IN FOCUS
Exercise

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892

	ARTICLE

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THE PERFORMANCE OF PHYSICAL work requires fundamental adjustments in the metabolism of the working muscle that are geared toward generating the energy-rich phosphates needed for increased energy consumption. The need to deliver substrates and oxygen and to remove carbon dioxide and other metabolic end products at the increased rate requires cardiovascular, endocrine, and central nervous system adaptations that represent a response to one of the most encompassing physiological disturbances of body homeostasis. Not surprisingly, therefore, the effects of acute and chronic, mild and exhaustive exercise have been the topic of numerous articles in a journal devoted to the understanding of regulatory processes of the entire organism.

A delay in oxygen uptake at the beginning of vigorous exercise and a resulting use of phosphocreatine stores and anaerobic glycolysis are well-known phenomena at the onset of physical activities. However, it has been unclear if this delayed O₂ uptake reflects a delay in O₂ delivery to the working muscle tissue or an inadequate oxygen extraction. A study that determined mean arteriovenous blood transit times and O₂ differences during 3 min of intense knee-extensor exercise indicates that muscle blood flow increases instantaneously and that even in the first seconds, O₂ availability is adequate (1). It has been suggested that the validity of these arguments could have been strengthened by an attempt to improve O₂ delivery, for example by hyperoxia (12). Nevertheless, in single skeletal muscle fibers, tension development in the first 50 s was in fact unaffected by a reduction in perfusate PO₂ from 159 mmHg to zero. Thus, in this time period, adequate ATP hydrolysis was maintained by phosphocreatine hydrolysis and anaerobic glycolysis. At times beyond 60 s, however, tension development declined faster and fatigue was reached earlier in anoxic fibers (40).

The response of the central nervous system in general and of the sympathetic nervous system in particular has been a long-standing theme in exercise physiology. Daytime physical activity has been shown to accelerate the phase shift of the circadian pacemaker, indicating that exercise may be useful in shortening jet lag (30). Because systolic arterial blood pressure typically increases during exercise, baroreflex control mechanisms should be affected in some way. An increase in baroreflex gain and operating range was found in response to static handgrip exercise at 30% of maximal force in human volunteers, as judged from determinations of muscle sympathetic nerve activity in the tibial nerve and diastolic pressure. This is possibly related to stimulation of a metabolic reflex pathway, because it was also seen after occlusion of arm circulation after the exercise, a procedure that would eliminate mechanic reflex pathways (19). The nature of the metabolic factors was studied by using microdialysis probes implanted into the vastus lateralis muscle of healthy volunteers. After 5 min of static quadriceps contractions, the existence of the pressor reflex was evident from the rise of heart rate and blood pressure and from the increased muscle sympathetic nerve activity in the contralateral leg. Exercise was accompanied by increments in interstitial phosphate, K, and lactate concentrations. The extent of the rise in interstitial K concentration was dependent on the work load and was always higher than found in venous blood draining the muscle. Surprisingly, interstitial hydrogen ion concentration decreased (18, 27). Increased K uptake into cells may be expected as a compensatory response to K loss. In fact, knee-extensor exercise in human volunteers at high intensity led to an increase in the content of ₂- and ₁-subunits of Na-K-ATPase in vesicular membrane preparations from the active leg compared with the inactive leg before exercise. This short-term pump upregulation was most likely due to translocation of Na-K-ATPase subunits into the membrane (17). Of methodological and functional interest is the observation that tendon stretch as well as isometric contraction-induced changes in heart rate, arterial pressure, and ventilation rate were greater when stimulus was applied to forelimb than hindlimb muscles in cats, even though stimulated muscle mass was roughly equal (9).

One bout of 60-min aerobic exercise desensitized -adrenergic receptors in adipose tissue as determined by the lipolytic response to two identical doses of norepinephrine or the -adrenergic agonists dobutamine (₁) or terbutaline (₂). Desensitization was seen when tested 1 h after the exercise (28). The importance of neural input for muscle substrate use was demonstrated in an experimental feat in which 10 patients with complete spinal cord injury performed leg exercise for 30 min at a rate of oxygen consumption (O₂) of 1 l/min on a computer-controlled electrical stimulation bicycle ergometer. Exercise in these patients was associated with a diminished liberation and utilization of free fatty acids compared with healthy controls, as well as an increased glycogen breakdown, glucose uptake, and lactate production. Thus afferent and efferent innervation is required for regulation of lipolysis during exercise (20).

