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1 Exercise Physiology and Metabolism Laboratory, Department of Physiology, and 2 Howard Florey Institute of Experimental Physiology and Medicine, The University of Melbourne, Parkville, Victoria 3052, Australia
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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To examine the effect of exercise on heat shock protein (HSP) 72 mRNA expression in skeletal muscle, five healthy humans (20 ± 1 yr; 64 ± 3 kg; peak O2 uptake of 2.55 ± 0.2 l/min) cycled until exhaustion at a workload corresponding to 63% peak O2 uptake. Muscle was sampled from the vastus lateralis, and muscle temperature was measured at rest (R), 10 min of exercise (Min10), ~40 min before fatigue (F-40 = 144 ± 7 min), and fatigue (F = 186 ± 15 min). Muscle samples were analyzed for HSP72 mRNA expression, as well as glycogen and lactate concentration. Muscle temperature increased (P < 0.05) during the first 10 min of exercise but then remained constant for the duration of the exercise. Similarly, lactate concentration increased (P < 0.05) when Min10 was compared with R but decreased (P < 0.05) thereafter, such that concentrations at F-40 and F were not different from those at R. In contrast, muscle glycogen concentration fell progressively throughout exercise (486 ± 74 vs. 25 ± 7 mmol/kg dry weight for R and F, respectively; P < 0.05). HSP72 mRNA was detected at R but did not increase by Min10. However, HSP72 mRNA increased (P < 0.05) 2.2 ± 0.5- and 2.6 ± 0.9-fold, respectively, when F-40 and F were compared with R. These data demonstrate that HSP72 mRNA increases progressively during acute cycling, suggesting that processes that take place throughout concentric exercise are capable of initiating a stress response.
contraction; glycogenolysis; real-time polymerase chain reaction; temperature
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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A MAJOR QUESTION IN BIOLOGY is how cells cope with disruption to homeostasis, which, if left unchecked, would lead to irreversible cell damage. To combat protein-related homeostatic disruption, cells respond by synthesizing a family of highly conserved proteins, termed heat shock proteins (HSP), which were first cloned in the 1960s (21). HSP bind to denatured proteins and are involved in the assembly of protein complexes (18), which is why they are also known as "molecular chaperones" (6). HSP are classified into families according to mass (for review, see Ref. 13). The most abundant and widely studied family is the 70-kDa family, which contains the constitutive HSP73 and inducible HSP72 forms.
Some of the conditions known to activate HSP72 include increased temperature (17), ischemia (16), protein degradation (2), hypoxia (7), acidosis (28), reduced glucose availability (24), oxyradical formation (27), and increased intracellular Ca2+ (29). These factors are characteristic of contracting mammalian skeletal muscle cells, and it is, therefore, not surprising that both HSP gene and protein expression are upregulated in the heart (23, 25), liver (23), and skeletal muscle (14, 23, 25) of rodents in response to acute treadmill running. Interestingly, however, no increase in HSP mRNA in rat heart muscles occurs after swimming exercise (8). Whether HSP gene and or protein expression increases during concentric exercise in human skeletal muscle is not known. It is possible, therefore, that HSP expression may only increase in human skeletal muscle in response to exercise, which is predominantly eccentric in nature because of the greater susceptibility to protein damage.
Because the increase in temperature and other cellular events take place simultaneously during contraction, it is not clear whether HSP72 expression can increase during exercise independent of changes in contracting cell temperature. Skidmore et al. (25) attempted to address this issue by exercising rats in a cool environment so that colonic temperatures did not differ from the basal state. The HSP72 content of the soleus, extensor digitorum longus, and gastrocnemius muscles was elevated 30 min after exercise, suggesting that factors other than heat that are associated with the exercise can contribute to the accumulation of HSP72. Whereas these data suggest that increased temperature generated during exercise may not be the only factor capable of inducing HSP, it is important to note that an absence of a rise in colonic temperature does not necessarily mean that the temperature of the contracting tissue was stable. Indeed, we have blunted the rise in rectal temperature in humans during exercise in a cool environment and observed a 3.3°C increase in vastus lateralis temperature (5). Further research is required to differentiate the effects of elevated temperature and other exercise-induced disruptions to cell homeostasis on HSP gene expression.
