Exercise-Induced Cardioprotection Endogenous Mechanisms

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.
1537-1543
2007The American College of Sports Medicine Exercise-Induced Cardioprotection: Volume 39(9), September 2007, pp 1537-1543
Endogenous Mechanisms
[BASIC SCIENCES: Symposium: Exercise, Antioxidants, and Cardioprotection]

STARNES, JOSEPH W.1; TAYLOR, RYAN P.2
1Cardiac
Metabolism Laboratory, Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, TX; and 2Division of Cardiology, The University of
Utah Health Sciences Center, Salt Lake City, UT
Address for correspondence: Joseph W. Starnes, PhD, Department of Kinesiology and Health Education, 1 University Station, D3700, University of Texas, Austin, TX 787120360; E-mail: jstarnes@mail.utexas.edu.
Submitted for publication December 2006.
Accepted for publication May 2007.
Outline
ABSTRACT
WHAT OCCURS DURING ISCHEMIA AND REPERFUSION?
NITRIC OXIDE
MITOCHONDRIA
SARCOLEMMA
SUMMARY
REFERENCES
Graphics
FIGURE 1-Some events...

FIGURE 2-Nitric oxid...
ABSTRACT^
It is now well established that exercise can result in cardioprotection against ischemia-reperfusion (I-R) injury (2,8-10,12,13,15,17,18,26,28,4043,45,51,60,61,65,) however, the adaptations within the heart that provide the protection are still in doubt. The cytoprotective proteins
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Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543
receiving the most attention to date are antioxidant enzymes and heat shock proteins. The extent of I-R injury is dependent on the
interactions of several events, including energy depletion, metabolite accumulation, oxidant stress, and calcium overload. Adaptations that
directly influence any of these could affect I-R outcome. Thus, the exercise-induced cardioprotective phenotype is likely to include
additional cytoprotective proteins beyond antioxidant enzymes or heat shock proteins. In this review, we will consider evidence for some of
these in the cytosol, mitochondria, and sarcolemma of the cardiomyocyte. We will not consider potentially important adaptations within
vascular tissue or the autonomic nervous system. Results of recent studies support the hypothesis that exercise leads to cardioprotective
adaptations that are unique from other forms of preconditioning against I-R injury.
Exercise-induced cardioprotection against ischemia-reperfusion injury (I-R) was first described in 1978 by McElroy and colleagues (46).
They found that chronic swim training induced a reduction in infarct size after coronary artery occlusion in the rat. Studies carried out by
Brinkman et al. (10) in 1988, using isolated perfused hearts, demonstrated that the protection, or at least a large component of it, was
attributable to adaptations within the heart-that is, independent of exogenous influences from the blood or other adaptations within the
body. Now it is well established that exercise can result in cardioprotection against I-R injury (2-13,15,17,18,26,28,40-43,45,48,51,60,61,65);
however, the specific adaptations that occur within the heart that provide this protection are not fully understood. The cytoprotective
proteins that have received the most attention to date are inducible heat shock protein (HSP72) and antioxidant enzymes, particularly
superoxide dismutase (SOD) (18,26,40,41,43,48,51,60,61,65). The antioxidant enzymes function to prevent lipid peroxidation and protein
dysfunction during the oxidative stress associated with both exercise and I-R, whereas HSP72 aids in the subsequent recovery by
promoting restoration of dysfunctional enzymes and preventing aggregation of severely denatured proteins (39,57). Together, the
complementary protective mechanisms of HSP72 and endogenous antioxidants are considered to form a strong defense against I-R injury.
However, there is now considerable evidence that other proteins may also be part of the exercise-induced cardioprotective phenotype, and
they may have significant roles in the protective process. The purpose of this brief review is to consider evidence for other potential
mediators. The focus will be on adaptations within the ventricular myocyte; adaptations within the vascular tissue or autonomic nervous
system will not be considered. However, it should be noted that improved autonomic tone is known to be an important component of
exercise-induced protection against cardiac arrhythmias (5,17).
WHAT OCCURS DURING ISCHEMIA AND REPERFUSION?^

