Abstract
Physical activity and its sustained and purposeful performance – exercise – promote a broad and diverse set of metabolic and cardiovascular health benefits. Regular exercise is the most effective way to improve cardiorespiratory fitness, a measure of one’s global cardiovascular, pulmonary and metabolic health and one of the strongest predictors of future health risk. Here, we describe how exercise affects individual organ systems related to cardiometabolic health, including the promotion of insulin and glucose homeostasis through improved efficiency in skeletal muscle glucose utilization and enhanced insulin sensitivity; beneficial changes in body composition and adiposity; and improved cardiac mechanics and vascular health. We subsequently identify knowledge gaps that remain in exercise science, including heterogeneity in exercise responsiveness. While the application of molecular profiling technologies in exercise science has begun to illuminate the biochemical pathways that govern exercise-induced health promotion, much of this work has focused on individual organ systems and applied single platforms. New insights into exercise-induced secreted small molecules and proteins that impart their effects in distant organs (“exerkines”) highlight the need for an integrated approach towards the study of exercise and its global effects; efforts that are ongoing.
Introduction
The salutary health effects of physical activity and exercise are indisputable and have been recognized since the dawn of ancient civilization. The concept of “exercise is medicine” has evolved from Hippocrates’ individual exercise prescriptions to a modern, global health initiative.1 An ever expanding body of science has highlighted the protean benefits of physical activity (PA) and exercise through investigation of individual organ systems as well as by studying its integrative physiology.2 Exercise promotes weight loss; improves body composition, lipid metrics, vascular health, and insulin and glucose homeostasis; and decreases the risk of type II diabetes and cardiovascular disease (CVD) among several other effects (Figure 1).3–8 Despite these advancements in our understanding of its effects, relatively little is known about the biochemical pathways and molecular targets that ultimately lead to exercise’s health benefits. Emerging technologies that permit large-scale biochemical profiling have provided enormous opportunity to unravel the molecular basis of exercise science and offer promise towards personalized exercise medicine.9 In this article, we review the relationship between PA, cardiorespiratory fitness (CRF) and cardiovascular morbidity and mortality. We then describe our understanding of the physiologic basis for exercise-induced cardiometabolic health adaptations. Finally, we explore some potential areas for future research, including the use of molecular profiling technologies to identify exercise-induced mediators of cardiometabolic health.
Figure 1.
Summary of the cardiometabolic health benefits of exercise
CO, cardiac output; CRF, cardiorespiratory fitness; LPL, lipoprotein lipase; WAT, white adipose tissue
Definitions of sedentary behavior, physical activity and exercise
The definitions of sedentary behavior, physical inactivity and exercise are important to understand as they pertain to physical health. Sedentary behavior is characterized by any waking behavior that amounts to an energy expenditure ≤ 1.5 metabolic equivalents of task (METs) while in a seated, reclined or lying posture.10 PA is any bodily movement produced by the skeletal muscle that results in energy expenditure, with physical inactivity defined as the absence of moderate- to-vigorous PA. Finally, exercise or exercise training (ET) is structured, repetitive, and purposeful PA undertaken to improve or maintain one or more components of physical fitness.11
Sedentary behavior and cardiovascular disease
Several large epidemiological studies have shown that sedentary behavior is associated with adverse health outcomes.12–14 In a Canadian study that included >17,000 adults followed for an average of 12 years, there was a progressive increase in risk of all-cause and CVD mortality across higher levels of sitting time, even after adjusting for potential confounders.12 A subsequent Australian study corroborated these findings, demonstrating an increased risk of all-cause and CVD mortality among individuals watching ≥ 4 hours of television per day compared with those watching < 2 hours per day.13 A meta-analysis of six studies involving nearly 600,000 adults further highlighted an increased risk of all-cause mortality for every 1-hour increase in sitting time.14 However, a linear dose-response relationship between sedentary behavior and cardiovascular morbidity and mortality has been challenged by a more recent meta-analysis that demonstrated a threshold effect, with an increased risk of CVD observed only among those with very high levels of sitting time (>10 hours/day).15
Physical activity and cardiovascular disease
Akin to the relationship between sedentary behavior and mortality, PA is also independently and inversely associated with CVD and all-cause mortality. In a study of 55,137 adults (mean age = 44 years) that were followed for 15 years, leisure-time runners had 30% and 45% lower adjusted risks of all-cause and CVD mortality, respectively, as compared to non-runners. In this study, the authors showed that a ‘minimum dose’ of 5 to 10 min/day (or 30 minutes to one hour per week) and at slow speeds <6 miles/h, was sufficient to reduce the risk of mortality.16
The relationship between exercise and CVD mortality is most frequently described as curvilinear with studies indicating that the greatest reduction in mortality risk is accrued by those who increase their exercise from none or minimal exercise to performing mild-moderate levels of exercise.17–19 This underscores a critical public health message: those who are least active stand to gain the most by modestly increasing their PA and subsequent fitness levels. Importantly, sedentary behavior and physical inactivity need not be mutually exclusive; for example, many individuals are sedentary for a large proportion of the day despite engaging 150–300 minutes of moderate- to vigorous PA per week. The interaction between sedentary behavior, PA and mortality is more complex and not fully understood. While the deleterious health outcomes of sitting appear to be independent of the benefits of PA,20 a more recent systematic review of over 1 million participants suggests that high levels of moderate-intensity PA attenuate, and in some populations eliminate, the increased mortality risk associated with sedentary behavior.21 Given the complexity of these interactions and inconclusive nature of the evidence, it is important that all individuals limit sedentary behavior and achieve moderate to high levels of PA and exercise.
