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Vol. 83, Issue 5, 1623-1629, 1997
1 Division of Geriatric
Medicine, ABSTRACT Larkin, Lisa, Eric R. Leiendecker, Mark Supiano, and Jeffrey
Halter. Glucose transporter content and enzymes of metabolism in
nerve-repair grafted muscle of aging Fischer 344 rats.
J. Appl. Physiol. 83(5):
1623-1629, 1997.
glucose transporter protein; messenger ribonuclease content; muscle
regeneration
INTRODUCTION AGING AND NERVE-REPAIR muscle grafting are associated
with a decrease in the ability of skeletal muscle to sustain power
during repetitive stimulation (21). One potential explanation for this decrease in the ability of the muscle to function during a bout of
endurance exercise is alterations in glucose delivery to the muscle.
Glucose enters skeletal muscle via a facilitated transport system
involving two isoforms of glucose transporters: GLUT-1, which is
responsible for uptake during basal conditions (16, 28), and GLUT-4,
which is responsible for insulin- and contraction-stimulated glucose
uptake (6, 23). Decreased expression of either isoform of glucose
transporter may lead to diminished fuel availability to muscle during
endurance exercise. In addition, alterations in the metabolic integrity
of the grafts, such as decreased glycolysis, diminished storage of
glucose, or decreased oxidative capacity, may contribute to the
inability of the grafted muscle to sustain power, and aging may be
associated with further decreases in metabolic capacity.
Denervation is associated with elevated basal glucose transport (5, 11)
and diminished insulin-stimulated glucose transport (5, 11). In
accordance, denervation is associated with altered expression of
skeletal muscle glucose transporter protein isoforms: upregulation of
GLUT-1 protein and mRNA content (3, 5, 11) and downregulation of GLUT-4
protein and mRNA content (3, 5, 11). To date, no studies have examined
the effect of reinnervation after a nerve-repair grafting procedure on
glucose transporter content. It is possible that continued alteration
in the expression of glucose transporters may lead to diminished fuel
availability during a bout of endurance exercise.
The effect of age on GLUT-4 expression has been studied in humans and
in several rat models. In the female Fischer 344 (F-344) rat, there is
no significant age-associated decline in GLUT-4 protein content (2),
and in the female Long-Evans rat there is no age-associated decline in
glucose uptake or GLUT-4 protein content (10). In contrast, in male
F-344 control (nonexercised) rats, Kern et al. (15) have shown a trend
toward an age-associated decline in GLUT-4 content in gastrocnemius and
extensor digitorum longus muscles. A recent study in aging humans
suggests an age-associated decline in GLUT-4 content in the vastus
lateralis but not in the gastrocnemius muscle in both men and women
(14). In a study of male F-344 × Brown Norway F1 hybrid rats
(F-334 × BN), ages 9, 20, and 31 mo, there was no age-associated
alteration in GLUT-1 expression in the soleus and epitrochlearis
muscles (4). Several studies have shown an age-associated increase in
the proportion of denervated skeletal muscle fibers (1, 17). Therefore, an alteration in the content of glucose transporters caused by an
increase in the number of denervated muscle fibers may play a role in
the decreased ability of senescent muscle to function during a bout of
endurance exercise.
Like disuse atrophy, denervation in skeletal muscle is associated with
a shift to a more glycolytic metabolism in which glycogen stores are
utilized as the major fuel for energy (24). Aging is also associated
with a shift to a more glycolytic metabolism, as indicated by an
age-related decline in skeletal muscle citrate synthase, an indicator
of the oxidative capacity, with no age-associated alteration in
glycogen content (20); in hexokinase, the key enzyme in the conversion
of cellular free glucose to glucose 6-phosphate (13); or in
phosphofructokinase, the key enzyme in glycolysis (13). It
is possible that the diminished ability of both grafted and senescent
muscle to perform a bout of endurance exercise may be explained by a
decrease in oxidative capacity of the muscle.
In this study, we investigated the effect of age and nerve-repair
grafting on GLUT-4 and GLUT-1 protein and mRNA content. We tested the
hypothesis that the medial gastrocnemius (MG) muscle of senescent male
F-344 rats would have a metabolic profile similar to denervated muscle.
Thus, with age, GLUT-1 protein and mRNA content would be upregulated
and GLUT- 4 protein and mRNA content would be downregulated. In
addition, we tested the hypothesis that, in senescent muscle, the
shifts in glucose transporter protein and mRNA content would be
exacerbated by a nerve-repair grafting procedure. We also tested the
hypothesis that aging and nerve-repair grafting of MG would be
associated with diminished glycogen stores and diminished activity of
enzymes of both glycolysis and the tricarboxylic acid
cycle.
