The vascular endothelium serves as an important modulator of vasomotor tone and function by synthesizing and releasing nitric oxide (NO) for flow-dependent dilatation of conduit arteries during periods of increased cardiac work (Kelm, 2002). However, endothelial function is dynamic and easily depressed by numerous factors. For example, postprandial lipaemia, hyperglycaemia, mental stress and/or physical inactivity can all lower NO expression levels in vessel walls (Abdu et al. 2001; Kelm, 2002). In addition, the coronary vascular response to acetylcholine depends on the integrity of the endothelium and the endothelial NO pathway (Kelm, 2002). Only if the endothelium is healthy can acetylcholine-mediated vasodilatation through NO occur. Patients with coronary endothelial dysfunction respond to acetylcholine by impaired production of endothelium-derived NO and a paradoxical vasoconstriction that is associated with diminished coronary blood flow (Hambrecht et al. 2000). Exercise training reversed the degree of endothelium-dependent vasoconstriction from acetylcholine in both epicardial coronary vessels and resistance vessels in patients with coronary artery disease (Hambrecht et al. 2000), suggesting a correlation between the health of coronary vessels and physical activity levels.
Interestingly, exercise of sedentary pigs enhances NO-mediated vasodilatation (Bowles et al. 2000). One of the mechanisms for this effect is via increased blood flow that occurs in the heart during exercise, which in turn produces shear stress in endothelial cells, ultimately resulting in enhanced NO levels and coronary endothelium-dependent relaxation (Muller et al. 1994). Exercise-mediated increases in NO levels are largely due to an up-regulation of endothelial nitric oxide synthase (ecNOS) mRNA (Sessa et al. 1994) and protein (Woodman et al. 1997) expression.
Many other mechanisms may underlie the maintenance of high NO levels during increased physical activity. For instance, extracellular membrane-bound superoxide dismutase (ecSOD) functions as a major cellular defence against oxygen free radicals (O2•−; Stroppolo et al. 2001). Extracellular SOD scavenges these free radicals and converts them into hydrogen peroxide, thereby preventing the formation of toxic metabolities such as peroxynitrite (Stroppolo et al. 2001). The prevention of these toxic metabolites is vital, since these metabolites can induce degradation of NO (Stroppolo et al. 2001). Exercise is associated with an increased level of ecSOD mRNAs in aortas of wild-type mice (Fukai et al. 2000). This adaptation was removed in transgenic mice lacking the eNOS gene (Fukai et al. 2000). The investigators interpreted their findings as suggesting that NO produced by endothelial cells stimulates increased ecSOD mRNA in adjacent smooth muscle cells, thus preventing O2•−-mediated degradation of NO as it traverses between the two cell types. Chronic aerobic exercise training selectively increases the levels of SOD-1 mRNA, protein and enzymatic activity in porcine coronary arterioles. This report (Rush et al. 2000) suggested that increased SOD-1 could contribute to the enhanced NO-dependent dilatation previously observed in coronary arterioles of exercised pigs by regulating the amount of superoxide in the vascular cell environment, thereby prolonging the biological half-life of NO.
Long-term exercise training increases the diameters of coronary blood vessels in exercise-trained monkeys (Kramsch et al. 1981). Kingwell et al. (2000) suggested that NO is one of the crucial signals for such adaptive changes in gene expression in the extracellular matrix that lead to the long-term increases in the vessel's structural diameter, resulting in enhanced coronary flow, and ultimately decreasing myocardial ischaemia. This adaptation would then lower shear stresses at a given blood flow and diminish a disruption in homeostasis.
Nitric oxide is also a potent anti-atherogenic agent, mediating its actions via vasodilatation, as well as inhibition of platelet aggregation, smooth muscle cell proliferation, and leucocyte adhesion to endothelial cells in the vessel wall (Wroblewski et al. 2000). A disturbance of endothelial function by the loss of NO and its consequent smooth muscle vasoconstriction is considered a key event in the development of atherosclerosis (Gielen et al. 2001).