Cardiorespiratory fitness and cardiovascular disease
CRF is one of the most powerful determinants of health outcomes in both healthy populations and among those with chronic diseases (Table 1). CRF represents the integration of multiple organ systems to effectively: i) deliver oxygenated blood to working skeletal muscle; ii) meet regional metabolic demands and iii) remove toxic metabolic byproducts that impair the ability of the muscle to sustain activity when accumulated in excess. CRF is best captured by one’s maximal oxygen uptake (VO2max), which may be directly measured through cardiopulmonary exercise testing (CPET) using gas exchange analysis, though it is commonly estimated from external work demands including exercise stress testing (i.e. peak energy expenditure in METs).
It has long been recognized that CRF is strongly associated with long-term health outcomes. In a seminal study, Blair and colleagues demonstrated a graded and inverse relationship between increasing fitness level and risk of CVD and all-cause mortality in a cohort of ~30,000 apparently healthy, middle-aged men and women who underwent maximal exercise testing as part of a routine preventive medical examination.22 Myers et al. subsequently built upon these findings by showing a similar relationship among patients with chronic diseases. In a cohort from the Veterans Affairs Healthcare System that included 3679 men with and 2534 without CVD, peak estimated CRF was strongly and inversely related to mortality risk among both groups.23 Further, every one MET increase in exercise capacity conferred a 12% lower risk of death. These findings have been replicated in several studies and among different populations, and a recent meta-analysis that included more than 100,000 participants demonstrated that those with low CRF (< 7.9 METs) had a significantly increased risk of all-cause mortality compared to those with high CRF (> 10.9 METs; RR, 1.70; 95% CI, 1.51–1.92).24 Increasingly, there is recognition of the importance of incorporating CRF into routine clinical practice; indeed, the American Heart Association has recently called for CRF to be included as a vital sign whose improvement should be emphasized as a standard part of a clinical encounter.25
Exercise effects on metabolic health
Insulin and glucose homeostasis
Skeletal muscle plays a major role in glucose homeostasis, accounting for 30% of resting metabolic rate in adults and roughly 80% of whole-body glucose disposal under insulin-stimulated conditions.26–28 In the post-prandial period, glucose uptake in skeletal muscle and adipose tissue is mediated by insulin transduction cascades that result in the translocation of the intracellular glucose transport carrier protein, GLUT4, to the plasma membrane, allowing for facilitated diffusion of glucose down its concentration gradient.29 Chronic over nutrition results in insulin resistance by inducing cellular stress, toxic metabolite accumulation, and inflammation,30 which leads to glucose intolerance, dyslipidemia, endothelial dysfunction, and ultimately to the development of type 2 diabetes and cardiometabolic disease.29 A large body of research has demonstrated the beneficial effects of PA and ET on glucose homeostasis and insulin sensitivity.31,32 An acute bout of exercise may increase insulin sensitivity for up to 72 hours by mechanisms that are not fully established.32,33 Furthermore, the response may vary depending on the duration and intensity of the exercise intervention.32 Regular ET improves insulin sensitivity by reducing adipose tissue mass; however, longitudinal studies evaluating the ability of regular exercise to confer long-term improvements in insulin sensitivity independent of weight loss are mixed.34
While ET enhances insulin sensitivity in the post-exercise period, glucose disposal in skeletal muscle during exercise is achieved through pathways independent of insulin transduction cascades.35 As exercise intensity increases from low- to high-intensity (i.e., < 30% VO2max to > 75% VO2max), the predominant fuel source for skeletal muscle shifts from plasma free fatty acids (FFAs) to plasma glucose and muscle glycogen.36 The regulation of exercise-stimulated glucose uptake in skeletal muscle involves three inter-related processes: glucose delivery, glucose transport across the cell membrane, and intracellular glucose metabolism.37 Glucose delivery to skeletal muscle increases proportionally to exercise intensity through increased cardiac output, peripheral vasodilation/capillary recruitment, and muscle contraction-induced venous return.38,39 The transport of GLUT4 from the intracellular compartment to the muscle plasma membrane during exercise is mediated by alterations in the intracellular metabolic state (via increased AMP-activated protein kinase [AMPK] activity) and through contraction-stimulated signaling cascades (involving Ca2+/calmodulin-dependent protein kinases [CaMK] and RAC1).39 Autocrine and paracrine signals, including IL-13, irisin, neuregulin, and urocortin-3, likely play a role in myocellular glucose metabolism during exercise, although the precise functions of these biochemical pathways is not fully understood.39
