https://orcid.org/0000-0002-8200-4341
This editorial refers to ‘Effect of chronic exercise in healthy young male adults: a metabolomic analysis’ by Y.C. Koay et al., pp. 613–622.
Regular physical exercise reduces the risk of lifestyle-related diseases such as diabetes and atherosclerosis and is associated with improved well-being and longer live expectancy.1–3 Exercise, therefore, may be prescribed as medicine for primary prevention or adjunctive treatment for a variety of disorders, including obesity, type 2 diabetes, cardiovascular diseases, dementia, and cancer.1–3 The beneficial effects of exercise had already been recognized by Hippocrates (c 460–377 BC), a physician living on the Greek island of Kos (Figure 1) and considered the ‘father of medicine’.4 Hippocrates introduced the concept of ‘physis’ and thereby changed the hieratic or theocratic medicine into a rational discipline.4 The structure of the Asclepieion of Kos, a healing temple named after Asklepios of Kos, indicates that Hippocrates practiced in a holistic health care model, and in his school science met with drug therapy, diets, and physical exercise.4 Indeed, patients at the Asclepieion were offered general treatment that included physical exercise and walks considered necessary to restore health.4 Hippokrates’ advice ‘walking is the best medicine’ can be considered as the first notion of ‘exercise is medicine’, and represents a timeless non-pharmacological prescription for health and longevity.4
Ancient Roman marble bust of Greek physician Hippocrates (c 460–377 BC), the ‘father of medicine’ and the earliest known promotor of ‘exercise is medicine’, from the personal collection of Flemish painter Peter Paul Rubens (1577–1640). Most of the busts were displayed in Rubens' house in Antwerp. This copper plate engraving on paper, made by Paulus Pontius (1603–1658), is based on a drawing of the bust made by Rubens and was completed by Pontius two years before Rubens' death at the age of 62. Text under the engraving: Sign. ‘P.P. Rubens delineavit. P. Pontius sculp. A: o 1638’;‘HIPPOCRATES HIRACLIDAE F. COVS. Ex marmore antiquo. Cum Priuilegiis Regis Christianiss Principum Belgarum et Ord. Batauiae.
Already 2000 years ago, Roman physician Claudius Galenus, known as Galen (c 129–210 AD), who followed Hippocrates’ teachings and recognized the potential of physical exercise on preventing chronic non-communicable diseases, noted not only ‘insensitivity and strength for function of the organs’ but also metabolic effects such as a ‘readier metabolism’ and ‘better nutrition and diffusion of all substances’ as additional benefits of exercise.5 Over the last decades, it has become evident that the exercising skeletal muscles release a number of active substances coined ‘exerkines’ that may exert their effects in either autocrine, paracrine, or endocrine manners.6 More recent evidence shows that these exerkines allow for the crosstalk between muscle and other organs, including the brain, adipose tissue, bone, liver, gut, pancreas, vasculature and skin, as well as communication within the muscle itself.7 Furthermore, an array of studies has revealed that exercise may induce key changes in circulating concentrations of several metabolites that belong to energy and other branches of metabolism, including lipolysis, glycolysis, and aminoacid metabolism, as well as determine utilization of different metabolic substrates compared to sedentary life. Identification of the full extent of metabolomic changes associated with physical activity, therefore, may be useful to better understand the protective action of exercise against cardiometabolic disease and allowing healthy ageing.1,–3
Koay et al.8 report the results of a carefully designed clinical study comparing plasma metabolomics (measured by use of liquid chromatography followed by tandem mass spectrometry) before and after a 80-day period of combined aerobic and strength exercise in a group of healthy young males; importantly, all other possible extraneous confounders, such as diet, sleeping pattern, work environment, stress and socio-economic status were absent, given that the participants were soldiers of similar age, living in the same environment and performing the same daily activities. As expected, chronic exercise was associated with a profound shift in overall metabolism, with a relevant decrease in plasma levels of those substrates used as fuel by exercising muscles, such as fatty acids and ketone bodies.8 In addition, marked changes were observed that were associated with increased aerobic fitness in many other classes of metabolic substrates, such as arginine metabolites, endocannabinoids, nucleotides, markers of proteolysis, products of fatty acids oxidation, microbiome-derived metabolites, markers of oxidative stress, and substrates of coagulation.8