I-R is caused by interactions of energy depletion, metabolite accumulation, oxidant stress, and calcium overload (11,14,30,33,37). The extent
of the injury depends on the magnitude of these changes; it ranges from reversible dysfunction (stunning) to infarction characterized by
irreversible cell death. In addition, reperfusion is associated with arrhythmias that are typically induced within seconds of the onset of
reflow and are potentially lethal (54). Before discussing potential mediators of exercise-induced cardioprotection, it may be helpful to
consider some of the events that occur during ischemia (Fig. 1A) and reperfusion (Fig. 1B). As illustrated in Figure 1A, with the loss of oxygen
comes an immediate cessation of mitochondrial ATP production, which triggers increased anaerobic glycolysis in an attempt to compensate.
As a result, hydrogen ions and lactic acid accumulate ultimately inhibiting glycolysis and causing further energy depletion. Intracellular Na+
concentration rises because the sarcolemmal sodium-hydrogen exchanger (NHE) becomes activated by decreasing pH, and the ATPdependent sarcolemmal Na+/K+ ATPase becomes inhibited by the acidic environment and low ATP levels. This situation also inhibits and Ca2
+
pumps located in the sarcolemma and sarcoplasmic reticulum. The decline in ATP also leads to opening of ATP-sensitive K+ (KATP)
channels on both the sarcolemma and mitochondria. Opening mitochondrial KATP (mito KATP) channels is considered to be a defense
mechanism to decrease reactive oxygen species (ROS) generation on reperfusion (55). There is evidence that opening sarcolemmal KATP (SL
KATP) channels protects against infarction (12), but it can also promote arrhythmias (5).
FIGURE 1-Some events occurring during ischemia (A) and reperfusion (B). The numbers in panel A represent the sequence of events.
Panel B displays how mitochondria may respond before and after preconditioning by an unspecified form of preconditioning. Large and
small font sizes for ATP, ROS, and Ca2+ indicate high and low amounts, respectively. K+ is entering the mitochondria via the mitochondrial
ATP-sensitive K+ channel. NHE, Na+/H+ exchanger; NCE, Na+/Ca2+ exchanger; NKpump, Na+/K+ ATPase; Ca2+pump, Ca2+ ATPase pump;
KATP, ATP-sensitive K+ channel; PT pore, mitochondrial permeability transition pore; cyt. c, cytochrome c. See text for further details.
On return of oxygen at reperfusion (Fig. 1B), a burst of reactive oxygen species are generated by mitochondria and other sources.
Intracellular Na+ overload continues during the initial phase of reperfusion because the NHE is further activated by ROS, which, along with
low ATP levels, delays reactivation of the Na+/K+ ATPase and Ca2+ pumps. The high Na+ concentration prompts the Na+/Ca2+ exchanger to
work in reverse mode, producing cytosolic and mitochondrial Ca2+ overload. Calcium overload leads to further mitochondrial ROS
production and to activation of proteases, resulting in decreased sarcoplasmic reticulum calcium transport and dysfunctional contractile
proteins. Sufficient amounts of calcium overload and oxidant stress also cause the mitochondrial permeability transition pore (PTP) to open
(11,25,33). The opening of this nonspecific, large-conductance channel in the inner membrane results in a loss of mitochondrial membrane
potential and ATP production, and release of cytochrome c into the cytoplasm, which activates caspases (25,33). If the I-R insult is severe,
the pores remain open and cell death will proceed via necrosis. After a less severe insult, the pores may reseal, allowing the mitochondria
to regain ATP production and undergo cell death by apoptosis, which requires energy to perform its lethal deed. Drugs that block the
opening of the PTP decrease both necrotic and apoptotic cell death (25,47). Of note, a recent study reported that 5 d of exercise training
reduced the occurrence of PTP opening in the intact rat heart during I-R (16).
NITRIC OXIDE^
Nitric oxide (NO) has been strongly linked to the enhanced cardioprotection that occurs 24+ h after various pharmacological treatments
(4,6,19,20,31), ischemic preconditioning (7,53), and even heat stress (1,35), which is a stress that also occurs during certain exercises.
Importantly, in most of the studies cited in the previous sentence, the protection was attributable to intrinsic adaptations within the heart,
as evaluations were carried out independently of exogenous influences from blood or the rest of the body. NO is produced from oxygen and