One of the many adaptations induced by exercise is a redistribution of cardiac output. For example, exercise causes a reduction in splanchnic blood flow that is due to an increase in its vascular resistance. Evidence that this is caused by an increase in sympathetic innervation is not strong. In studies in young men exercising at 50 and 70% of maximal capacity on a bicycle ergometer it was shown that the reduction in splanchnic blood flow was also not affected by enalapril, although converting enzyme inhibition prevented the almost 10-fold rise in plasma ANG II with exercise. Enalapril did not alter the increases in growth hormone, epinephrine, norepinephrine, or ACTH concentrations, whereas plasma cortisol was more significantly elevated. It is noteworthy in view of the widespread use of angiotensin-converting enzyme inhibitors that enalapril did not affect exercise performance in these healthy individuals (2). The powerful vasodilator nitric oxide seems to affect muscle function through a variety of mechanisms in addition to its vasoactive properties. Nitric oxide synthases (NOS) are expressed in both cardiac myocytes and skeletal muscle cells. The regulation of NOS expression may be different between these two types of muscle cells. After 45 min of treadmill running, mRNA and protein levels of endothelial NOS were significantly reduced in the heart of rats parallel to a reduction of nitrite/nitrate production (14). In contrast, isolated diaphragm and soleus muscles stimulated in vitro showed an increase in NO release that was identical in wild-type and NOS-3 knockout mice, suggesting that it was due to NOS I (10). Thus the role of NO in muscle function is likely to be a mixture of direct and indirect actions.

The limits to the ability to perform work and methods to improve this ability are of considerable theoretical and practical relevance. A result that seems to disagree with some standard perceptions is that the decrease in power output during prolonged exercise parallels mean integrated electromyogram activity, suggesting that muscle activity is under central control and muscle innervation is the limiting factor. Muscle glycogen did not seem to affect this decrease in power output, because there was no difference between individuals who were carbohydrate loaded and had higher muscle glycogen before the trial (41). Chronic exercise causes an upregulation of GABAergic inhibitory mechanisms in the caudal hypothalamus, a cardiovascular control region. Thus central nervous system effects contribute to the blood pressure-lowering effect of exercise (23). Substrate availability becomes a limiting factor at very long-lasting types of work performance. A study in birds after a several day flight that included a 500-km open water crossing and was performed without refueling represents an analysis of the ultimate endurance exercise. Success in this undertaking requires sufficiently large fat stores so that energy consumption does not include major breakdown of body proteins. In birds with reduced adiposity, muscle mass was reduced and plasma uric acid was elevated, indicating protein catabolism. This was accompanied and possibly caused by elevated levels of the stress hormone corticosterone (15).

Sprint performance may be limited by sarcoplasmatic Ca handling. A 5-wk sprint training on bicycle ergometer (20 × 10 s all out sprints with 50-s rests, 3 times a wk) caused an increase in sarcoplasmatic Ca release and in the total number of ryanodine receptors without changing Ca uptake rate or Ca-ATPase capacity. There was no transformation of slow-twitch to fast-twitch fibers as judged from measurements of myosin heavy chain isoforms. The more rapid availability of Ca may be advantageous in improving sprint performance (33).

Downhill walking is an example for a type of exercise where the muscle is activated while actually getting longer. Lengthening or eccentric contractions can cause muscle cell necrosis in the untrained. On the other hand, a training regimen employing lengthening contractions can actually protect against muscle degeneration (21). In a novel approach to examine the effectiveness of eccentric training, male volunteers underwent eccentric or concentric training on bicycle ergometers at increasing intensities up to 65% of maximal heart rate. The work performed (force × shortening or lengthening) was substantially higher during eccentric training (489 vs. 128 W), and this was associated with an increase in isometric leg strength and muscle fiber diameter only in the eccentric group. Pain as a sign of muscle damage was only reported in the first days of eccentric training. The authors suggest that eccentric training may be beneficial as a means to permit exercise at sufficient levels of intensity in individuals with compromised cardiovascular function (25). Studies of triceps brachii muscles of rat after 8 wk of eccentric training (downhill running on a treadmill) showed increased active and passive lengthening forces. The plasticity of the elastic recoil properties (spring constant) may be important in optimizing locomotion and may be the consequence of changes in the expression of cytoskeletal proteins (36). For example, downhill running of rats for 130 min (5-min run, 2-min rest) caused changes in expression of collagen type IV as well as in matrix metalloproteinase-2, a collagen degrading enzyme, in the red part of quadriceps muscle, and this correlates with myofiber injury (22), probably the result of myofiber reorganization. Interestingly, protection against muscle damage caused by lengthening contractions is also afforded by training with passive or isometric contractions, a finding that only emphasizes the overall beneficial effect of training (21).