METHODS
Aging and grafting are associated with decreased
ability of muscle to sustain power, likely reflecting diminished fuel
availability. To assess mechanisms that may contribute to availability
of glucose, we studied GLUT-1 and GLUT-4 protein as well as mRNA
contents and enzymes of glucose metabolism in grafted and control
medial gastrocnemius (MG) muscles of 6-, 12-, and
24-mo-old male Fischer 344 rats. There was no effect of age or grafting
on MG GLUT-4 content. There was both an age- and graft-associated increase in GLUT-1 content (P = 0.0044 and 0.0063, respectively). There was no effect of aging or grafting on
hexokinase and phosphofructokinase activity or on protein and glycogen
content. Muscle mass and citrate synthase activity were significantly
diminished with grafting. Citrate synthase activity was significantly
greater in the 12-mo-old compared with the 6- and 24-mo-old animals.
Grafting in combination with aging had no impact on any of the
parameters measured. We conclude that diminished glucose transporter
expression cannot explain the decreased ability of aged muscle to
sustain power. In addition, we conclude that the diminished ability of
the grafted MG muscle to sustain power may be explained, in part, by a
decrease in energy available from oxidative metabolism.
1 · min1)
by using the method of Serre (30). Hexokinase activity (U/mg protein)
was measured by using the method of Easterby and Qadri (7). Phosphofructokinase activity
(µmmol · mg
protein1 · min1)
was measured by using the method of Mansour et al. (22). Protein content (mg/g tissue) was determined by using a Bradford protein assay
kit from Bio-Rad (Richmond, CA).
GLUT-1 and GLUT-4 Western blotting.
Total membranes were isolated from 100 mg of frozen gastrocnemius
muscle as follows. Frozen tissues (200 mg) were powdered in a mortar
and pestle that were cooled in liquid
N2. Powdered tissues were
suspended in 5.0 ml of ice-cold SSS buffer (10 mM NaHCO3, 0.25 M sucrose, and 5.0 mM
NaN3) and homogenized twice for
10 s by using a Brinkman polytron (setting 7). Homogenates were
centrifuged at 1,200 g for 10 min at
4°C. Pellets were resuspended in 5 ml of ice-cold SSS buffer and
centrifuged at 1,200 g for 10 min at
4°C. Supernatants were combined and centrifuged at 190,000 g for 66 min at 4°C. Pellets were
then resuspended in 500 µl ice-cold SSS buffer and stored at
70°C.
Western analysis of GLUT-1 and GLUT-4 was performed by using vertical
slab polyacrylamide gel electrophoresis in the presence of sodium
dodecyl sulfate (SDS) on molecular weight markers (Amersham, Arlington
Heights, IL) and aliquots of muscle membranes, each containing 30 mg
protein. An internal control sample was run on all gels; the sample
consisted of an aliquot (30 mg protein) of a muscle membrane pool
obtained from combined muscle homogenates. Duplicate
samples from each animal were separated on a 10% polyacrylamide resolving gel and then eletrophoretically transferred onto Immobilon polyvinyldifluoride membrane (Millipore, Milford, MA).
Immobilon polyvinyldifluoride membranes were then blocked for 60 min
with tris(hydroxymethyl)aminomethane -buffered saline with Tween-20 (100 mM tris(hydroxymethyl)aminomethane, 0.9% NaCl, 2.0 ml Tween-20, pH 7.5) and 5% Carnation nonfat dry milk. Immunoblotting was performed by using a rabbit polyclonal antibody against rat brain GLUT-1 or
insulin-regulatable GLUT-4 protein (East Acres Biologicals, Southbridge, MA), followed by
125I-labeled anti-rabbit
immunoglobulin (Amersham) and exposure of the transfer membrane to
Kodak X-OMAT film at 80°C for 24 h. 125I-labeled transfer membranes
were then cut and counted on a gamma counter (Tm Analytic, Elk Village,
IL). Total counts per minute were corrected for background, and then
specific counts were normalized for the internal standard. There was a
single band for both GLUT-1 and GLUT-4 protein at a molecular mass of
45 kDa.
GLUT-1 and GLUT-4 Northern blotting.
RNA was isolated from 100 mg of frozen gastrocnemius muscle by using
TRI reagent, a single-step method of RNA isolation by using acid
guanidinium thiocyanate-phenol-chloroform extraction (Molecular
Research Center, Cincinnati, OH). Then 10 µg per lane of RNA were
electrophoresed on 1% formaldehyde-agarose gels and transferred onto
nylon Biotrans membranes (Boehringer Mannheim, Indianapolis, IN).
