UPDATE ON THE WAR AGAINST CHRONIC DISEASE: THE GOOD NEWS AND THE BAD

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Our society is currently at war against the ominous enemy of chronic disease. Chronic disease presents a heavy burden to society, in terms of both medical costs and human suffering (103). The good news is that exercise intervention and exercise biology are vital and potentially effective components of our arsenal in the war on chronic disease. In a previous call to arms in this fight (25), we reviewed the overwhelming epidemiological evidence linking most chronic diseases to the rise in physical inactivity during the past century. The bad news is that exercise and exercise biology appear to be the least used weapons in our arsenal. It is our perception that 1) much of the medical community underpractices primary prevention as it pertains to appropriate levels of physical activity for health and 2) much of the research community undervalues the importance of understanding the cellular, molecular, and genetic bases of diseases caused by physical inactivity. For many, exercise is viewed solely as a research or diagnostic tool and not as a true weapon against chronic disease. In reality, however, exercise attacks the roots of chronic disease, that is, physical inactivity. For us to follow a common battle plan, there is an apparent need to convince the medical community that chronic disease is rooted in physical inactivity. Thus, in this review, we focus on these roots by compiling the scientific evidence to date showing the biological basis of how physical inactivity leads to chronic disease. One purpose of this review is to demonstrate that exercise is more than a tool, such as in treadmill testing of humans for cardiac dysfunctions. To address these misconceptions, a number of weapons will be employed in this review.

	BATTLE PLAN TO PROVE THE DEPTH OF KNOWLEDGE FOR EACH CHRONIC HEALTH CONDITION AFFECTED BY PHYSICAL INACTIVITY

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The first portion of this review details the concept that the human genome has been evolutionarily programmed for physical activity. The strategy is to show that physical inactivity interacts directly with the genome and thus that physical inactivity is an initiating factor in the molecular mechanisms of disease. Next, in the longest portion of this review, a generic battle plan for each health condition is presented, with each plan consisting of three distinct rounds of discussion. First, a short synopsis of epidemiology for that condition is given. The strategy is to document the epidemiological evidence that physical inactivity does increase the prevalence of the particular health condition. Second, intermediate mechanisms by which physical inactivity induces the onset of the particular condition are given. Third, the cellular/molecular mechanisms, if known, are presented. Our strategy is to prove that, as for most inactivity-related chronic health conditions, a solid cellular/molecular mechanism of how physical inactivity increases disease prevalence does exist. To reinforce the impact of the final discussion, speculation, when reasonable, is presented as to how physical inactivity might drive an inappropriate expression from a genome that had been evolutionarily programmed for more physical activity than exists in modern American culture. In addition, our battle plan includes a large number of chronic health conditions whose prevalence is increased by physical inactivity. Our strategy is to overrun disbelievers' defenses by the sheer mass of conditions influenced by physical inactivity.

The approach here is to document the need to understand the mechanisms of chronic health conditions produced by physical inactivity, just as it is legitimate to understand disease mechanisms for atherosclerosis, cancer, and Type 2 diabetes. This battle will be considered won if the emphasis of biological research would change to one that strives to understand the molecular mechanisms of disease induced by a sedentary lifestyle acting on a genome programmed for physical activity. In summary, at the start of the new millennium, we are uniquely poised to wage war against physical inactivity by using the modern ammunition of cellular, biochemical, and molecular biological breakthroughs of the 21st century to begin dissection of the underlying mechanisms concerning the impact of physical activity on health.

This review does not intend to be inclusive by providing all known information for each inactivity-related disorder; rather, we have chosen a portion of those papers supporting the role of inactivity in disease. Although we attempted an unbiased selection of material and believe that this is a fair presentation, the reader needs to be cautioned that our passion could unintentionally affect our objectivity. The reader also needs to be cautioned that the less than exhaustive coverage of each disease means that the reader will have to take what is presented as only a starting point for further study. The authors thus apologize for the possible omission of any specific references.

