal flexor mass are shown in
Table 2. Body mass of GLUT-4(/
) mice
was significantly lower than WT littermates. Dorsal flexor mass of
GLUT-4(
/
) mice amounted to 59.2 ± 5.8 mg, which was
significantly lower than the dorsal flexors of the WT (69.3 ± 9.7 mg). In contrast, heart mass of the GLUT-4(
/
) mice showed a
significant 1.4-fold increase compared with WT.
|
Single isometric and shortening contraction.
Maximal torque developed during a single isometric tetanic contraction
of the dorsal flexors at a 125-Hz stimulation frequency was 1.3-fold
higher (P < 0.05) in WT than in GLUT-4(/
) mice (Table 3). However, when the maximal
torque was normalized to dorsal flexor mass, the values of
GLUT-4(
/
) mice did not differ from their WT littermates.
Half-relaxation time after a maximal tetanic contraction was not
significantly different between GLUT-4(
/
) and WT.
|
Fatigue protocol.
When the dorsal flexors were subjected to a series of 150 shortening
contractions, three different phases in the specific work output could
be observed (Fig. 1A). In WT,
specific work output remained stable at ~3.4 mJ/g wet wt for the
first 25 shortening contractions (phase 1).
Thereafter, specific work output gradually declined (phase
2). From the 110th shortening contraction, specific work output
became steady again and was ~1.3 mJ/g wet wt (phase 3). Figure 1A clearly shows that phase 1 is
lacking in GLUT-4(/
). Specific work output by GLUT-4(
/
) muscles
immediately declined when subjected to the fatigue protocol. Specific
work output stabilized at 1.0 mJ/g wet wt after the 90th shortening
contraction (phase 3, Fig. 1A).
Statistical analysis revealed that specific work output at each
distinct contraction was significantly lower in GLUT-4(
/
) than in
WT.
|
Glycogen and high-energy phosphate content.
Resting muscle glycogen content was significantly lower in
GLUT-4(/
) dorsal flexors than in WT (Fig.
2). After 150 shortening contractions, WT
mice showed a significant decline of muscle glycogen from 112 ± 16 to 66 ± 13 µmol glycosyl U/g dry wt. In contrast, GLUT-4(
/
) dorsal flexors showed no statistically significant decline in glycogen, i.e., pre- and postexercise levels were 74 ± 19 and 55 ± 22 µmol glycosyl moieties/g dry wt, respectively.
|
Fiber-type composition and fiber cross-sectional area.
Both in tibialis anterior and EDL muscle, GLUT-4(/
) mice showed a
significant decline in relative number of IIB fibers compared with the
fiber distribution in the corresponding WT muscles (Table 4). In contrast, the relative number of
type IIA fibers increased in GLUT-4(
/
) muscle. Type IIA fibers
showed a relatively higher contribution to the muscle cross-sectional
area in GLUT-4(
/
) at the expense of type IIB fibers. The absolute
cross-sectional area of single fibers belonging to the respective
subtypes did not differ between WT and GLUT-4(
/
), neither in
tibialis anterior nor in EDL muscle.
|
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DISCUSSION |
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The bulk of glucose taken up by skeletal muscle tissue is facilitated by GLUT-1 and GLUT-4, where GLUT-4 is the predominant glucose transporter in muscle cells after a contraction stimulus. Here we provide more insight into the consequence of GLUT-4 deficiency for contractile performance of the intact dorsal flexors during a single isometric and shortening contraction. Moreover, we have investigated whether GLUT-4 deficiency results in enhanced fatigability of the dorsal flexors in their natural surrounding during repetitive shortening contractions.
Single isometric tetanic contraction.
The present findings show that the maximal tetanic torque output in
dorsal flexors of GLUT-4(/
) is significantly declined compared with
age-matched WT. Interestingly, the mass of the dorsal flexors of
GLUT-4(
/
) was also significantly declined compared with WT. After
normalization of tetanic torque to muscle mass, no significant
difference between GLUT-4(
/
) and WT could be observed (Table 3).
These results corroborate earlier findings in an isolated muscle
preparation, which showed that isometric peak tension per unit muscle
mass was comparable between GLUT-4(
/
) and control mice
(27). The content of high-energy phosphates was found to
be comparable between resting WT and GLUT-4(
/
) dorsal flexors. This
observation underlines the notion that the decrease in tetanic torque
in GLUT-4(
/
) is mainly caused by decreased muscle mass rather than
a decline in available high-energy phosphates.
Muscle performance during shortening contractions.