Clinical and postmortem investigations of recent hunter-gatherer societies (artic Eskimos, Kenyan Kikuyu, Solomon Islanders, Navajo Indians, Masai pastoralists, Australian Aborigines, Kalahari San (Bushman), New Guinea highland natives and Congo Pygmies) reveal little or no heart disease (see Eaton et al. 1988 for references). Eaton et al. (1988) contend: ‘Like our Palaeolithic ancestors, they (recent hunter-gatherer societies) lacked tobacco, rarely had hypertension, and led lives characterized by considerable physical exercise. In addition, their serum cholesterol levels were low (Eaton et al. 1988). When individuals from hunter-gatherer societies became ‘westernized" (migrations of Japanese, Chinese and Samonans to the USA), their incidence of coronary heart disease rises (Eaton et al. 1988). Peery (1975) in his Ward Burdick Award address commented: ‘Ischaemic heart disease should be looked upon as new disease, largely due to greater consumption of meat and dairy products, and the more sedentary lifestyle that have been adopted in the United States as a result of our greater affluence.’ However, Cordain et al. (2002) found from field studies of thirteen 20th century hunter-gatherer societies that they consumed 65 % of their energy from animal food, yet were relatively free of signs and symptoms of cardiovascular disease. They suggest that qualitative differences in fat intake, high intakes of antioxidants, fibre, vitamins and phytochemicals, along with low salt intake may have operated synergistically with more exercise, less stress, and no smoking to prevent cardiovascular disease in the hunter-gatherers (Cordain et al. 2002).
Deficient physical activity in the current sedentary culture lowers NO production in endothelial cells of human coronary blood vessels producing vasoconstriction (Hambrecht et al. 2000). Hambrecht et al. 2000, concluded: ‘This finding provides a pathophysiologic framework for the elucidation of the positive effects of exercise on myocardial perfusion and emphasizes the therapeutic potential of endurance training for patients with stable coronary artery disease.’ The lack of exercise-induced blood flows producing nitric oxide could be a potential contributing factor to explain, in part, the Centers for Disease Prevention's finding that showed ‘no exercise’ accounted for 248 317 deaths from heart disease in the US in 1986 (34 % of total heart deaths) (Hahn et al. 1990).
There are two major categories of cardiac hypertrophy: one in which cardiac reserve (i.e. the maximum percentage that the cardiac output can increase above normal; Guyton & Hall, 1996) and contractility are enhanced (physiological hypertrophy associated with ‘athletes’); and the other in which contractility diminishes (pathological hypertrophy produced by pressure overload, such as hypertension, leading to congestive heart failure; Wikman-Coffelt et al. 1979). For example, according to Guyton & Hall (1996), cardiac reserve is 300–400 % in the healthy young adult, 500–600 % in the athletically trained person, and zero in heart failure. The significance of physiological cardiac hypertrophy is that it improves cardiac function by decreasing oxygen cost per unit of work, resting and submaximal heart rates, as well as increasing filling time, venous return and maximal cardiac output.
Does scientific evidence favour physiological cardiac hypertrophy or the sedentary healthy heart as the physiological norm in AD 2000? The current data seem to support the former possibility. On the basis of gross and microscopic examinations of the hearts of labourers, Linzbach (1947) coined the term ‘physiological left ventricular hypertrophy’. Physiological hypertrophy of cardiac myocytes cannot solely be explained by an inherited and fixed genome, but rather is attributable in part to the plastic nature of cardiac tissue, which in turn is influenced by a dynamic and changing microenvironment. For example, heart dimensions of sedentary young men rapidly increase with swim training and decrease with deconditioning (Ehsani et al. 1978). As Palaeolithic humans laboured for their survival, we speculate that they exhibited left ventricular hypertrophy and high cardiac reserves. Curiously, the term physiological cardiac hypertrophy is almost always now associated with ‘athletes’, rather than ‘labourers’. For example, the JAMA issue dedicated to the 1976 Olympic Games contained an article entitled ‘The Athletic Heart’ (Raskoff et al. 1976). In 2001, Iemitsu et al. wrote: ‘Chronic exercise training causes cardiac hypertrophy, which is defined as the athletic heart.’ This conversion of the population group with physiological cardiac hypertrophy from ‘labourers’ to ‘athletes’ illustrates a shift in the written physiologic norm, as well as a shift in the designation of the control group.