	PHYSICAL ACTIVITY IS PROGRAMMED INTO OUR GENOMES FROM THE LATE PALEOLITHIC ERA1

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All that we can do, is to keep steadily in mind that each organic being is striving...that each at some period of its life, during some season of the year, during each generation or at intervals, has to struggle for life and to suffer great destruction. When we reflect on this struggle, we may console ourselves with the full belief, that the war on nature is not incessant, that no fear is felt, that death is generally prompt, and that the vigorous, the healthy, and the happy survive and multiply.
(Charles Darwin, The Origin of Species)

From Darwin's (48) seminal work, we have now accrued the scientific basis for the notion of how environmental forces directly modify the fates of genes and how in turn that inextricable connection remains intertwined and integrated with our day-to-day existence. Those fundamental concepts are now refined and applied to the understanding of how the environmental-genetic interaction molds our susceptibility, our selection, and, as we shall describe here, our struggle against the onslaught of modern chronic diseases. Indeed, environmental factors have been identified as 58-91% of causal factors for three of the most dominant chronic health conditions afflicting individuals in modern-day America: Type 2 diabetes, coronary heart disease, and most site-specific cancers (113, 153, 227). This is a dramatic shift in the preponderance of incidence of such conditions that once were very rare.

There is now unequivocal evidence in the literature supporting the notion that all environmental factors combined, including physical inactivity (defined here as the activity equivalent of <30 min of brisk walking/day), account for the majority of chronic health conditions (153) [these conditions are characterized as chronic because they are slow in progression and long in continuance (53)]. A Scandinavian twin study (153) showed that 58-100% of site-specific cancers had an environmental origin. The Harvard Center for Cancer Prevention in a 1996 report (95) estimated that, of the total number of cancer deaths, 30% were due to tobacco, 30% to adult diet and obesity, 5% to occupational factors, and 2% to environmental pollution. This report predated much of the work regarding exercise's preventive effect on many site-specific cancers. A total of 91% of the cases of Type 2 diabetes (113) and 82% (227) of the coronary artery disease cases in 84,000 female nurses could be attributed to habits and so-called high-risk behavior [defined by the study as body mass index (BMI) >25, diet low in cereal fiber and polyunsaturated fat and high in transfat and glycemic load, a sedentary lifestyle, and currently smoking]. Thus the majority of deaths from chronic health conditions in the United States are of environmental origin. Physical inactivity is the third leading cause of death in the United States and contributes to the second leading cause (obesity), accounting for at least 1 in 10 deaths (88).

Studies showed that ~30-50% of all cases of Type 2 diabetes, coronary heart disease, and many cancers were prevented by 30 min of moderate-intensity exercise each day in middle-aged women (e.g., walking >3 miles/h) compared with cohorts who exhibited lower levels of physical activity (42, 113, 165). Hence, the question arises: how does an environmental factor such as physical inactivity trigger the underlying intrinsic genetic composition of an individual to induce susceptibility to such detrimental health conditions, when our genes have been programmed for maximal preservation by natural selection?

To provide an evolutionary-genetic hypothesis to the above question, we will focus on physical activity and how a sedentary lifestyle is a potent environmental trigger for the development of several chronic health conditions as detailed above. Environmental factors are thought to exert their influence by altering the expression of a subpopulation of genes that results in a phenotype that passes a threshold of biological significance to where overt clinical symptoms appear (the pathological state) (17) (Fig. 1). Physical inactivity constitutes an important component of these environmental factors. Modern Homo sapiens are still genetically adapted to a preagricultural hunter-gatherer lifestyle (67) because the overall genetic makeup of Homo sapiens has changed little during the past 10,000 years (56). Hunter-gatherer societies likely had to undertake moderate physical activity for more than 30 min each day to provide basic necessities, such as food, water, shelter, materials for warmth, and so forth, to survive. One can speculate, although not prove, that any phenotype preventing a hunter-gatherer from engaging in physical activity would increase the likelihood of the random elimination of this organism or its offspring at some time. On the other hand, a phenotype that would support moderate physical activity by allowing a greater capacity for flux of substrates for ATP production to fuel physical work would have been more likely to survive, and its gene pool would be transferred to future generations. In essence, we are extending Darwinian thought (169) to include a concept that random elimination is less likely to occur during the hunter-gatherer era for phenotypes that had a high capacity to support increased metabolic rates during moderate physical work. Thus it is likely that many metabolic features of modern humans evolved as an adaptation to a physically active lifestyle, coupled with a diet high in protein and low in fat, interspersed with frequent periods of famine (67, 257).