Recent advances in proteomics and bioinformatics have uncovered the breadth of the signaling cascades involved in glucose uptake by skeletal muscle during exercise. In response to a high-intensity cycling session, Hoffman et al. identified approximately 1,000 significantly regulated phosphorylation sites on over 500 skeletal muscle proteins.40 These included several previously described exercise-regulated protein kinases, including AMPK, PKA, CaMK, MAPK, and mTOR. However, the majority of these newly identified kinases and phosphosites - including the elucidation of AKAP1 as an important AMPK substrate involved in mitochondrial respiration - had not previously been implicated in the regulation of exercise-induced skeletal muscle glucose uptake, highlighting the breadth of exercise biology that remains to be uncovered even in an organ system that has received much attention.
Lipid Metabolism
Aerobic exercise produces beneficial effects on plasma lipids and lipoproteins, including increased HDL cholesterol, decreased VLDL triglycerides, and increased average particle size of circulating LDLs.44 While changes in LDL subfractions are not discernable on a traditional, enzymatic lipid panel, a higher ratio of small, dense LDL particles is associated with CHD even in individuals with normal LDL cholesterol.45
Several mechanisms have been proposed to explain exercise-induced alterations in lipid metabolism. Cholesterol ester transport protein (CETP) is an HDL-bound plasma protein that exchanges esterified cholesterol and triglycerides between lipoprotein particles, ultimately increasing the cholesterol ester content of VLDL particles and the triglyceride content of HDL and LDL particles.51 Triglyceride-rich HDL and LDL particles subsequently interact with triglyceride lipases to form small, dense HDL and LDL subfractions.51–53 Habitual aerobic exercise decreases the plasma concentration of CETP which contributes to the favorable shifts in lipid distributions.54 Moreover, acute and regular bouts of exercise increase skeletal muscle lipoprotein lipase (LPL) content and activity, thereby increasing hydrolysis of circulating triglycerides.56,57 More recent investigations have identified other potential mediators of exercise-induced HDL alterations,55 including the modulation of reverse cholesterol transport via increased expression of the transcription factor liver X receptor (LXR)58,59 and the membrane-associated ATP-binding cassette transporter A-1 (ABCA1) in macrophages.60,61
Additionally, genomic and transcriptomic analyses from the HERITAGE Family Study have identified several genetic variants that influence changes in lipids in response to endurance ET.62–64 Overall, the heritability estimate for exercise-induced alterations in lipids is roughly 30%.65 Notably, exercise produces a wide range in the magnitude of triglyceride reduction,66 and as many as 10% of individuals will have a paradoxical increase in triglycerides after regular exercise.67 A recent analysis from the HERITAGE Stduy identified a small number of single-nucleotide polymorphisms (SNPs) that explain a majority of the genetic variance of triglyceride changes in response to exercise interventions.64 Furthermore, the authors elucidated that the genetic variation may be mediated by pathways related to heparin sulfate, a glycosaminoglycan that is involved in the cell surface binding of LPL. Similarly, variants at the CETP, APOE4, and the APOA1 gene loci have been associated with variability in the response of HDL to regular exercise.63,68,69
Adipose Tissue