Possibly motivated by the interest in improving athletic performance, several studies investigated the effect of training under hypoxic conditions. Exercise after acclimatization to hypoxia at 350 Torr (inspiratory PO₂ 70 mmHg) for 21 days in rats did not alter the maximal O₂ uptake capacity during exercise in the hypoxic condition, although blood Hb levels increased significantly. Increased oxygen carrying capacity is offset by a decrease in maximal cardiac output because of a reduction in maximal heart rate. This is correlated with a decrease in - and -adrenergic receptor density and an increase in muscarinic Ach receptor density (7). Thus one might argue that because of the reduced maximal O₂ uptake, training intensity at high altitudes is limited and this may actually limit conditioning. The conclusion that height acclimation is equally effective with or without exercise was one of the conclusions of a study in which muscle metabolism was examined in trained mountaineers before and after a 21-day expedition to the summit of Mt. Denali in Alaska. Peak O₂ uptake was not altered, and there were no changes in resting levels of adenine nucleotides or phosphocreatine in biopsy samples from vastus lateralis muscle. After exercise, phosphocreatine fell less and lactate rose less after acclimation. Overall, acclimation did not induce major changes in the oxidative or glycolytic potential (8). Nevertheless, horses that were height acclimatized for a short period performed somewhat better at low altitude, and this was accompanied with increased red cell volume and 2,3-diphosphoglycerate/Hb (46). Consistent with the increased hematopoeisis plasma and tissue iron levels were decreased after 3 mo of swimming exercise for 2 h/day in rats. Nitrite/nitrate levels in liver, spleen, and bone marrow cells increased, and N^G-nitro-L-arginine methyl ester partly reversed the decrease in iron content, suggesting that it was caused by NO (35). NO may be important in making iron available to bone marrow cells for Hb production, possibly through increasing transferrin-receptor expression.

Humoral factors may well be responsible for the growth-promoting and anabolic effects of exercise. In fact, systemic concentrations of growth hormone and insulin-like growth factor-I increased after 10 min of unilateral wrist-flexion exercise in volunteers, whereas that of fibroblast growth factor-2 decreased markedly. The mechanisms responsible for these effects of low-intensity local exercises are unclear (6). Extensive exercise has also been shown to stimulate the production and release of cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)- by monocytes (37). One of the consequences of the interaction of growth factors and cytokines with muscle cells is activation of the mitogen activated protein (MAP) kinase signaling cascade. This activation by exercise includes MSK1 and MSK2, p90 ribosomal S6 kinase, and MAP kinase-activated protein kinase 2, and these kinases remain activated for the duration of the exercise (24). Structural changes with prolonged exercise include an increase of cytoskeletal protein expression (like dystrophin-glycoprotein complex), and this could improve transversal cohesion of muscle fibers and fiber-matrix relationship (3). Goats kept outdoors for a normal winter season in Wyoming had an increase in maximal O₂ uptake that was greater than that seen in trained goats at warm temperatures and could be translated into an increase in running speed. Thus cold exposure in itself can result in increased aerobic performance and can therefore be considered equivalent to training. It is noteworthy, however, that the cold-trained muscles perform with a lower efficiency as determined by the ratio of maximal O₂ uptake over running speed (39). A study that addresses the question of potentially adverse effects of training used forced treadmill running for 8 wk as an exercise regimen. Rats had less of a weight gain than sedentary controls and an increase of citrate synthase activity as signs of training success. Citrate synthase activity, a marker of aerobic capacity and mitochondrial density, was also found to be higher in human vastus lateralis muscles of trained vs. untrained individuals (26). However, the treadmill-trained rats also showed symptoms of chronic stress, such as adrenal hypertrophy, thymus involution, and immunosuppression (31). At what point exercise becomes maladaptive is an issue of substantial importance, but one guesses that its practical relevance for the health-oriented individual may not be overwhelming. Reasonable rates of exercise clearly have beneficial effects such as a reduction in behavioral depression and immunosuppression induced by stress (32). The familiar experience that cycling appears to be less strenuous at higher revolutions is now supported by data that show a greater increase in heart rate, longer duration of the elevations in blood pressure, and lactate concentrations after cycling at 40 vs. 80 rpm. In addition, cycling at 40 rpm caused a significant elevation of plasma cortisol, whereas cycling at 80 rpm did not (5).