Quality of RNA was confirmed by staining with methylene blue. RNA was
fixed to the membrane by baking the membrane in a vacuum oven for 2 h
at 80°C. GLUT-1 cDNA was obtained from Dr. Frank C. Brosius, and
GLUT-4 cDNA was obtained from Dr. Jessica Schwartz, both at the
University of Michigan, Ann Arbor, MI. Both cDNAs were used to
synthesize a cRNA probe with the use of T7 polymerase and the Genius 4 RNA-labeling kit as described by the manufacturer (Boehringer
Mannheim). Hybridization of the cRNA probe was carried out at 65°C
in a hybridization solution consisting of 50% formamide, 5×
saline sodium citrate (SSC), 0.2% SDS, 0.1% N-lauroysarcosine, and 2% blocking
reagent (Genius System, Boehringer Mannheim). Membranes were washed
twice for 15 min in 2× SSC, 0.1% SDS at 65°C and twice for
15 min in 0.5× SSC, 0.1% SDS at 65°C. Detection of
digoxigenin-labeled GLUT-1 and GLUT-4 mRNA was performed by using the chemiluminescent substrate Lumi-Phos 530, Genius System
(Boehringer Mannheim) and exposing the membrane to Kodak X-OMAT film at 25°C for 1.5 h. The abundance of GLUT-1 and GLUT-4 mRNA signal was determined by using a densitometer. Each membrane consisted of duplicate samples from one animal from each age group randomly loaded into inner lanes and duplicate samples of a control sample loaded into the two outside lanes. The average signal for each animal was corrected for the average control signal on
the membrane. The signal was then expressed as a percentage of the 6-mo-old age group.
Statistics.
Values are presented as means + SE. Statistical analysis was performed
by using Statview 4.01 (Abacus Concepts, Berkeley, CA). An analysis of
variance was used to compare differences between rats at various ages
and grafted groups. When a significant main effect was found, the
Fisher's least-significant difference post hoc test was used to
determine differences between the age and grafted groups. Differences
were considered significant at P < 0.05.
RESULTS
1 · mg
protein1) activity or
protein (mg protein/g tissue) and glycogen (µmol/g muscle) content
(Table 1). Muscle mass (g) and citrate synthase activity
(µmol · µg
protein1 · min1)
were both significantly lower in the grafted muscles
(P = 0.0162 and
P = 0.0004, respectively; Table 1).
There was also a significant effect of age on muscle mass and citrate
synthase activity (P = 0.0036 and
P = 0.001, respectively). However, the
age effect on citrate synthase activity was complex; it was
significantly greater in the 12-mo-old compared with the 6- and
24-mo-old animals. There was no significant interaction of grafting
with aging on any of the parameters measured. Thus the effect of
grafting was not greater in older compared with younger animals.
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GLUT-1 protein and mRNA content. There was both a significant age- and graft-associated increase in GLUT-1 protein content (Fig. 3). After the grafting procedure, there was no greater increase in GLUT-1 protein content in senescent grafted muscle compared with younger grafted muscles. There tended to be an age-associated increase in GLUT-1 mRNA content of control muscle (Fig. 4). However, this did not reach statistical significance. There was a significant graft-associated increase in GLUT-1 mRNA content. After the grafting procedure, there was no greater increase in GLUT-1 mRNA content in senescent grafted muscle compared with younger grafted muscles.
DISCUSSION
Previous studies (3, 5, 11) have shown that after denervation of muscle, GLUT-1 protein content is increased and GLUT-4 protein content is decreased. The present study extends these previous observations by showing that 120 days after a nerve-repair graft in MG muscle, as in acute denervation, both GLUT-1 protein and mRNA content are significantly increased. However, unlike the case in denervation, GLUT-4 content and mRNA content were not significantly altered in stabilized nerve-repair graft MG muscles. In addition, the present study shows that in the MG muscle GLUT-1 protein content increased, whereas GLUT-4 protein content remained unchanged, with increasing age. The mRNA contents of the two glucose transporters followed the same trends as the respective protein contents. There was an age- and graft-associated decline in citrate synthase activity that suggests diminished oxidative capacity of these muscles. In addition, there was no age- or graft-associated alteration in glycogen content, hexokinase, or phosphofructokinase activity. This result suggests there is no alteration in the glycolytic capacity of these muscles. Grafting in combination with aging had no further impact on any of the parameters measured.