arginine by the enzyme nitric oxide synthase (NOS), whose various isoforms are found within the myocyte and the vasculature. There is
evidence that an exercise-induced increase in endothelial NOS and greater NO bioavailability in the vasculature is beneficial in the in vivo
situation where blood is present and the inflammatory response may cause injury (29). However, it is not clear whether NO protects the
exercise-trained heart by intrinsic mechanisms independently of the inflammatory response at the blood-vascular interface. A recent review
discusses the possibility that NO production from inducible NOS (iNOS) within the myocyte may be the common intrinsic protective
mediator of a wide array of cardioprotective interventions, including exercise (34). However, studies specifically addressing the intrinsic
protective contribution of iNOS and NO to exercise-induced cardioprotection are in disagreement (2,61).
Recent research on statins (HMG-CoA reductase inhibitors) provides insight into how NO can provide intrinsic cardioprotection
independently of the inflammatory response. The statin drugs were originally developed to inhibit cholesterol production, but they are now
known to have effects that are independent of cholesterol level. For example, statins upregulate the expression of iNOS and
cyclooxygenase-2 (COX-2) (6). As reviewed by Jones and Bolli (34), COX-2 and iNOS are coinduced in cardiac myocytes in response to
stresses such as cytokines and ischemia, and some of the NO from NOS stimulates COX-2 to produce cardioprotective prostaglandins. The
protaglandins, particularly prostacyclin (PGI2), exert cardioprotection by opening mito KATP channels (55). Activation of mito KATP channels
can attenuate mitochondrial Ca2+ overload, thereby preventing the opening of the mitochondrial permeability transition pore. Considerable
evidence now exists that statins, ischemic preconditioning, and some other pharmacological treatments induce the cardioprotective
pathway that goes from NOS to COX-2 to PGI2 to mito KATP channel opening. Furthermore, the mito KATP channel has been implicated as
the ultimate effector because cardioprotection is abrogated when the channel is inhibited (24,50).
Studies carried out on exercising animals suggest that the NOS/COX-2/mito KATP channel pathway may be less critical to exercise-induced
cardioprotection than for statin-induced cardioprotection. Domenech et al. (21) have demonstrated that the mito KATP channel inhibitor, 5hydroxydecanoate (5-HD), does not abolish exercise-induced delayed preconditioning against myocardial infarction in vivo in dogs. Also,
Brown et al. (12) have demonstrated that 5-HD was ineffective in abolishing exercise-induced protection against infarct development after IR in the isolated perfused rat heart. Nagy et al. (49) report that COX-2 inhibition does not prevent exercise-induced cardioprotection
against ventricular arrhythmias after coronary occlusion in dogs, and a recent abstract reports that exercise does not increase COX-2
expression in the rat heart (52). However, some support for a role of increased inducible NOS as a mediator of exercise-induced protection
comes from a study by Babai et al. (2). They found that one bout of exercise in dogs markedly reduced the incidence of ventricular
fibrillation during in vivo coronary occlusion at 24 h, but not 48 h, after exercise. Because the ischemic bout was carried out under
anesthesia, influences from the autonomic nervous system can be presumed to be absent. The activity of iNOS was elevated threefold at
24 h after exercise, and the exercise-induced cardioprotection was abolished by aminoguanidine, an inhibitor of iNOS. Thus, they conclude
that the protection was mediated by nitric oxide. However, the loss of protection 48 h after exercise is curious, because late-phase
preconditioning against mechanical dysfunction and infarction normally lasts for several days after exercise and several other stresses
(40,59). A possible explanation for the loss of arrhythmia protection at 48 h is that there may be differences in endogenous cardioprotective
mechanisms against cell death and arrhythmias.
Because of the insufficient evidence to implicate NO in exercise-induced cardioprotection, we recently explored the role of NOS in mediating
cardioprotection against I-R injury in rats after two consecutive days of exercise (61). The following day, myocardial function was evaluated
before and after a bout of I-R in an isolated, perfused, working heart model. This preparation allows the left ventricle to pump as it does in