View larger version (12K): [in this window] [in a new window]   Fig. 1.   Demonstration of the concept that physical inactivity alters normal gene expression, which produces a pattern of protein expression that approaches the threshold of physiological significance. This threshold is passed if susceptibility gene X and physical inactivity are present, thereby allowing for the development of an overt clinical disease. A: appropriate physical activity moves gene expression away from a threshold at which symptoms of overt clinical disorders occur. B: physical inactivity alone moves the phenotype toward the threshold of clinical disorders. C: a gene polymorphism alone predisposes a person to a clinical disorder (susceptibility gene X) and moves the phenotype toward the threshold for overt clinical disorders. D: dual presence of a susceptibility gene X and physical inactivity causes gene expression to pass the threshold of physiological significance at a rapid rate, allowing for overt clinical disorders to occur.

The "Thrifty Gene" Hypothesis Applied to Physical Activity

Plasticity of metabolic pathways in skeletal muscle likely provides an adaptive advantage during periods of famine and physical inactivity. Wendorf and Goldfine (257) proposed that the thrifty phenotype in Type 2 diabetes could in fact be (or contribute to) insulin resistance seen in muscle. They wrote that a selective insulin resistance in muscle would have the effect of blunting the hypoglycemia that occurs during fasting, which suggested to them a survival advantage during periods of food shortage. The current literature suggests that the plasticity of many of the same metabolic proteins found with nutritional state (57, 218) extends to physical activity (105, 202). Because inactive skeletal muscles in periods of famine do not require as much blood glucose, we speculate that the pathways conserving the uptake of blood sugar into an inactive skeletal muscle were programmed into the human genome during the Late Paleolithic era. Furthermore, we propose that the exercise-induced enhancement of glucose uptake only into contracting muscle evolved to overcome muscle insulin resistance to permit the physical activity associated with food gathering in periods of famine. Thus the present interpretations of alterations in gene expression with changes in daily physical activity should consider their potential origins of being programmed into the human genome as survival mechanisms during the Late Paleolithic period. As such, they are more than the current faddish description of an environmental perturbation of genes; rather, they should be thought of as a constitutive function for normal gene function. In other words, physical inactivity is an abnormal event for a genome programmed to expect physical activity, thus explaining, in part, the genesis of how physical inactivity leads to metabolic dysfunctions and eventual metabolic disorders such as atherosclerosis, hypertension, obesity, Type 2 diabetes, and so forth (Fig. 2).

View larger version (19K): [in this window] [in a new window]   Fig. 2.   Biological basis for the hypothesis that the human genome requires physical activity to maintain health is depicted. We speculate that the human genome evolved to support higher metabolic rates and strength activities of a physically active lifestyle. The human genome has remained largely unchanged during the past 10,000 years. However, we further speculate that the recent occurrence of a more physically inactive lifestyle does not maintain the required metabolic fluxes and muscle loading. As a consequence, genes expecting physical activity for normal function have altered expression such that the resultant phenotype induces a cross of a threshold of clinical significance whereby overt clinical disorders appear.

Daily physical activity was an integral, obligatory aspect of our ancestor's existence (45). The weekly activity pattern of hunter-gatherers in this century followed what has been called a Paleolithic rhythm of days of fairly intense physical activity that alternated with days of rest and light activity: men commonly hunted from 1-4 nonconsecutive days a week with intervening days of rest and women routinely gathered every 2 or 3 days (214). Other activities involving physical labor included tool making, butchering and other food preparation, preparing clothing, carrying firewood and water, and moving to new campsites (214). Dances (often lasting hours) were a major recreational activity in many cultures, often taking place several nights per week (214). Skeletal remains from preagricultural hunter-gatherers showed that they had habitual activity that made them more muscular and stronger than postagricultural society (56). Today, most Americans are quite weak relative to our ancestors, possibly contributing to the premature onset of physical disability (226).

The estimated caloric expenditure of daily physical activity is much less today than in the hunter-gatherer society. The total energy expenditure of contemporary humans is ~65% that of Late Paleolithic Stone Agers, with the assumption that comparisons to modern day foragers are feasible (45). However, when differences in body size are considered, the energy expenditure per unit body mass for physical activity for contemporary American adults is ~38% that of our smaller human ancestors (45). The 30 min of moderate exercise daily in present guidelines results in expenditure of only 44% of the calories of two 20th century hunter-gatherer societies, which according to Cordain et al. (45) is much below estimates for calories expended in preagricultural human ancestors. Cordain et al. wrote that the current level of physical activity is "very likely, below the level of physical exertion for which our genetically-determined physiology and biochemistry have been programmed through evolution."