In contrast to contractile performance during isometric contractions,
the maximal peak power, even after normalization to muscle mass, was
significantly lower in GLUT-4(/
) muscle than in WT, i.e., 260 vs.
360 mW/g wet wt. Peak power output depends, among others, on the fiber
composition of the muscle under investigation. This notion is supported
by data in literature about differences in power output of distinct
types of skinned fibers (3, 21, 32). Bottinelli and
coworkers (3) reported that peak power of rat skinned
fibers, measured at 12°C, was substantially higher for fast-twitch
glycolytic (IIB) fibers than fast-twitch oxidative (IIA) fibers.
Because in both the tibialis anterior and the EDL muscle of
GLUT-4(
/
) mice the relative contribution of IIA fibers to the
muscle cross-sectional area increased at the expense of IIB fibers, it
is tempting to state that the change in fiber-type composition in
GLUT-4(
/
) dorsal flexors contributes to the lower peak power per
unit muscle mass in GLUT-4(
/
).
Tissue glycogen content.
In the present study, an appreciably lower glycogen content was
observed in the dorsal flexors, consisting of the tibialis anterior and
EDL muscle, of male GLUT-4(/
) mice compared with age-matched WT.
From the literature, no consistent pattern emerges on this subject.
Fiber-type composition.
A striking observation in this study is the decline in the relative
number of type IIB fibers and the increase in the relative number of
type IIA fibers in both EDL and tibialis anterior muscle of
GLUT-4(/
) mice. These changes resulted in an increased contribution of type IIA and a decreased contribution of type IIB fibers to the
cross-sectional area of the muscle. Of interest is the finding that the
cross-sectional area of individual muscle fibers did not change. At
present, it is unclear what caused the change in the fiber-type
composition of GLUT-4(
/
) muscles. Taking into account that the
overall muscle mass is lower in GLUT-4(
/
) than in age-matched WT
one may assume atrophy specifically of type IIB fibers. In the case of
atrophy, one should expect a significant decline of the cross-sectional
area of the affected muscle cells. Because the cross-sectional area of
IIB fibers in the muscles under investigation tended to increase rather
than decrease, atrophy of type IIB fiber is less likely. Alternatively,
the decline observed in the number of type IIB fibers may also be
caused by a decline in IIB fiber formation during prenatal development
of muscle tissue or by atrophy during an early stage of postnatal life
as a direct or indirect consequence of the genetic defect.
Theoretically, changes in physical activity may also contribute to the
altered fiber-type composition in GLUT-4(
/
) muscle. However, we
consider this possible cause for the shift from type IIB to IIA fibers less likely since previous studies have shown that relatively high
training levels are required to evoke a change in fiber-type composition (34), but we failed to notice a difference in
spontaneous physical activity of the GLUT-4(
/
) mice in their cages
(unpublished observations).
Fatigue protocol.
When subjected to the fatigue protocol, WT muscles showed a typical
pattern in both specific and relative work output. After an initial
phase of stable work output during the first 25 shortening contractions, work output declined rapidly (phase 2)
until another phase of steady-state work output was reached
approximately at the 110th contraction (phase 3).
GLUT-4(/
) muscles were found to lack the first phase of relatively
stable work output. In contrast to WT, in GLUT-4(
/
) signs of
fatigue were immediately apparent after the onset of the shortening
contraction protocol. On average, the rate of decline in work output
was comparable between GLUT-4(
/
) and WT mice (phase
2). Numerous studies have been performed to elucidate the
mechanisms underlying muscular fatigue (8). Among others,
evidence is accumulating that the amount of endogenous glycogen
available for energy conversion and the occurrence of fatigue are
closely related (1, 4, 6). One may therefore speculate
that the low glycogen content in GLUT-4(
/
) dorsal flexors at the
start of the shortening contraction protocol and the apparent inability
of the muscle cells to break into the carbohydrate store contribute to
the absence of the initial phase of constant work output and the early
onset of fatigue.
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ACKNOWLEDGEMENTS |
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We acknowledge Dr. H. van Straaten from the Department of Anatomy/Embryology, Maastricht University, The Netherlands for support in analyzing muscle fiber composition. We are thank Claire Bollen for help in preparing the manuscript.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. J. van der Vusse, Dept. of Physiology, Maastricht Univ., P.O. Box 616, 6200 MD, Maastricht, The Netherlands (E-mail: vandervusse{at}fys.unimaas.nl).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00085.2001
Received 2 March 2001; accepted in final form 24 September 2001.
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