Although the effect of exercise on the HSP response in rodents is well documented (8, 12, 14, 15, 23, 25), there are relatively few studies that have examined this phenomenon in humans, and these have produced conflicting results. Acute exercise either increases (22) or has no effect (1) on HSP72 protein expression in human leukocytes. Only one study has previously examined the effect of acute exercise on HSP72 in human skeletal muscle. Puntschart et al. (20) had five humans undertake treadmill exercise for 30 min and examined HSP72 mRNA and total protein content before and after exercise. The authors reported an exercise-induced increase in HSP72 mRNA 4 min after exercise but no increase in total HSP72 protein content. No studies have previously measured HSP gene expression in human skeletal muscle throughout exercise. This is important because cellular events, such as increased temperature, acidosis, and reduced glucose availability, take place throughout exercise. In addition, because protein damage is a major stimulus of HSP expression, it is important to examine HSP gene expression during exercise that is predominantly concentric or nonweight bearing in nature to investigate whether cellular events other than muscle protein degradation or damage can induce a heat shock response.
The purpose of the present study, therefore, was to examine HSP72 mRNA expression in human skeletal muscle progressively throughout steady-state cycling exercise. We also measured some other factors, such as muscle temperature (Tm), glycogen availability, and lactate formation, which are known to stimulate HSP expression in human muscle. We hypothesized that HSP72 gene expression would increase during exercise because factors characteristic of contracting mammalian skeletal muscle cells are known activators of HSP.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Five healthy but untrained humans (20 ± 1 yr; 64 ± 3 kg) volunteered for the experiment. The experimental procedures and possible risks of the study were explained to all subjects before they gave their informed, written consent. The experiment was approved by the Human Research Ethics Committee of The University of Melbourne.
Peak oxygen uptake.
Each subject initially performed a cycling test to volitional fatigue
on an electromagnetically braked cycle ergometer (Lode Instrument,
Groningen, Netherlands) to determine peak oxygen uptake (
O2 peak) as previously described
(4). O2 peak averaged
2.55 ± 0.2 l/min, and a workload corresponding to ~65% O2 peak was calculated from the oxygen
uptake vs. workload regression equation.
Experimental procedure.
At least 1 wk after the O2 peak test,
subjects returned to the laboratory to perform a familiarization trial.
This trial served to familiarize subjects with the cycling protocol and
enabled us to check the workload and determine an approximate time to
fatigue. Subjects were instructed to refrain from alcohol, caffeine,
tobacco, and strenuous exercise and to consume their normal diet for
the preceding 24 h. Subjects arrived in the laboratory in the
morning after an overnight fast, were weighed, and then commenced
cycling on the previously mentioned cycle ergometer at the
predetermined workload. The laboratory was maintained at an ambient
temperature of 20°C, an electric fan was used to circulate air, and
water was provided ad libitum. Subjects were instructed to cycle at the
predetermined work rate, maintaining a pedal frequency of 80-90
rpm until fatigue. Fatigue was defined as the inability to complete one
pedal revolution because the work rate on the electrically braked cycle
ergometer was non-pedal-frequency dependent.
Tissue treatment and analysis. Muscle samples were split into two (15- to 50-mg) fragments. One portion was freeze dried for 24 h, dissected free of any blood and connective tissue, powdered, extracted, and analyzed for glycogen and lactate as previously described (4).
Isolation of total RNA.