the body, but in the absence of whole blood, autonomic nervous system, or other exogenous influences. We also measured lactate
dehydrogenase (LDH) release as a biochemical marker of tissue damage (primarily necrosis). Consistent with earlier studies, exercise
significantly improved recovery of pump function (Fig. 2A) and decreased LDH release (Fig. 2B) after the ischemic stress. However, the
exercise-induced protection was not abolished, or even attenuated, by inhibiting all forms of NOS with L-NAME, a nonspecific NOS inhibitor.
Furthermore, exercise did not increase myocardial iNOS expression above that in the sedentary animals (61). We recently carried out the
same experiments on rats that exercised for 4 wk; again, we found that L-NAME did not lessen the exercise-induced protection
(unpublished data). These results provide clear evidence that increased NO production is not required for protection of the isolated heart
after exercise. However, as mentioned previously, greater NO bioavailability in the vasculature may be important to attenuate the
inflammatory response in vivo (29).
FIGURE 2-Nitric oxide does not mediate exercise-induced protection in isolated perfused hearts. Hearts underwent 22.5 min of global
ischemia followed by 30 min of reperfusion. Lactate dehydrogenase (LDH) release reached its peak at 10 min of reperfusion. SED,
sedentary; RUN, exercised by treadmill running; SED-LN and RUN-LN, hearts perfused with L-NAME to block nitric oxide production; CO,
cardiac output; SP, systolic pressure. Adapted from Taylor et al. (61). Used with permission. * Significantly different from SED (P < 0.05).
MITOCHONDRIA^
As illustrated in Figure 1B, mitochondrial calcium uptake and ROS generation are believed to play key roles in I-R injury (11,33). There are at
least two adaptive strategies within mitochondria that could contribute to cardioprotection; they could decrease ROS production or increase
their ability to tolerate high calcium levels. Recent studies indicate that both strategies may be part of the exercise-induced
cardioprotective phenotype. These studies will be discussed below.
Venditti and colleagues (63) were the first group to report that chronic endurance training of Wistar rats could reduce mitochondrial ROS
production. However, their mitochondria population was from gastrocnemius muscles, not from the heart. As in many other studies,
oxidant production from intact mitochondria was estimated by measuring the production of H2O2 as it diffuses out of the mitochondria. The
originating ROS, the superoxide ion, is primarily formed on the inside of the inner mitochondrial membrane, but it will not reach the
surrounding media because the ion is impermeant to the inner mitochondrial membrane (27). However, the superoxide ion is almost
immediately dismutated by superoxide dismutase to H2O2, which then freely diffuses out. In the first study of myocardial mitochondria,
Judge et al. (36) report that lifelong voluntary wheel activity decreased H2O2 production by about 10% (P< 0.05) in 24-month-old male
Fischer 344 rats compared with their sedentary peers. They found similar reductions in both interfibrillar and subsarcolemmal mitochondrial
populations. However, because younger animals were not included, it was uncertain whether the exercise program decreased H2O2
production independently of aging, or whether it acted primarily to attenuate a possible age-related increase (3). To determine whether the
decrease would also occur in young rats, we exercised young adult rats of the same sex (male) and strain (Fischer 344) by forced treadmill
running for 4 months (58). Myocardial mitochondria were isolated and H2O2 production was determined under conditions that generate high
levels of ROS, which is the situation that exists during the early phase of reperfusion after ischemia. Similar to the results of Judge et al.
(36), we found that exercise training decreased myocardial mitochondria ROS production by 11% (58).
Decreased ROS generation could be attributable to increased mitochondrial antioxidant enzyme activity or to less superoxide production.
Whether myocardial antioxidant enzymes increase with exercise training is currently a matter of considerable debate. Both Venditti et al.
(63) and Judge et al. (36) speculate that the decrease in ROS is attributable to less superoxide production, because they found that
antioxidant enzymes did not increase. Assuming they are correct, what could cause the decrease in ROS generation? One method proposed
to attenuate the rise in ROS during I-R is an uncoupling of mitochondrial respiration (47). The magnitude of ROS generation is exponentially