Previous studies from our laboratory (19) have shown that, at 120 days after nerve-repair grafting, muscle contractile function has stabilized but has not returned to control values. The ability of the stabilized graft muscle to perform an endurance exercise protocol in decreased by ~50% compared with control muscle. It is possible that altered glucose transporter expression could diminish fuel available to working muscle and, thereby, decrease the ability to perform an endurance-exercise protocol. In the present study, GLUT-4 protein, which is responsible for insulin- and contraction-stimulated glucose uptake (6, 23), is not diminished in nerve-repair grafted compared with control muscle. Therefore, it is not likely that decreased expression of GLUT-4 plays a role in the diminished ability of the MG to perform endurance exercise. In fact, data from a study in humans (25) showed that the increase in skeletal muscle GLUT-4 protein content observed with endurance training is associated with diminished exercise-stimulated glucose uptake, suggesting that glucose disposal may be inversely related to GLUT-4 protein content in some metabolic conditions. Although the content of GLUT-4 is correlated with the uptake of glucose into skeletal muscle during contractions, the translocation of the glucose transporter to the plasma membrane from intracellular pools and the intrinsic activity of the transporter once docked at the plasma membrane are also factors influencing the uptake of glucose into working muscle and must be investigated in future studies.
The observed increase in GLUT-1 content in the senescent and grafted muscle is compatible with the altered expression of glucose transporter isoforms observed in populations of denervated fibers. Block et al. (3) first noted that denervation was associated with reexpression of neonatal isoforms of glucose transporters. In the fetus, GLUT-1 is the primary isoform of glucose transporter in skeletal muscle, whereas GLUT-4 protein content is undetectable (29). At birth, GLUT-1 protein content diminishes and GLUT-4 protein content increases, both reaching adult levels at ~10 days of age (29). Several studies (3, 5, 11) have demonstrated that, at 3 days postdenervation in skeletal muscle, GLUT-1 protein and mRNA content are increased while GLUT-4 protein and mRNA content are diminished. The increased GLUT-1 protein content may improve the ability to recover after an injury by increasing basal glucose transport and by increasing available energy for tissue repair. Ren et al. (28) have demonstrated that overexpression of the GLUT-1 isoform is associated with a 10-fold increase in glycogen concentration in the skeletal muscle that was not caused either by an increase in glycogen synthase activity or by a decrease in glycogen phosphorylase activity.
This being the case, the increase in GLUT-1 content in the MG muscle of grafted and aged animals could enhance glycogen storage and increase substrate available for use during an endurance exercise bout. However, we observed no significant increase in glycogen content in the grafted compared with control muscle. The increases in GLUT-1 protein content that we observed, ranging from 43 to 16% (6 and 24 mo, respectively), are substantially less than the changes seen by Ren et al. (28) in transgenic mice and therefore may not have been enough to enhance the storage of glycogen. Furthermore, because limited tissue was available for study, we were unable to investigate the specific location (perineural vs. muscle plasma membrane) of the increased GLUT-1 protein. Thus it is possible that the increase was in neural rather than muscle tissue with negligible effect on muscle metabolism. Further studies need to be done to investigate this possibility.
A previous study (4) in male F-344 × BN rats reported no age-associated alteration in GLUT-1 expression in either the soleus or the epitrochlearis muscle. In contrast, in the present study, we observed an age-associated increase in GLUT-1 protein content in the MG muscle of male F-344 rats. The discrepancy between these two studies may possibly be explained by the different muscles, the age of the rats, and/or the strain of rats studied. In the F-344 × BN study, there was a tendency for increased GLUT-1 content in the epitrochlearis muscle, which is similar to the MG in fiber type; in the 9-mo-old compared with the 20-mo-old rats; and in the decline to 9-mo-old values in the 31-mo-old animals. The median life span for the F-344×BN rat is 28 mo and for the F-344 rat is 24 mo. It is possible that GLUT-1 content in muscles with predominantly type IIb fibers (epitrochlearis and MG) is increased with age until the median life span is reached and that there is then an age-associated decline in GLUT-1 content concomitant with the age-associated decline in muscle weight.