The second muscle fragment was extracted by a modified acid guanidinium
thiocyanate-phenol-chloroform extraction method for total RNA
(3). Briefly, tissue samples were cut into small (<5 mg)
pieces and homogenized for 30 s with 500 µl of RNAzol B
(Tel-test, Friendswood, TX) in round-bottom sterile tubes. Fifty microliters of chloroform/isoamylalcohol (24:1) were subsequently added
to the homogenates, mixed for 15 s, and left on ice for 5 min. The
samples were subsequently spun at 18,000 g at 4°C for 15 min. The upper aqueous phase containing the total RNA was transferred to a sterile tube, and, after the addition of an equal volume of
ice-cold isopropanol, the samples were placed at 
20°C for 60 min.
After this, 1 µl of 20 mg/ml glycogen was added for the aid of
pelleting the total RNA and the solution mixed before centrifugation at
18,000 g at 4°C for 15 min. The supernatant was aspirated
off, and 500 µl of 75% ethanol were added to rinse the samples,
which were subsequently spun at 10,000 g at 4°C for 10 min. The supernatant was removed, and the total RNA pellets were air
dried before being resuspended in water (0.05% diethyl pyrocarbonate
treated). The total RNA content and purity were established by
measuring absorbance readings at 260 and 280 nm.
RT-PCR.
For each total RNA sample, 0.1 µg was reverse transcribed in a
10-µl reaction containing 1 × TaqMan RT buffer, 5.5 mM
MgCl2, 500 µM each 2'-deoxynucleoside 5'-triphosphate,
2.5 µM random hexamers, 0.4 U/µl RNase inhibitor, and 1.25 MultiScribe RT (PE Biosystems, Foster City, CA). Although samples were
DNase treated, control samples were analyzed when total RNA samples
received all reagents except the RT. The reverse transcription
reactions were performed by using a GeneAmp PCR system 9600 (PE
Biosystems) with conditions at 25°C for 10 min, 48°C for 30 min,
and 95°C for 5 min. Each reaction was then diluted 1:10 in 0.01 M
EDTA, pH 8.0, and stored at 80°C until further use.
CT value. The resting
value for each subject was then subtracted from the exercise
samples for each subject to derive a CT value.
The expression of human HSP72 relative to the resting sample was then
evaluated by using the expression 2
CT. The coefficient
of variation, determined on the CT value of the 18S samples
for each of the four samples for each subject, was <1%. In addition,
our laboratory has previously demonstrated that the intra-assay
coefficient of variation for one target gene is <5%
(11).
Statistical analyses. Data were examined for normality of distribution by using a normal probability plot. The analyses revealed that Tm, muscle glycogen, and lactate were normally distributed. However, data for HSP72 mRNA were not normally distributed. To ensure data homogeneity for this variable, data were log transformed before statistical analyses. A one-way ANOVA with repeated measures on the time factor was used to compare the data throughout the trial. A Newman-Keuls post hoc test was used to locate difference when the ANOVA revealed a significant interaction. All data are reported as means ± SE unless otherwise stated. The level of significance for all tests was set at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects cycled for 186 ± 15 min at a workload that
corresponded to 63% O2 peak.
Tm increased (P < 0.05) during the first
10 min of exercise. However, subsequent to this time, there was no
further increase in Tm (Fig.
1).
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Similarly, muscle lactate increased (P < 0.05) when
Min10 is compared with R. It subsequently fell such that the
concentrations at F-40 and F were not different when compared with R
(Fig. 2). In contrast, muscle glycogen
concentration decreased (P < 0.05) progressively
throughout exercise, and concentrations were very low (<50 mmol
glucosyl U/kg dry wt) at F (Fig. 3).
HSP72 mRNA was detected in all resting samples; however, within 10 min
of exercise, there was no increase in gene expression. HSP72 mRNA increased 2.2-fold (P < 0.05) and 2.6-fold
(P < 0.05), respectively, when F-40 and F are compared
with R (Fig. 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study is the first to demonstrate that HSP72 mRNA increases progressively in human skeletal muscle during prolonged exercise. Despite a marked increase in Tm and lactate accumulation in the first 10 min of exercise, HSP72 mRNA did not increase. However, even though Tm did not increase and intramuscular lactate content fell to resting levels beyond 10 min of exercise, HSP72 mRNA increased after this time (Fig. 4). Interestingly, this increase coincided with reduced intramuscular glycogen availability.