related to a high membrane potential and high NADH/NAD ratio (27,62). Therefore, ROS generation is decreased by mild uncoupling
because it decreases mitochondrial membrane potential. However, it is unlikely that mitochondrial uncoupling was responsible for the
decreased ROS generation observed by Judge and colleagues (36), because they also found that respiratory rates and respiratory control
ratios were similar in the sedentary and exercised groups. Another possibility is that favorable adaptations occur at the sites within the
electron transport chain where electrons can escape to form the superoxide radical. Heart mitochondria are known to produce superoxide
at complex I and complex III of the electron transport chain (62). We recently have reported evidence that chronic endurance training
results in less superoxide generation at complex I in myocardial mitochondria, whereas complex III is not affected (58). It is also
interesting to note that decreased electron leak at complex I has been reported after long-term caloric restriction (22) and in mitochondria
from long-lived species compared with short-lived species (32). How superoxide generation at complex I may change is not yet known. This
is partially because there is limited knowledge about the exact structure of this very large enzyme complex, and the general mechanism of
superoxide production there has not been established (23). Clearly, more research is needed in this area.
Mitochondria of endurance-trained animals may also be better able to tolerate high levels of calcium. Marcil and colleagues (44) evaluated
the effects of endurance training on calcium-induced opening of the permeability transition pore in isolated heart mitochondria from female
Sprague-Dawley rats. The exercise program consisted of 10 wk of treadmill running for 4 dwk-1 at 25 mmin-1 up a 16% slope for 90 min.
They found that the amount of Ca2+ required to open the PTP was 45% greater after exercise training when the metabolic substrate was
succinate, which enters the electron transport chain at complex II (FADH2). However, in the presence of a complex I substrate (glutamate/
malate), there was no difference in calcium sensitivity between exercise and sedentary groups. Also, the investigators did not observe any
differences in factors that are known to influence the sensitivity of pore opening. For example, mitochondria from sedentary and exercised
rats were found to be similar in regard to ROS production, membrane potential, NADH/NAD ratio, and calcium-uptake kinetics. Thus, the
reason for the substrate-specific effect is not clear. The authors speculate that the increased resistance to calcium-induced PTP opening
after training may be attributable to a favorable change within the mitochondria in the ratio of antiapototic Bcl-2 and Bclxl relative to
proapoptotic Bax, which has been reported by other lab groups (38,56).
Protective adaptations at the mitochondria, and at other locations that directly impact the mitochondria, could at least partially explain our
observations made more than 10 yr ago in the intact heart. In 1994, we reported that the increased postischemic contractile function and
high-energy phosphates in working hearts from trained rats were associated with increased myocardial oxygen consumption, increased
efficiency of cardiac work, lower diastolic stiffness, and less total calcium overload (9). A unifying explanation for all of these findings is that
exercise resulted in intrinsic changes that enable mitochondria to regain their ability to produce ATP faster and decrease their ROS
production during reperfusion compared with sedentary animals. Greater mitochondrial ATP production would allow more work to be
performed, would decrease diastolic stiffness by providing energy for sarcoplasmic reticulum ATPase (SERCA) calcium uptake and by
facilitating myosin release from actin (less rigor), and would minimize calcium overload by providing energy to reactivate the sarcolemmal
Ca2+ pump and Na+/K+ ATPase. The latter would help with calcium overload by pumping out excess sodium and, therefore, decreasing the
driving force for the sodium-calcium exchanger to act in the reverse direction (Fig. 1B). Less ROS production on reperfusion would result in
less dysfunction of SERCA and the Na+/K+ ATPase as well as less activation of the NHE. Evidence that SERCA is operating better in the
trained hearts is their lower diastolic stiffness (discussed above) and greater efficiency of work (indicating better relaxation and use of