Previous studies have shown that the recovery of muscle functionality in grafted muscle is associated with the degree of reinnervation and revascularization of the muscle after the grafting procedure. In our model, incomplete revascularization cannot explain the diminished endurance capacity in the grafted MG muscle because the vasculature was left intact during the surgical procedure. On the other hand, the nerve to the MG muscle was severed and repaired during the grafting procedure, so incomplete reinnervation could be a contributing factor. One study has shown that disuse of skeletal muscle due to denervation leads to a decrease in the oxidative capacity of skeletal muscle (27). We found that citrate synthase activity, an indicator of oxidative capacity in skeletal muscle, was lower in the grafted compared with control muscle. Therefore, the diminished ability of the grafted muscle to perform an endurance-exercise bout may be caused in part by incomplete reinnervation of the MG muscle, thus leading to disuse and subsequent decreased activity of enzymes associated with oxidative metabolism. Further studies are needed to determine the completeness of the reinnervation of grafted MG muscles and to test this hypothesis.
In physiological conditions in which low oxidative capacity exists, such as disuse atrophy after denervation, skeletal muscle will shift to a more glycolytic metabolism and utilize glycogen stores as the major fuel for energy (24). With recovery from denervation, oxidative enzymes increase and the muscle shifts back to a more oxidative energy metabolism. In the present study, GLUT-4 protein content and hexokinase activity did not significantly differ in grafted compared with control muscle. This result suggests that the capacity for glucose uptake into the muscle cell is unchanged. In addition, the activity of phosphofructokinase, the key regulatory enzyme for glycolysis, was unchanged after the grafting procedure, suggesting no impairment in the glycolytic pathway. In contrast, citrate synthase, an indicator of oxidative capacity, was diminished in the grafted compared with control muscle. It is possible that the stabilized grafted MG muscle has shifted toward glycolytic metabolism and could be relying on glucose uptake from the circulation as well as its glycogen stores as the major sources of energy. However, glycogen stores may become rapidly depleted and are thus unsuitable for supplying needed energy for endurance exercise.
Previous studies have shown varied age-associated changes in glycogen content of resting muscle. The soleus and gastrocnemius muscles showed no age-associated change, whereas the extensor digitorum longus showed an age-related decline in glycogen content (18). Fitts et al. (8) showed that, although glycogen content in old muscle was not significantly different from mature muscle, when the aging muscle was subjected to 30 min of contractile activity, there was a significant decrease in the ability to spare glycogen. Lactate reached twofold higher levels, and glycogen fell to considerably lower levels in the muscles of the old rats, suggesting an increased glycolysis and glycogen utilization during contractile activity in aged rats (8). Hexokinase, the key enzyme in the conversion of cellular free glucose to glucose 6-phosphate, remains unchanged with age in both slow-oxidative and fast-glycolytic muscles (13). Phosphofructokinase (the key enzyme in glycolysis) has been shown to remain unchanged in slow-oxidative and to decrease in fast-glycolytic muscles of old (28-mo-old) compared with mature (9-mo-old) rats (13). Citrate synthase, an indicator of the oxidative capacity of muscle, has been shown to decrease with increasing age in gastrocnemius muscle of male F-344 rats (20). It is possible that, like denervated skeletal muscle, aging muscles metabolize carbohydrate via glycolytic rather than oxidative pathways to a greater degree than do younger muscles.
In conclusion, we have shown that a 120-day recovery period after a nerve-repair grafting procedure is associated both with continued upregulation of both GLUT-1 protein and mRNA content and with no alteration in the expression of GLUT-4 content and mRNA. In addition, aging is associated with a glucose transporter profile similar to that of denervated muscle, in that GLUT-1 protein content increased with increasing age. However, unlike the case with denervation, GLUT-4 protein content remained unchanged with increasing age. Aging is not associated with a decreased ability to express glucose transporters after a nerve-repair grafting procedure because there was no further impact on either GLUT-1 or GLUT-4 protein or mRNA contents. Furthermore, the decreased ability of grafted and senescent muscle to function during a bout of endurance exercise may not be explained by a decrease in GLUT-4 protein content. Finally, we conclude that the diminished ability of the aged and grafted MG muscle to sustain power may be explained, in part, by a decrease in energy available from oxidative metabolism.
ACKNOWLEDGEMENTS
This research was supported in part by National Institute on Aging Training Grant T32-AG-00114; the Core Facility for Aged Rodents of the Claude Pepper Older Americans Independence Center at the University of Michigan (AG-08808); National Institute on Aging Grant K01-AG-00710; the Medical Research Service of the Department of Veterans Affairs; and the Geriatric Research, Education, and Clinical Center, Ann Arbor Veterans Affairs Medical Center.
FOOTNOTES
Address for reprint requests: L. M. Larkin, Geriatrics Center, MSRB3, 6301, 1150 West Medical Center Dr., Univ. of Michigan, Ann Arbor, MI 48109-0642.
Received 4 April 1997; accepted in final form 8 July 1997.
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