Only one previous study has attempted to quantify HSP72 in human muscle in response to an acute exercise bout. Using fixed cycle PCR methodology, Puntschart et al. (20) measured HSP72 mRNA and protein expression in five men before and after a 30-min run. These authors reported a fourfold increase in HSP72 mRNA 4 min after exercise. This increase was exacerbated after 30 min of recovery and was still elevated threefold 3 h after exercise. Interestingly, the increase in gene transcription did not result in any protein translation 3 h postexercise. In the present study, we did not measure HSP72 protein because of insufficient tissue. Although it would have been desirable to measure protein levels, it was unlikely, based on the previous study (20), that we would have observed any increase in protein expression during the exercise bout. Further work that samples muscle into recovery for periods longer than 3 h is necessary to determine the time course for HSP gene transcription to protein translation in human muscle in response to a single bout of acute exercise.
To our knowledge, this is the first study to use real-time PCR for the study of gene expression in human skeletal muscle in response to exercise. We established that as little as 0.05 ng of starting material per PCR reaction could be used for quantitation of the human HSP72 gene. This is a result of the fluorescence being detected by the sequence detector system very early on during cycling at the beginning of the exponential phase of PCR, when PCR fidelity is highest. Hence, this technique allows for the precise quantitation of many genes from a small (<20-mg) percutaneous muscle biopsy. It has, therefore, good potential for the study of human muscle gene expression not only in response to exercise but also in pathogenesis.
Although, in the present study, we used a more precise method for measuring gene expression than did Puntschart et al. (20), it is interesting to compare the previous data with ours. The magnitude of the increase in our study was less than threefold (Fig. 4), compared with an ~4.5-fold increase reported previously (20). It is important to note that a major difference when the two studies are compared was the mode of exercise chosen. In the previous study, subjects ran on a treadmill, whereas our subjects cycled on an ergometer in the present study. It is well known that running entails an eccentric component to contraction, whereas cycling primarily involves concentric contractions. This appears to be an important difference with respect to the disruption to cellular homeostasis. Indeed, after 2 h of running exercise, plasma interleukin-6, a cytokine released at the site of inflammation, increases to ~100 pg/ml (19). In contrast, we have recently observed that a similar duration and intensity of cycling exercise results in a plasma interleukin-6 concentration of <2 pg/ml (26). Hence, the differences observed when HSP72 mRNA expression in the present study is compared with the results of Puntschart et al. (20) may be related to the mode of exercise and the amount of protein damage associated with the exercise. Notwithstanding the fact that the increase in HSP72 mRNA was lower in the present study, compared with the previous study (20), it was nonetheless elevated. This demonstrates that changes that occur within muscle cells during exercise that result in minimal damage are capable of initiating a heat shock response.
It has previously been demonstrated that the HSP72 content of the contracting rodent muscle was elevated 30 min after exercise in the absence of any exercise-induced increase in colonic temperature. The authors suggested that factors other than heat that are associated with the exercise may contribute to the accumulation of HSP72 (25), although the absence of a rise in colonic temperature does not necessarily mean that the temperature of the contracting tissue was stable (5). In the present study, Tm did not increase beyond 10 min, but HSP72 mRNA markedly increased thereafter. Given these results, it is tempting to speculate that, during exercise, cellular events other than an increase in cell temperature can induce a "heat shock" response. However, our data cannot determine whether the increase in HSP72 mRNA was due to factors other than cell temperature, because Tm increased in the first 10 min of exercise. It is possible that a time lag existed between the stressor (elevated Tm) and gene transcription. Hence, we cannot dismiss the early increase in Tm being responsible for the augmented gene expression late in exercise. To conclusively test the hypothesis that cellular events other than an increase in contracting cell temperature can induce a heat shock response, the Tm must be clamped at basal levels throughout exercise. This is technically very difficult to achieve because contracting muscle is the major site for heat production during exercise.