Adults in the present United States have Late Paleolithic preagricultural hunter-gatherer genes but live in a sedentary, food-abundant society whose appearance as a culture is less than 200 years old (56). Eaton et al. (56) contend that there is now a mismatch between our ancient, genetically controlled biology and certain aspects of our daily lives. The thrifty phenotype is now disadvantageous in sedentary individuals who are allowed free access to food (257). They store fat in anticipation of a famine that does not come because food is available on demand. Some of those who develop obesity and Type 2 diabetes likely have the thrifty phenotype. Eaton et al. maintain that this discordance promotes chronic degenerative disorders that have their main clinical expression in the postreproductive period and account for ~75% of deaths in the United States. We would also like to extend the concept of the maladaptation of the "thrifty phenotype" to the maladaptation of the "activity phenotype." Metabolic processes in the body have evolved to support physical activity. When physical inactivity is present during states of continuous feeding, as is the norm in the United States today, there is a downregulation of the activity phenotype with the maintenance of the evolutionarily conserved thrifty phenotype. This would allow for a manifestation of metabolic dysfunction in the form of insulin resistance, which is an underlying part of syndrome X [the metabolic or insulin resistance syndrome of atherosclerosis, hypertension, and Type 2 diabetes (93)].

Physical Activity Is a Prerequisite for Normal Physiological Gene Expression Based on the Following Reasoning

The importance of understanding the molecular basis for disease is unequivocally clear. For example, Francis Collins wrote (43)

For me, as a physician, the true payoff from the Human Genome Project will be the ability to better diagnose, treat, and prevent disease, and most of those benefits to humanity still lie ahead. With these immense data sets of sequence and variation now in hand, we are now empowered to pursue those goals in ways undreamed of a few years ago. If research support continues at vigorous levels, it is hard to imagine that genomic science will not soon reveal the mysteries of hereditary factors in heart disease, cancer, diabetes, mental illness, and a host of other conditions.

We hope that our presentation in this review will demonstrate that physical activity should be added to Collin's list of hereditary factors, as we have inherited a genome programmed for physical activity, and physical inactivity precedes some of the onset of heart disease, cancer, diabetes, and mental illness. Genomic science, as described by Collins, can only be a part of his call for better prevention of disease. Understanding the popularized "gene-environmental" interaction will provide the most effective prevention of disease.

As delineated above, major "environmental" factors of the Late Paleolithic era set the level of physical activity required by genes to maintain a healthy metabolic function. Therefore, without that threshold of physical activity expected by our genomes (secondary to our current sedentary lifestyles), physiological dysfunction is likely to occur from pathological gene expression, eventually leading to chronic health conditions. We agree with Francis Collins' vision that genomic science will reveal the mysteries of the hereditary factors of heart disease, cancer, and Type 2 diabetes, and we support research regarding this vision. However, these diseases will continue to occur until we unravel the mysteries of the inherently enmeshed interplay of genetics and environment, particularly regarding how environmental factors such as physical inactivity modify Late Paleolithic heredity to produce much of the premature death and suffering seen in present-day human society (Fig. 2). Thus we propose dual-track research that includes genomic science and how the interaction between our environment and genome occurs. A more complete vision of the human genome project would be to use every possible approach in the war against chronic health conditions and not limit research to only a portion of the possible mechanisms.

	HEALTH CONSEQUENCES OF PHYSICAL INACTIVITY

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Physically Active Humans Are in the Control Group Based on Genotype and Phenotype

	CARDIOVASCULAR DISEASES

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Heart Disease: Coronary Artery Disease, Angina, and Myocardial Infarction

Evidence that inactivity increases incidence. The Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (61) concluded on evidence-based medicine

Physical inactivity is likewise a major, underlying risk factor for coronary artery disease. It augments the lipid and non-lipid risk factors of the metabolic syndrome. It further may enhance risk by impairing cardiovascular fitness and coronary blood flow. Regular physical activity reduces very low-density lipoprotein levels, raises HDL cholesterol, and in some persons, lowers LDL levels. It also can lower blood pressure, reduce insulin resistance, and favorably influence cardiovascular function. Thus, ATP III recommends that regular physical activity become a routine component in management of high serum cholesterol.