Another supporting set of data for the physiologic norm being physiological cardiac hypertrophy is the comparison between mice allowed to run on voluntary running wheels with their sedentary group housed without wheels. Mice housed with voluntary running wheels ran 3–5 km day−1 (Rothermel et al. 2001) or 7 km day−1 (Allen et al. 2001) with a resultant physiologic cardiac hypertrophy of 30 % and 18 %, respectively, as compared with the sedentary groups. We speculate that mice with running wheels more closely approximate the ‘wild’ or conditions under the environment that selected the genotype to survive. Based upon the phenotype determining survival in the Palaeolithic era, we believe that the physically active mice should be the control group. Our rationale is that mice in the ‘exercise’ group voluntarily ran, thereby suggesting that control must be considered as the voluntarily physically active group because the physiologic norm of their phenotype from their genotype is voluntarily running. Thus, we propose that the answer to the above question is that the scientific evidence favours physiological cardiac hypertrophy as the true norm for the genotype selected in an environment demanding physical activity for survival.
Dissection of the underlying mechanisms for this physiologic hypertrophy revealed a protein called calcineurin to have a likely role in the production of exercise-induced physiological hypertrophy in sedentary subjects. Rats who underwent voluntary running had a 250 % increase in myocardial calcineurin phosphatase activity (Eto et al. 2000). Another report found that MCIP1 overexpression in transgenic mice blocks calcineurin signalling and prevented about 50 % of the exercise-induced cardiac hypertrophy (Rothermel et al. 2001). Thus, the calcineurin-signalling pathway plays an important role in exercise-induced physiological hypertrophy. Potential roles for IGF-I and noradrenaline in physiological hypertrophy are inferred from the observations of a greater release of IGF-I and noradrenaline into the coronary venous blood of soccer players while at rest, as compared with sedentary controls (Neri Serneri et al. 2001). Approximately 50 % of isoprenaline-induced cardiac hypertrophy in mice was blocked by MCIP1 (Rothermel et al. 2001), which we interpret to mean that the aforementioned noradrenaline overspill reported in the heart of soccer players (Neri Serneri et al. 2001) could be signalling physiological hypertrophy.
A remarkably different gene expression pattern was noted between physiologic and pathologic cardiac hypertrophy. Rats permitted access to voluntary running wheels for 6 weeks had a 22 % increase in left ventricular weight to body weight ratio, and a subsequent 100 % selective increase in TGF-1 mRNA, with no associated changes in TGF-3, fibronectin, preprocollagen-1 or prepro-ANP (Calderone et al. 2001). Intriguingly, the latter four mRNAs were markedly upregulated in pathologic cardiac hypertrophy (Calderone et al. 2001). This selective expression implicates a potentially critical role for TGF-1 in myocardial remodelling, as suggested by Calderone et al. (2001). In addition, a greater accumulation of total collagen has been observed in hearts from pressure-overloaded rats than found in rats that ran on motor-driven treadmills (Burgess et al. 1996), thereby further corroborating the association of increased myocardial fibrosis with decreased compliance (Burlew & Weber, 2000).
In summary, these reports show that exercising produces a unique cardiac phenotype with superior physiological and clinical function. Nevertheless, the human heart of a sedentary subject is defined as ‘normal’ or ‘control’ according to current dogma, while physiological hypertrophy (i.e. an athlete's heart) is defined as an adaptation. We suggest that this designation may be incorrect based upon the fact that the human genotype selected in the Late Palaeolithic period probably favoured hearts with high physiologic capacity and high levels of physical activity, which were necessary for survival. We therefore suggest that the appropriate physiological control heart is from the physically active phenotype.
Ironically then, while the likely norm in 10 000 BC was physiological cardiac hypertrophy that facilitated survival, the prevalent form of cardiac enlargement in the present-day labour-free environment is pathological cardiac hypertrophy. Pathological cardiac hypertrophy reduces cardiac function with a progression to heart failure and shortened survival. This is yet another example whose conclusion is analogous to the thrifty gene hypothesis (Neel, 1999): a genotype that favoured survival in the physically active Palaeolithic era now fails to favour survival in a sedentary culture.
In sum, rather than considering cardiac hypertrophy as an adaptation to exercise, it may be more accurate to consider the notion that the true adaptation in AD 2000 may in fact be cardiac deconditioning due to a lack of exercise, i.e. a sedentary lifestyle. The physiological and clinical significance of this misnomer is that current research that is concerned with the genomic and proteomic adaptations of the compensated and failing heart to pressure overload makes comparisons with a sedentary ‘control’ group, when in fact the true ‘control’ group may be the physically active Late Palaeolithic heart. Thus, incorrect differentially expressed genes may be identified by a comparison of pathological hearts with sedentary hearts rather than the phenotype that determined the surviving genotype.