Adipose tissue may be broadly classified into two main types: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT has several physiological functions, including energy storage, endocrine signaling, and immune system regulation. WAT is subclassified according to its anatomic distribution: subcutaneous WAT (scWAT) lies below the dermis, whereas visceral WAT (vWAT) surrounds the internal organs. Importantly, these fat depots have distinct physiological health implications. Visceral WAT is strongly associated with increased cardiometabolic risk.76,77 In contrast, scWAT may confer beneficial effects on insulin and glucose homeostasis and lipid metabolism.78–80
BAT - only recently proven to be biologically functional in human adults - is most metabolically active in the supraclavicular fossa and axilla.81,82 BAT is distinguished by its capacity to generate heat through non-shivering thermogenesis, mediated by the expression of uncoupling protein 1 (UCP1) on the inner mitochondrial membrane.82 A third type of adipose tissue, known as ‘beige’ adipose tissue, can arise from WAT in response to certain stimuli through a process known as ‘beiging’ (also referred to as ‘browning’). Beige adipose tissue assumes a phenotype similar to that of BAT. As described below, the ability of exercise to induce beiging of WAT is under investigation and has significant implications relating to metabolic health due to its capacity to promote energy expenditure.
Exercise-stimulated adipose tissue adaptations are most well-understood in WAT and have been reviewed in depth by Vidal and Stanford as summarized below.83 First, both animal model and human studies have demonstrated increased mitochondrial activity in scWAT in response to exercise,84–87 whereas changes in vWAT mitochondrial activity have only been observed in animal models.88 Second, rodent studies have demonstrated exercise-induced alterations in lipid metabolism and the lipidomic profile of scWAT.89 These changes are less well understood in humans, but studies indicate exercise-responsive modifications in gene expression result in enhanced fat oxidation in WAT.85,87 Third, exercise alters the endocrine signaling profile of adipose tissue. Adipokines are bioactive factors released by adipose tissue with systemic metabolic effects.90 Several adipokines are modulated by exercise, including increased expression of TNF-α, IL-6, TGF-β2, and decreased expression of adiponectin and leptin.91–93 Numerous studies have further demonstrated significant ‘crosstalk’ between myokines (muscle-secreted factors) and adipokines, which act synergistically on respective tissue sites to promote beneficial cardiometabolic effects.93–95
Exercise-stimulated myokine signaling is also involved in the beiging of WAT. During exercise, the hormone irisin is upregulated via the transcription factor PGC1-α and released from skeletal muscle, triggering WAT beiging.96 Recently, a novel small molecule, β-aminoisobutyric acid (BAIBA), was identified in both rodents and humans that is also responsive to PGC1-α during exercise, provoking both in vitro and in vivo beiging of scWAT.97 In participants in the Framingham Heart Study, BAIBA was inversely correlated with cardiometabolic risk factors.97 However, while the beiging of WAT has been well established in animal models, human studies have been mixed and require further investigation.84,97–100
Researchers have also investigated whether different exercise interventions have variable effects on reducing adipose tissue mass. In one recent trial, 300 adults with abdominal obesity were randomized to either no exercise or one of three endurance exercise interventions (low-amount/low-intensity, high-amount/low-intensity, high-amount/high-intensity aerobic ET).101 The reductions in waist circumference and overall weight loss across all intervention groups were significantly greater than the control group but did not differ between groups. A subsequent trial of 103 adults with abdominal obesity randomized to similar ET interventions showed comparable results.102 Other studies, however, have demonstrated improvements in body composition under high-intensity ET as compared to lower intensities and it remains unclear which exercise protocols are best suited to reduce specific fat mass subgroups.103,104 Furthermore, randomized controlled trials comparing the effects of aerobic exercise versus resistance exercise have shown that both modalities are effective at decreasing abdominal fat;105,106 however, these findings have been challenged by other data.107 Taken together, the body of evidence suggests that sustained commitment to an exercise routine to improve body composition should be emphasized over a particular exercise modality and intensity until additional data from a broader population is obtained.