Starling's law) compared with sedentary hearts. Evidence that the Na+/K+ ATPase is not inhibited and that NHE is not activated is the lower
calcium content, which is directly related to sodium content. In the trained heart, preventing NHE activation may be especially important
because it is reported to be upregulated by exercise training (64).
SARCOLEMMA^
Considerable ion movement occurs through the sarcolemma during both ischemia and reperfusion (Fig. 1). Thus, changes in one or more of
the sarcolemmal ion pumps/channels could be expected to have an impact on the severity of I-R injury. Indeed, Brown et al. (12) have
provided evidence that increased expression of sarcolemmal KATP channels are very important to the improved cardioprotection associated
with exercise. They demonstrate that pharmacological blockade of the SL KATP in female Sprague-Dawley rats abrogated the exerciseinduced reduction in infarct size after I-R in isolated perfused hearts. Increased SL KATP may protect the heart by facilitating K+ efflux from
the myocyte to conserve energy by shortening stage 3 of the action potential and by inhibiting Ca2+ entry through the L-type Ca2+ channel
during stage 2 (24). There is also a possibility that the increase in SL KATP assists a survival pathway that inhibits PTP opening (30).
However, it should be pointed out that activation of the SL KATP may also lead to heterogeneity of repolarization and induction of
arrhythmias (5,54). In fact, a current therapeutic antiarrhythmic strategy is to administer medications that selectively inhibit the SL KATP
(5). Brown et al. (12) have not documented incidences of arrhythmia. Thus, the overall role of the SL KATP in exercise-induced
cardioprotection remains to be clarified.
All of the studies discussed up to this point were carried out on normal, healthy animals. In hypertensive animals, exercise-induced
changes in the sodium-calcium exchanger seem to be important for improving cardioprotection. Collins et al. (17) found that NCE
expression increases in hypertensive rats, and the increase was associated with an earlier onset of ventricular arrhythmias after coronary
occlusion. Allowing hypertensive rats access to voluntary running wheels for 10-12 wk lowered NCE content and significantly prolonged the
time of arrhythmia onset. Phospholamban expression changed in the opposite directions and also may have played a significant role in
decreasing the onset of arrhythmias and normalizing intracellular calcium. These mechanisms of protection may be specific for
hypertensive animals, but they are important because hypertension increases the risk of a cardiac event.
SUMMARY^
Overall, it seems that exercise leads to unique and coordinated cardioprotective adaptations. The uniqueness of the adaptations has been
suggested by Brown et al. (12); they report that the sarcolemmal KATP was more important for exercise-induced cardioprotection than the
mitochondrial KATP, which is a key mediator of other forms of preconditioning. Our finding that inhibition of nitric oxide synthesis does not
abolish the cardioprotective effect of exercise (61), but does abolish the effect of some other forms of preconditioning, also supports the
unique nature of exercise-induced cardioprotection. Furthermore, the finding on hypertensive rats by Collins et al. (17) leads to the
speculation that the specific, exercise-induced cardioprotective phenotype may be influenced by the initial condition of the participants.
Unraveling the mechanisms for how exercise induces myocardial self-protection has enormous health care implications, including reducing
health care costs and providing the conceptual framework for developing therapeutic strategies aimed at mimicking the cardioprotective
benefits of exercise.
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Key Words: REACTIVE OXYGEN SPECIES; PRECONDITIONING; MITOCHONDRIA; NITRIC OXIDE; SARCOLEMMA
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Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.

[BASIC SCIENCES: Symposium: Exercise, Antioxidants, and Cardioprotection]

FIGURE 1-Some events...

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

WHAT OCCURS DURING ISCHEMIA AND REPERFUSION?^

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

Int. J. Sports Med. 21:163-167, 2000. [Context Link]

Ovid: STARNES: Med Sci Sports Exerc, Volume 39(9).September 2007.1537-1543

induced dysfunction. J. Appl. Physiol. 102:1793-1798, 2007. [Context Link]

Accession Number: 00005768-200709000-00015

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