Intermediate mechanisms. A key cell type through which inactivity mediates its effects on blood vessels is likely the endothelial cell. Evidence is accumulating that endothelial dysfunction is the initiating event in the development of atherosclerosis (212). Indeed, assessing endothelial function has become an important tool for detection of preclinical cardiovascular disease (8). The present data point to the concept that physical inactivity produces endothelial dysfunction, in part, by diminishing the number of pulsatile increases in blood flow through coronary blood vessels (see Ref. 26 for references). The lack of shear stresses produced from the absence of exercise-induced increases in blood flow removes the stimulus for vasodilation (acute) and structural enlargement (chronic) adaptations. In addition to its effects on blood flow, physical inactivity also enhances endothelial dysfunction indirectly through its modulation of the blood levels of certain metabolites and hormones (1). The prevalence of some clinical conditions that depress endothelial function is enhanced by physical inactivity. For example, 1) obesity and insulin resistance are associated with blunted endothelium-dependent but not endothelium-independent vasodilation (9); furthermore, hyperinsulinemia fails to augment endothelium-dependent vasodilation (228); 2) patients with Type 1 or 2 diabetes have significant abnormalities in endothelial function (1); and 3) low blood high-density lipoprotein (HDL) is associated with endothelial vasomotor dysfunction (269), as therapies that increase HDL may improve endothelial vasomotor function independent of low-density lipoprotein (LDL) cholesterol (60). Hypercholesterolemia, diabetes mellitus, and hypertension are associated with reduced synthesis and/or increased degradation of vascular nitric oxide (NO) (152), which reduces the vessel diameters. The reduction in the activity of vascular NO is also likely to play a significant role in the development of atherosclerosis. Exercise ameliorates these disease processes through its action of increasing NO production in endothelial cells (128). Exercise training of patients with coronary artery disease attenuated the paradoxical vasoconstriction in response to acetylcholine by improving the endothelium-dependent vasodilatation in both epicardial coronary vessels and resistance vessels (92).

Cellular mechanisms. Physical inactivity decreases NO production by less shear stress and thus lower NO synthase (NOS) expression (26). Studies that used exercise to recover from sedentary conditions have shown a progressive series of adaptations initiated by NO (170). NO produces vasodilation and initiates enlargement of the vessel circumference, although the latter alteration is not apparent until after numerous daily bouts of exercise.

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Heart Disease: Congestive Heart Failure

Evidence that inactivity increases incidence. The incidence and mortality rate of congestive heart failure (CHF) have been steadily increasing over the past 10 years. Approximately 4.6 million individuals in the United States have a diagnosis of CHF, with ~400,000 new cases occurring and 43,000 individuals dying annually (6). Hospitalizations from CHF increased from 377,000 in 1979 to 870,000 in 1996 (6). Lack of physical activity is considered an independent risk factor for the development of CHF (97). In addition, other primary risk factors include obesity, hypertension, and diabetes. According to He et al. (97), physical inactivity can account for 9.2% of all cases of CHF, whereas hypertension can account for 10.2%, diabetes for 3.2%, and obesity for 8.0%. Furthermore, patients diagnosed with CHF benefit greatly from participating in exercise-training programs. For example, exercise training of patients with moderate to severe CHF lowered all-cause mortality by 63% and reduced hospital readmission for heart failure by 71% (19). Therefore, physical inactivity can directly or indirectly account for the development of a significant percentage of cases of CHF and also exacerbate conditions associated with previously diagnosed CHF patients.