Systemic Inflammation
Physical inactivity and abdominal obesity are associated with low-grade, systemic inflammation108,109 and chronic inflammation has been closely linked with the development of cardiometabolic disease.110,111 Exercise’s beneficial effects on intermediate and long-term cardiometabolic health outcomes have, thus, been postulated to proceed at least partially through its effects on inflammation. Studies of acute exercise have demonstrated an increase in plasma levels of muscle-derived IL-6, which acts downstream to amplify anti-inflammatory cytokines (e.g., IL-1ra and IL-10) and to inhibit pro-inflammatory cytokines (e.g., 1L-1β and TNF-α).112 Acute bouts of exercise also increase circulating levels of epinephrine and cortisol, which may be partial mediators of the proposed anti-inflammatory effects of ET.112,113
Despite the mechanistic basis for these studies and observational data supporting anti-inflammatory effects of exercise,114 interventional trials have demonstrated mixed findings.115–117 A recent trial that included 119 young adults randomized to a 12-week aerobic ET program versus controls found no significant difference in post-intervention inflammatory markers.118 Furthermore, a systematic review and meta-analysis of the anti-inflammatory effects of exercise in patients with coronary artery disease found that post-exercise C-reactive protein and von Willebrand factor were significantly lower in exercise groups, but its impact on inflammatory cytokines was equivocal.119
Regular exercise may otherwise protect against chronic systemic inflammation through reducing abdominal fat mass. Myokines, such as IL-6 and IL-15, may be partially responsible for these effects.112 In one recent mechanistic study, adults with abdominal obesity were randomized to receive the IL-6 receptor antibody, tocilizumab, or placebo during a 12-week bicycling intervention.120 The reductions in visceral adiposity achieved by the exercise intervention were negated in the group that received tocilizumab, indicating that changes in body fat composition may be regulated by IL-6 signaling.
Exercise’s anti-inflammatory effects are particularly relevant to atherosclerotic cardiovascular disease (ASCVD), as high levels of circulating inflammatory leukocytes are associated with ASCVD and play a role in its pathogenesis. Recently, Frodermann et al. demonstrated that regular exercise in mice resulted in decreased proliferation of hematopoietic stem and progenitor cells and reduced circulating inflammatory leukocytes, mediated by diminished adipose tissue-derived leptin.121 These efforts highlight the potential for exercise science to serve as a discovery platform for novel biochemical pathways that may ultimately inform pharmacotherapy development for cardiometabolic and/or other chronic diseases.
Exercise effects on cardiovascular health
Cardiac adaptations to exercise
Several structural and morphological cardiac adaptations occur in response to regular exercise. More than a century ago, Eugene Darling observed cardiac enlargement among Harvard University rowers122, a finding that has been corroborated by cross-sectional data in endurance athletes over the subsequent century.123 More recently, prospective and longitudinal assessments of competitive athletes confirmed that regular endurance exercise promotes cardiac chamber enlargement.124 Such training-induced changes in cardiac structure are also seen in healthy but sedentary young individuals after one year of intense aerobic endurance training.125
At the cellular level, exercise-induced cardiac hypertrophy is mediated predominantly by hypertrophy of the cardiomyocytes themselves.126 This may occur through the addition of new sarcomeres either in parallel, or in series, resulting in concentric or eccentric hypertrophy, respectively, according to the training stimulus. Typically, endurance ET is accompanied by eccentric hypertrophy, while static ET leads to concentric cardiac hypertrophy.124
In addition to the morphologic changes that occur with exercise, the physiological increase in wall thickness from repetitive endurance exercise (physiologic hypertrophy) evolves in distinction to left ventricular wall thickening from pathologic conditions including hypertension, aortic stenosis, and other causes of pressure overload (pathologic hypertrophy) at both the ultrastructural and functional levels as well as in its prognostic significance.127,128 Pathological left ventricular hypertrophy is accompanied by ventricular stiffening whereas endurance exercise-induced physiologic adaptations promote enhanced lusitropy and early diastolic left ventricular filling as assessed by tissue doppler echocardiography.129 Even four to five exercise sessions/week throughout adulthood attenuates age- and sedentary-related declines in left ventricular compliance and distensibility.130 More recently, a single-center exercise trial that carefully measured cardiac mechanics demonstrated that a combination of high- and moderate-intensity endurance and resistance training could reverse sedentary, age-related cardiac stiffness in a group of healthy, middle-aged participants.131
Although exercise-induced cardiac remodelling involves a complex series of biochemical processes, several key processes have been identified, including the insulin-like growth factor 1 (IGF-1)-phosphatidyl inositide 3-kinase (PI3K)-Akt pathway. In mouse models, IGF-1 overexpression results in short-term cardiac growth with preserved or improved cardiac function,132,133 and overexpression of the IGF-1 receptor in the heart leads to increased activation of PI3K and downstream Akt phosphorylation.134 Transgenic mice expressing a dominant negative p110α isoform of PI3K (PI3K(p110α)) in the heart display significant cardiac hypertrophy and dilatation in response to pressure overload but not ET.135 Similarly, Akt1 knockout mice demonstrate a blunted hypertrophic response to ET but not to pressure overload, and Akt1 knockout adult murine cardiac myocytes are resistant to IGF-1-, but not endothelin-1-stimulated protein synthesis.136 These findings indicate a critical role for PI3K(p110α) and Akt1 in the development of physiological, but not pathological cardiac hypertrophy and dilation. Downstream of Akt1, a reduction in C/EBPβ, mediated, in part, by increased CITED4, is a central signal in physiologic hypertrophy and proliferation.137 In addition, both Akt and exercise-induced increases in circulating catecholamines promote activation of eNOS, leading to increased nitric oxide production and its beneficial paracrine effects on cardiomyocytes,138,139 further highlighting the important role of this pathway in favorable cardiac remodeling.