It is founded perhaps more on epidemiological than experimental evidence that there is a genetic component to endurance performance, a complex trait dependent on maximal O₂ uptake capacity, threshold for lactate generation, and running efficiency. As a first step to identifying genes responsible for intrinsic running capacity, rats with low and high running capacity were generated by selective breeding. Currently, high-capacity runners run four times as long until exhaustion than low-capacity runners. In the isolated heart preparation, hearts from high-capacity runners had a 50% higher cardiac output at constant pre- and afterloads than low-capacity runners, a difference entirely due to a difference in stroke volume. Interestingly, hearts from both strains were equally sensitive to cardiac ischemia, a finding that distinguishes intrinsic increases in aerobic capacity from exercise training-induced increases where tolerance to cardiac ischemia is enhanced (13).

Fatigue is the decline of contractile muscle function after high-intensity work performance. One of the factors leading to fatigue in heavy dynamic exercise of the forearm is an O₂ extraction deficit that results from too short recovery times between contractions (45). The increase in resting tension that would result from incomplete relaxation may be partially prevented by activation of K_ATP channels, the result of a decrease of ATP levels. This and other possible effects of activated K_ATP channels are enhanced by denervation, possibly by altering the expression of K channels (29). At the level of an isolated rat soleus muscle, an increase in extracellular K for 60 min reduces excitability and force generation, and this could contribute to fatigue. When these "fatigued" muscles were stimulated by short tetanic stimulations for 20 min at 1-min intervals, force recovered and this is thought to be due to activation of Na-K-ATPase. This would be an intrinsic mechanism to delay a reduction in membrane excitability and therefore fatigue (34).

Postcontractile depression, the decreased ability to produce force after exhausting contractions, is accompanied by decreased Ca release as well as decreased Ca sensitivity. It is reversible when fibers are electrically stimulated during the depressed phase (11). In muscle tissue taken from the vastus lateralis of human volunteers after fatiguing exercise, maximal Ca-ATPase activity and maximal sarcoplasmatic Ca uptake were depressed. This would subsequently cause a reduction in sarcoplasmatic Ca release, lowering force generation (44). After exercise, arterial blood pressure decreases for several hours in hypertensives, both animals and humans. Postexercise hypotension is due to a resetting in the operating point of the baroreflex mechanism. Recent work in spontaneously hypertensive rats indicates that postexercise hypotension was prevented by right lateral ventricle administration of a V₁ antagonist, indicating that arginine vasopressin (AVP) might be responsible for baroreflex adjustments (4). AVP is released during exercise in healthy volunteers especially when work is performed at levels >60-70% of maximum O₂. This release appears to be dependent on an increase in plasma osmolarity and the decrease in plasma volume that accompanies these levels of exercise. AVP release is not modified to a major degree by hypoxia (43). A beneficial effect of AVP for water conservation under strenuous exercise is easy to understand.

Several studies investigated the effect of disease on muscle function. Hypothyroidism is a known condition of increased fatigue sensitivity and reduced contraction and relaxation velocities. Studies in knockout mice have shown that this appears to be related to an insufficient action of thyroid hormone receptor (TR)-₁, because TR-₁-deficient mice mimic the hypothyroid phenotype (16). Endotoxin reduces the effect of calcium on force generation in skinned muscle fibers from a number of skeletal muscles of the rat. Thus the well-known effect of sepsis to decrease appears to include a functional change at the level of the contractile protein (42).

A chronically reduced O₂ transport rate has been shown to be responsible for the diminished maximal O₂ uptake in patients with chronic renal failure. In fact, oxygen uptake at peak exercise (knee-extensor exercise) was the same in these patients breathing 100% oxygen than in controls breathing room air. In this situation, the capillary to myocyte O₂ gradient was higher in the patients with chronic renal failure than in controls. This would suggest that mitochondrial oxidative capacity is comparable and that a diminished O₂ conductance is the limiting factor. The reason for this is unclear chronic renal failure but may reflect structural alterations that augment diffusion distances (38).

	FOOTNOTES

Address for reprint requests and other correspondence: J. Schnermann, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1370 (E-mail: jurgens{at}intra.niddk.nih.gov).

10.1152/ajpregu.00146.2002

	REFERENCES

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