Intermediate mechanisms. Although the primary defective organ in CHF is the heart, the peripheral musculature becomes a secondary defective organ of major clinical significance in that skeletal muscle limits exercise tolerance. Further skeletal muscle dysfunction in CHF improves with exercise training, whereas the function of the primary defect, the heart, remains unaffected by training. In the heart failure syndrome, two of the main symptoms are fatigue and limitation in exercise capacity. In many heart failure patients, an inherent defect in skeletal muscle function is an operative rather than a hemodynamic limitation (234). CHF is a multifactorial condition that occurs because of the onset of many of the described conditions within this review. For example, coronary artery disease accounts for nearly 60% of cases of CHF (97). The mechanisms by which inactivity can mediate its effects on coronary artery disease have been described above. Physical inactivity also increases the risk of other chronic health conditions that can lead to CHF. Therefore, it is likely that many of the cellular mechanisms that contribute to the development of these above-mentioned diseases during physical inactivity may also contribute to the development of CHF. Therefore, we will describe how exercise may improve the function of those inflicted with CHF rather than reiterating how inactivity increases the risk of developing conditions that ultimately contribute to the development of CHF.

Cellular evidence that exercise may improve the overall function in CHF patients. Bed rest and exercise restriction lead to deconditioning and increased morbidity in patients with symptomatic heart failure (234). Conversely, the evidence is quite clear that exercise improves the overall function and exercise capacity of people inflicted with CHF. It appears that the reductions in exercise capacity in CHF are not solely due to alterations in myocardial function (251). For example, various indicators of cardiac function (i.e., ejection fraction) do not correlate well (r = 0.06) with overall exercise capacity in CHF patients (72). However, exercise capacity does correlate well with measures of peripheral muscular strength and endurance (r = 0.90), which suggests that alterations in the periphery greatly contribute to exercise intolerance in CHF patients (177). This lends reasoning that, if one is to improve the overall functional capacity of the CHF patient, then it is necessary to attenuate the cellular alterations that are occurring in the periphery because of CHF. Furthermore, results from chronic heart failure studies do not demonstrate improvements in left ventricular performance or central hemodynamics after exercise training, although the patients exhibit significant improvements in overall exercise capacity (27). Therefore, it is likely that the reduction in exercise capacity in CHF patients is due to a peripheral limitation, and the utilization of exercise in CHF patients appears to improve overall exercise capacity through the alteration of peripheral mechanisms (27).

Hypertension

Evidence that inactivity increases incidence. From a meta-analysis of 44 randomized trials of physical training, it was concluded that sedentary populations had blood pressures that were higher by 2/3 (systolic/diastolic) mmHg in normotensive subjects and by 7/6 (systolic/diastolic) mmHg in hypertensive patients compared with the physically active groups (62).

Intermediate mechanisms. Patients with mild untreated essential hypertension who briskly walked for 30 min five to seven times per week for 12 wk lowered their systolic and diastolic blood pressures and had increased forearm blood flow in response to acetylcholine infusion, whose increase was blocked by a NO inhibitor (102), suggesting a role for NO. There was an inverse relationship between change in ratio of total cholesterol to HDL cholesterol and the increase in maximal forearm blood flow response to acetylcholine after the 12-wk training in these hypertensive patients (102), suggesting a role of high cholesterol on endothelial dysfunction.

Cellular mechanisms. Presently, little information is available describing cellular mechanisms.

Stroke

Evidence that inactivity increases incidence. Physical inactivity increases the risk of stroke (81). At least 22 publications report that regular exercise reduces the risk of ischemic stroke in men and women (Ref. 115 and see Ref. 146 for references). A statement for healthcare professionals from the Stroke Council of the American Heart Association (81) made the recommendation that, as per guidelines endorsed by the Centers for Disease Control and Prevention and the National Institutes of Health, regular exercise (>30 min of moderate-intensity activity daily) is part of a healthy lifestyle and helps to reduce comorbid conditions that may lead to stroke. The effect of physical activity's prevention of stroke seems more convincing for ischemic stroke than for hemorrhagic stroke (3, 115).

Intermediate mechanisms. It has been suggested that the protective effect of physical activity may be partly mediated through its effects on various risk factors for stroke (85). Physical activity lowers blood pressure, increases HDL cholesterol concentration, is associated with reductions in plasma fibrinogen level and platelet aggregation, and elevates plasma tissue plasminogen activator activity (85). Physical activity also facilitates weight loss and weight maintenance (126). Convincing epidemiological data demonstrate that the beneficial effects of physical activity on the risk of Type 2 diabetes is an important risk factor for stroke (113).