Vascular adaptations to exercise
Regular exercise promotes vascular health through an attenuation of age-related deteriorations in arterial stiffness and endothelial function. Vascular stiffness reflects functional changes involving endothelial regulation of vascular smooth muscle tone and structural alterations in the vascular media, including increased collagen deposition and reduced elastin content, and is a marker of CVD risk.140–142 Vascular stiffness leads to an increase in central aortic systolic pressure and a decrease in diastolic pressure, which, taken together, result in a marked increase in pulse pressure for a given pattern of left ventricular ejection.143 These changes are independently associated with incident CVD, particularly in older populations.144–146 Aortic pulse wave velocity is an additional, well-established and non-invasive measure of vascular stiffness that increases with age, even in non-hypertensive adults without CVD.147
Exercise improves both of these measures of vascular health. Both central aortic pressure and stiffness assessed by cardiovascular magnetic resonance imaging-based measures improve after six months of marathon training in previously healthy, but untrained, individuals. Training for, and completing, a marathon even at relatively low exercise intensity has been estimated to confer approximately a four-year reduction in vascular age, with the greatest benefit observed in older, slower individuals.148 Similarly, aortic pulse wave velocity is significantly lower in endurance trained masters athletes relative to their sedentary peers.147 Pre-clinical studies of mice suggest that these effects may be mediated through the promotion of a more favourable adventitial fibroblast phenotype and decreased deposition of collagens in large arterial walls.149 This theory is supported by limited human data whereby administration of ascorbic acid, a potent anti-oxidant, increases carotid artery compliance in sedentary post-menopausal women to levels indistinguishable from their habitually-exercising counterparts.150 Additional human data in subjects with the metabolic syndrome has found that aerobic-exercise leads to decreases in plasma markers of tissue remodelling, including specific factors that are positively associated with carotid-femoral pulse wave velocities, although further investigation is needed to the mechanistic relevance of these findings.151 Interestingly, improvements in pulse wave velocity were not seen after a resistance training intervention suggesting that its response may be dependent on exercise modality.152
Exercise training, cardiorespiratory fitness, and individual differences in training response
The key cardiorespiratory and metabolic adaptations that take place after ET include central and peripheral adaptations comprising an increase in stroke volume, cardiac output, and favourable changes in the vascular and skeletal muscle systems.153–156 The relative and absolute contributions of individual organ systems to exercise performance and CRF have been described elsewhere.157 Despite our understanding of the determinants of CRF and our understanding of training-induced cardiometabolic adaptation, substantial individual heterogeneity in CRF responsiveness to ET exists. Small, early studies demonstrated large individual differences in maximal aerobic capacity changes in response to standardized aerobic ET programs.158–160 Subsequently, these findings were tested and quantified in the much larger HERITAGE Family Study. In this important effort, 742 apparently healthy, sedentary adult members of Caucasian and African American two-generation biologic families completed a standardized, fully supervised 20-week endurance ET program in order to 1) quantify the cardiorespiratory and metabolic effects of regular exercise and 2) assess the genetic contributions to exercise responsiveness. VO2max from cycle ergometry was directly measured by a metabolic cart on two separate occasions both before and after ET in order to quantify the technical error of the measurement.161 In a substudy of Caucasian HERITAGE subjects, the mean increase in VO2max was approximately 400 ml/min after ET, however some individuals experienced little or no gain, whereas others gained >1.0 L/min.162 These findings have been reproduced in the African American HERITAGE participants.64 While the failure of some individuals to increase VO2max raised the concept of exercise “non-responders,” this notion remains controversial.163–165 Nonetheless, data from the HERITAGE Family Study and several other standardized exercise trials provide evidence that there is indeed considerable individual variation in training responses to standardized exercise programs,67,166 and highlights knowledge gaps that remain in understanding what leads to such heterogeneity.