Functioning of exercise-responsive genes in exercise deficiency
The current review has gone beyond a listing of changes in exercise-induced gene expression by contrasting phenotypes with high (hunter-gatherer societies) and low (i.e. cultures no longer requiring physical labour for food acquisition) physical activity levels. One stimulus for this comparison was the statement by Gerber & Crews (1999): ‘For those interested in the health and well-being of humankind, a basic understanding of evolutionary pressures that have shaped human physiological responses to the environment is a necessity.‘
Physical activity is one example of an environmental pressure that shaped the human genotype and phenotype. The differences in caloric expenditure are not trivial, and hence cannot be ignored. For example, Mexican Pima Indians have 21–31 kJ kg−1 day−1 more physical activity than do Arizonan Pima Indians, who are estimated to have geographically separated 700–1000 years ago (Esparza et al. 2000). Cordain et al. (1998) found that recently studied hunter-gatherers had 72 kJ kg−1 day−1 more physical activity than the typical US adult. An exercise deficiency of 72 kJ kg−1 day−1 is the work equivalent of a 70 kg human walking 19–33 more kilometers per day (12-21 more miles per day). Phenotypic changes associated with exercise deficiency are: decreased size and strength of skeletal muscle, lower capacity of skeletal muscle to oxidize carbohydrates and fats, higher insulin resistance, greater homeostatic disruption of cellular metabolism in skeletal muscle at a given absolute work load, lesser vasodilator capacity in perfusion vessels to the heart, smaller maximal cardiac outputs and stroke volumes, and sarcopenia (Holloszy & Booth, 1976; Heath et al. 1983; Åstrand & Rodahl, 1986; Åstrand, 1992; Kingwell, 2000; Tipton, 2001; McGuire et al. 2001). Examples of some of the changes and the mechanisms of such changes in gene expression that underlie the altered phenotypes are also delineated in this review. Trevathan et al. (1999) have asserted: ‘A better understanding of many modern health problems will emerge when we consider that most of human evolution took place when our ancestors were hunter-gatherers.’ Thus, the current review has employed an evolutionary approach to better understand the functions of genes in a high physical activity and exercise-deficient state.
The phenotype associated with exercise deficiency often shows that thresholds of biological significance have been surpassed by altered gene expression so that overt clinical conditions occur (Beaudet et al. 1995). For example, a deficiency in caloric expenditure of only 450 kJ day−1 (107 kcal day−1) from walking > 21 min day−1 to not walking at all is associated with increased prevalences of mortality and many chronic health conditions spanning from diabetes to cancer (Hu et al. 1999, 2000, 2001; Leitzmann et al. 1999; Manson et al. 1999; Martinez et al. 1997; Rockhill et al. 1999, 2001). Exercise deficiency also leads to an increased prevalence of obesity, hypertension, intermittent claudication, sarcopenia, osteoporosis and Alzeihmer's disease (Chakravarthy et al. 2002). Exercise deficiency contributed to 57 million US adults having a metabolic dysfunction (Syndrome X, the cluster of hypertension, atherosclerosis, truncal obesity and insulin resistance) in the US in 1990 (Ford et al. 2002). Conversely, a current dietary antioxidant deficiency, compared with hunter-gatherer diets, could also contribute to an increased prevalence of cardiovascular disease (Eaton & Konner, 1985; Cordain et al. 2002). Thus, although many other factors (for example, high fat/low fibre dietary habits, tobacco or free radicals) clearly contribute to the increased incidences of these disorders (Cordain et al. 2002; Eaton et al. 1988, 2002; Gerber & Crews, 1999; Trevathan et al. 1999), our experience has been that a lack of understanding by the general scientific, medical, judicial and legislative communities for the magnitude of the altered gene expression by exercise deficiency has led to their underestimation or non-consideration of the significance of the functions of exercise-induced gene expressions.
If the exercise-deficient phenotype did not contribute to overt clinical disorders, exercise-induced changes in gene expression would only be physiological phenomena (Booth et al. 2002). However, alterations in gene expression by exercise deficiency contribute to morbidity and mortality, which emphasizes the importance of using the evolutionary pressures that have shaped human physiological responses to define better the functions for exercise-induced changes in gene expression in both physiological and pathophysiological conditions.