Cellular mechanisms. Endothelial dysfunction in essential hypertension is due to a selective abnormality of NO synthesis, probably related to a defect in the phosphatidylinositol/Ca²⁺ signaling pathway (31). NO, a potent vasodilator, is produced by the endothelium of cerebral arteriolar resistance vessels and is crucial to maintaining appropriate cerebral perfusion (172). Hypertensive rats that are sedentary have a higher thrombotic potential in cerebral vessels compared with rats either exercised via voluntary wheel running or fed L-arginine, a NO inducer (192). Cerebral arterioles in the sedentary rats were significantly smaller in diameter than those in the exercise and L-arginine groups (192). Noguchi et al. (192) interpreted these results as providing clear evidence for the beneficial effects of L-arginine intake and voluntary exercise in mechanisms related to hypertension, thrombosis, and stroke. Potential modes by which NO may be working are as follows: NO inhibits medial hypertrophy and remodeling, wards off inappropriate thrombus formation by inhibiting platelet aggregation and adhesion, prevents adhesion and infiltration of monocytes, and blocks endothelial production of the potent vasoconstrictor/mitogen endothelin (172). Exercise training has been thought to increase sheer stress in vascular endothelial cells, enhancing eNOS expression in vascular beds (144, 183, 215) rather than cerebral, which is yet to be tested.

Intermittent Claudication

Evidence that inactivity increases incidence. The age-adjusted prevalence of peripheral arterial disease is ~12% for those over 60 yr of age (101). A meta-analysis of 21 studies found that the average distance to the onset of claudication pain increased 179% and to maximal claudication pain increased 122% after a program of exercise rehabilitation (76). Exercise also improved functional status regarding activities of daily living (207).

Intermediate mechanisms. Exercise training is not associated with substantial changes in blood flow to the legs, and the changes that occur do not predict the clinical response (101). Exercise training improves oxygen extraction in the legs independent of alterations in blood flow (270), likely through improvements in intermediary metabolism of skeletal muscle (101). Exercise training also improves gait and walking efficiency, which then lowers the O₂ cost for a given workload (101).

Cellular mechanisms. Breen et al. (28) demonstrated that 1 h of acute, submaximal treadmill running resulted in increases in capillary growth factors, i.e., a three- to fourfold increase in vascular endothelial growth factor (FGF) mRNA and more modest increases in transforming growth factor-1 and basic fibroblast growth factor mRNA in the rat gastrocnemius. Gavin et al. (78) found that NO is an important signaling mechanism in the regulation of the exercise-induced increase in vascular endothelial growth factor mRNA. NOS inhibition has been shown to block arteriogenesis in response to exercise, but not angiogenesis, in peripheral arterial insufficiency (159).

Platelet Adhesion and Aggregation

Evidence that inactivity increases incidence. Sedentary individuals have a higher platelet adhesion and aggregation at rest and during physical exercise than those partaking in regular low- to moderate-intensity physical activity (204). Deconditioning for 30 days largely reversed these training effects back to the pretraining state (253).

Intermediate mechanisms. Wang et al. (253) showed that exercise training in women at the midfollicular phase enhanced plasma nitrite and nitrate and platelet cGMP levels and suppressed basal and ADP-induced platelet intracellular Ca²⁺ concentration elevation. These events have been shown to suppress platelet reactivity.

Cellular mechanisms. Presently, little information is available describing cellular mechanisms.

	METABOLIC DISEASES

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Type 2 Diabetes

Evidence that inactivity increases incidence. The prevalence of obesity and Type 2 diabetes continues to increase among US adults and is classified as an "epidemic" by the Centers for Disease Control (197). The Centers for Disease Control has written, "In general restoring physical activity to our daily routines is crucial to the future reduction of diabetes and obesity in the US population" (180). Most of the prevalence of Type 2 diabetes in the United States can be attributed to a change in lifestyle that involves a genome evolved from a Paleolithic lifestyle. For example, although the overall prevalence of Type 2 diabetes among adults of industrialized countries ranges from 6 to 10%, it is only 0-2% in native populations that have maintained a lifestyle of the hunter-gatherer cultures (56). Another example was provided by Hu et al. (113), who found that 91% of the cases of Type 2 diabetes in the Harvard nurse's study could be attributed to habits and forms of behavior that did not conform to the low-risk pattern (113). They defined "low risk" as a combination of five variables: a BMI <25, a diet high in cereal fiber and polyunsaturated fat and low in transfat and glycemic load, engagement in moderate-to-vigorous physical activity for at least 0.5 h/day, not currently smoking, and the consumption of an average of at least one-half a drink of an alcoholic beverage per day (113). We provide this list to emphasize that physical inactivity is but one factor contributing to those environmental factors that cause 91% of Type 2 diabetes in the United States. However, lack of physical exercise is a quantitatively important environmental contributor, as shown by a clinical trial (135).