Molecular profiling to identify mediators and predictors of exercise training response
Over the past decade, there have been significant advancements in high-throughput molecular profiling technologies that now allow for the rapid measurement of hundreds to thousands of small molecule metabolites, lipids, and proteins to complement genetic, epigenetic, and RNA sequencing data. These tools have emerged as a promising means to understand how exercise promotes its salutary effects, and what underlies individual and disease-specific variation in exercise responsiveness.9,40,167–170 Early work from the HERITAGE study, a familial study by design, demonstrated that heritability explained nearly half of the variance observed in trainability of CRF.162 However, subsequent candidate gene and genome-wide association studies using the HERITAGE data demonstrated that genetic contributions to CRF and its adaptation to training were only a small piece of the puzzle.171–173 The addition and integration of molecular profiling efforts in the skeletal muscle, heart, adipose, and plasma have provided further insights into the molecular determinants of exercise adaptation.174,175 While acute exercise leads an orchestrated response involving multiple pathways central to cardiometabolic health, vasculogenesis and tissue regeneration,176,177 the relationship between these acute changes and health adaptations from regular exercise remains uncertain. Furthermore, molecular profiling of exercise intervention studies has provided deeper insights into the heterogeneity of exercise responsiveness. In a proof-of-concept study from the HERITAGE Study, investigators showed that a circulating metabolite and biomarker of metabolic dysfunction, dimethylguanidino valeric acid (DMGV), was associated with an attenuated response in HDL-cholesterol traits and insulin sensitivity even among a group of young (mean age = 36 years old), apparently healthy individuals.178 While this study requires validation in external exercise cohorts, it highlights the prospect of using novel biomarkers to identify individual or health specific responses to ET.
Despite these efforts, significant knowledge gaps remain in part because reductionist strategies oversimplify what is clearly a complex process involving multiple biochemical pathways and inter-organ communication.2 Indeed, an emerging paradigm within the field of exercise science is the capacity for locomotor activity to induce the secretion of bioactive factors that target distant organs. These “exerkines”, briefly described above, include small molecule metabolites and proteins secreted from skeletal muscle (myokines), adipose tissue, liver, and even bone, and work in autocrine, paracrine, and endocrine fashion.94,97,179,180 The realization of multi-level, scalable molecular profiling techniques coupled with growing enthusiasm within the exercise science community promises to expand our understanding of how novel exerkines ‘cross-talk’ with distant organs, in turn facilitating a better understanding of the global effects of exercise. Indeed, the ongoing efforts by the Molecular Transducers of Physical Activity (MoTrPAC) Consortium to perform comprehensive molecular profiling in both sedentary adults and highly active individuals before and after either an endurance or resistance ET intervention will provide an enormous opportunity for such discovery.170
Conclusion
Although reductionist strategies applying isolated molecular profiling techniques in exercise studies have provided incredible insights into the field, there remain large gaps in our understanding of the integration across biological systems that lead to exercise’s health benefits. Future research that combines multi-level molecular profiling technologies to establish the biological function of genes, transcription factors, proteins, amino acids, lipids, and metabolites in a range of tissues and bodily fluids is needed, as our dedicated efforts to examine the differences across various exercise modalities, intensities, and durations. Towards this end, the ongoing MoTrPAC Consortium promises to lay a strong foundation that can seed additional efforts in different populations, including those with existing chronic disease. Exercise remains one of the most powerful health promoting tools in medicine and is ubiquitous; efforts to unravel the molecular basis for its effects to further harness it towards precision medicine and novel therapeutic discovery are both tantalizing and achievable.
Acknowledgments
Sources of Funding: This study is supported by the National Institute of Health grants K23 HL150327–01A1 [Dr. Robbins]
Footnotes
Conflicts of Interests: The authors have no conflicts of interest to report
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