Of note, the increase in HSP72 gene expression occurred late in exercise when intramuscular glycogen availability was reduced to low levels (Fig. 3). It has been demonstrated previously that reduced glucose availability is capable of inducing a heat shock response (24), and our data are consistent with the hypothesis that HSP gene expression in contracting muscle during exercise increases when glucose availability is compromised.
In summary, we have observed that HSP72 gene expression progressively increases during submaximal exercise, suggesting that cellular processes that take place throughout prolonged concentric exercise are capable of initiating a heat shock response.
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ACKNOWLEDGEMENTS |
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We acknowledge the medical assistance of Dr. Andrew Garnham and the technical assistance of Jane Dancey in collecting the tissue samples. We also acknowledge the assistance of Robin Murphy for advice in refining the RNA extraction procedure.
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FOOTNOTES |
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The following foundations contributed to the purchase of the ABI PRISM 7700 sequence detector: The Sylvia and Charles Viertel Foundation, The Clive and Vera Ramaciotti Foundation, The Philip Bushell Foundation, and The Harold and Cora Brennen Benevolent Trust. We thank them.
Address for reprint requests and other correspondence: M. A. Febbraio, Exercise Physiology and Metabolism Laboratory, Dept. of Physiology, The Univ. of Melbourne, Parkville, Victoria 3052, Australia (E-mail: m.febbraio{at}physiology.unimelb.edu.au).
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. §1734 solely to indicate this fact.
Received 24 March 2000; accepted in final form 28 April 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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C.-L. Su, C.-P. Wu, S.-Y. Chen, B.-H. Kang, K.-L. Huang, and Y.-C. Lin Acclimatization to neurological decompression sickness in rabbits Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1214 - R1218. [Abstract] [Full Text] [PDF]
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A. G. Holmes, M. J. Watt, and M. A. Febbraio Suppressing lipolysis increases interleukin-6 at rest and during prolonged moderate-intensity exercise in humans J Appl Physiol, August 1, 2004; 97(2): 689 - 696. [Abstract] [Full Text] [PDF]
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M. H. S. Chan, A. L. Carey, M. J. Watt, and M. A. Febbraio Cytokine gene expression in human skeletal muscle during concentric contraction: evidence that IL-8, like IL-6, is influenced by glycogen availability Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R322 - R327. [Abstract] [Full Text] [PDF]
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T. Ogata, Y. Oishi, R. R. Roy, and H. Ohmori Endogenous expression and developmental changes of HSP72 in rat skeletal muscles J Appl Physiol, September 1, 2003; 95(3): 1279 - 1286. [Abstract] [Full Text] [PDF]
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A. R. Tupling, H. J. Green, B. D. Roy, S. Grant, and J. Ouyang Paradoxical effects of prior activity on human sarcoplasmic reticulum Ca2+-ATPase response to exercise J Appl Physiol, July 1, 2003; 95(1): 138 - 144. [Abstract] [Full Text] [PDF]
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K.-L. Huang, C.-P. Wu, Y.-L. Chen, B.-H. Kang, and Y.-C. Lin Heat stress attenuates air bubble-induced acute lung injury: a novel mechanism of diving acclimatization J Appl Physiol, April 1, 2003; 94(4): 1485 - 1490. [Abstract] [Full Text] [PDF]
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R. M. Murphy, K. K. O. Watt, D. Cameron-Smith, C. J. Gibbons, and R. J. Snow Effects of creatine supplementation on housekeeping genes in human skeletal muscle using real-time RT-PCR Physiol Genomics, January 15, 2003; 12(2): 163 - 174. [Abstract] [Full Text] [PDF]
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K. C. Kregel Molecular Biology of Thermoregulation: Invited Review: Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance J Appl Physiol, May 1, 2002; 92(5): 2177 - 2186. [Abstract] [Full Text] [PDF]
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