Intermediate mechanisms. According to James (118), the protective effect of physical activity on Type 2 diabetes appears to be mediated by insulin levels and the metabolic syndrome factors (HDL, triglycerides, blood pressure, heart rate), suggesting an impact that is mediated by improved insulin sensitivity. Numerous studies show that glucose is cleared more slowly from the blood after a meal and insulin rises more if physically active subjects became sedentary (98) or underwent continuous bed rest (156). In other words, physical inactivity leads to prolonged periods of postprandial hyperglycemia and hyperinsulinemia. These events are then analogous to the sequence of events leading to overt clinical Type 2 diabetes. In normal individuals, pancreatic -cells secrete insulin in response to an elevation in blood glucose levels. In the insulin-resistant state, -cells compensate for a reduction in insulin-stimulated glucose uptake by increasing basal and postprandial insulin secretion. Eventually, -cells can no longer compensate and fail to respond appropriately to the impairment in glucose disposal, which produces hyperglycemia. Finally, -cells become unable to secrete insulin (i.e., overt clinical Type 2 diabetes).

Cellular mechanisms. Several studies have clearly demonstrated that the proximal insulin-signaling steps are not components of the cell signaling mechanism in which exercise stimulates glucose uptake (83). Thus signaling studies demonstrate that the underlying molecular mechanisms leading to the insulin- and exercise-induced stimulation of glucose uptake in skeletal muscle are distinct (83). Winder and Hardie (261) first published that AMP kinase (AMPK) was activated in type IIa muscle during treadmill running. AMPK has been designated as one of the energy-sensing/signaling proteins of the muscle (260). AMPK has pleiotropic effects, such as 1) fatty acid oxidation: AMPK phosphorylates and inactivates acetyl-CoA carboxylase, principally through the phosphorylation of serine 79 (260). This phosphorylation event is a molecular switch to increase fatty acid oxidation during muscular contraction and limits fatty acid biosynthesis during times of ATP and glucose depletion (250). 2) Contraction of skeletal muscle enhances membrane glucose transport capacity by recruiting GLUT-4 to the sarcolemma and T tubules (see Ref. 210 for references). Exercise training increases the expression of GLUT-4 in skeletal muscle (see Ref. 83 for references). The activation of AMPK by 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR) increased GLUT-4 mRNA (271) and protein (109) expressions in fast-twitch, but not slow-twitch, skeletal muscle. Furthermore, AICAR increased GLUT-4 transcription by a mechanism that required 895 bp of human GLUT-4 proximal promoter and that may be cooperatively mediated by myocyte enhancer factor-2 (271).

Obesity

Evidence that inactivity increases incidence. Each year, an estimated 300,000 adults die of causes related to obesity (180), making it the second greatest environmental cause of death after tobacco. Data for adults suggest that overweight prevalence has increased by more than 50% in the past 10 yr (180). An overweight condition is the most common health problem facing American children, particularly for African Americans and Hispanics (230). More than one decade ago, the direct costs of obesity and physical inactivity accounted for 9.4% of the US health care expenditures; therefore, these cost must be greater now.

Intermediate mechanisms. The findings reported in the previous section suggest that physical activity, as an environmental factor, interacts with signaling pathways to genes, independent of the percentage of body fat.

Cellular mechanisms. Because physically active subjects have smaller adipose tissue stores, biochemical changes favoring a smaller steady-state size of adipose tissue would be hypothesized; indeed, the present literature is beginning to support these notions. Compared with untrained persons exercising at the same absolute intensity, persons who have undergone endurance training have greater fat oxidation during exercise without increased lipolysis (111). Blood catecholamine levels are less in the trained state at the same absolute workload (133); thus it appears that fat cells become more sensitive to catecholamines. Trained subjects have an increased efficiency of activation of the lipolytic -adrenergic pathway in subcutaneous abdominal adipose tissue, alth