Interestingly, one of the arginine metabolites, dimethylguanidino valeric acid (DMGV), was able to track a maladaptive metabolic response to exercise.8 Also, the participants with greater post-exercise increment in plasma levels of DMGV showed higher values of some variables associated with cardiovascular risk, such as body fat, total and LDL-cholesterol, and systolic blood pressure.8 The potential value of DMGV as an early marker of metabolic dysfunction had already been suggested by a previous study, in which elevated DMGV predicted the absence of a beneficial metabolic response to exercise (in terms of improvements in HDL traits and insulin sensitivity) in sedentary, overweight individuals.9 The findings of Koay et al.8 expand those former observations, by demonstrating that DMVG serves as a biomarker indicating poor metabolic response to prolonged physical activity also in young, healthy, fit males. Surprisingly, whereas Robbins et al.9 reported a reduction in circulating DMGV levels after 20 weeks of endurance training, with a significant inverse correlation found between baseline DMVG levels and their decrease after exercise, in the study of Koay et al.8 DMGV levels were significantly augmented after prolonged exercise training. The reasons of these discrepancies are difficult to explain, but it is conceivable that differences in the baseline characteristics of the participants and in the duration or type of the exercise protocols might have contributed to these divergent outcomes. DMGV has been previously identified as a strong, independent biomarker of non-alcoholic fatty liver disease (NAFLD) by an investigation in the offspring cohort of the Framingham Heart Study integrating non-targeted metabolomics, genetics and detailed phenotyping.10 Thus, DMGV circulating levels were significantly elevated in patients with biopsy-proven non-alcoholic steatohepatitis, a condition that is highly interconnected to visceral adiposity and may confer high cardiometabolic risk independent of general fat.11 In addition, in the study of Robbins et al.9 plasma DMGV was an independent predictor of future development of Type 2 diabetes and was significantly decreased following weight loss obtained through bypass surgery. Remarkably, the participants in both studies of Koay et al.8 and Robbins et al.9 were not obese and had not clinical evidence of NAFLD. Taken together, these findings highlight the diagnostic and perhaps prognostic potential of circulating DMGV as a risk indicator even in patients without apparent metabolic disease.
The study of Koay et al.8 used a longitudinal design to track post-exercise changes in biochemical traits compared to baseline values and did not include a control group. Also, its cohort included only young and healthy males, with a high level of fitness at baseline. These restrictions, therefore, do not permit generalization of its findings and, more importantly, do not allow insights into potential mechanism(s) underlying the relationship between increased DMGV levels and maladaptive responses to exercise training. Another unanswered question relates to the potential value of DMGV as a predictor of the vascular adaptation to physical activity. DMGV is the product of transamination of asymmetric dimethylarginine (ADMA), by alanine-glyoxylate aminotransferase 2, an enzyme mainly expressed in human kidney and liver,12 which represents another elimination pathway of ADMA, in addition to dimethylarginine dimethylaminohydrolase.13 ADMA, in turn, is a competitive inhibitor of the nitric oxide synthase (NOS) enzyme family, including endothelial NOS, a crucial protective factor in the regulation of vascular homeostasis. Koay et al.8 have reported that exercise training, in conjunction with higher circulating levels of DMGV, results in increased plasma levels of arginine, the substrate of NOS, and L-NMMA, a non-selective competitive inhibitor of the NOS enzymes. The net effect of these combination of changes in the arginine metabolism on nitric oxide availability after chronic exercise is unknown, given that no measurements of NO levels or activity were performed by Koay et al.8 An assessment of this parameter, however, would be of great interest, in order to ascertain whether metabolic resistance to exercise is coupled with impairment of vascular function or, by contrast, elevated DMGV does not herald a defective vascular benefit of physical activity.
Although exercise has been a cornerstone in the prevention and treatment of chronic non-communicable diseases for thousands of years,4,5 identification of prognostic biomarkers of a favourable response to exercise training is a relevant, still unmet, clinical need in order to determine individual disease risk and to allow for early intervention. Since subjects with increased visceral and liver fat are less likely to improve their metabolic profile after lifestyle interventions,14 the study of Koay et al.8 highlights the potential value of DMGV as a predictor of the metabolic response to exercise in a group of healthy, young subjects without metabolic disease. If confirmed, these findings could have potential clinical implications, suggesting that individuals with high levels of DMGV may exhibit metabolic resistance to exercise training, requiring alternative interventions to improve their metabolic profile and hence reduce their cardiovascular risk. Notwithstanding its potential prognostic significance, maintaining or achieving normal body weight in combination with a regular exercise ‘regimen’ remains the most important and cost-effective intervention for primary and secondary prevention of arterial hypertension, diabetes, cardiovascular disease, and dementia, inhibiting inflammatory activation and improving endothelial cell functions.2,3 Physicians need to become aware of and embrace the fact that «exercise is medicine» and one should increase the number of exercise prescriptions as much as possible for the benefit of our patients.15 Regular physical exercise will help to compress the period of senescence and morbidity at the end of life increasing the number of those who will experience healthy ageing.1–3
Disclosure
M.B. served on the Diabetic CKD Advisory Board and the Steering Committee of the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial conducted by AbbVie, Inc. M.B. has also served as a consultant for AbbVie, Inc. and for Pharmazz, Inc. C.C. has no competing interests to disclose.
Funding
This work was supported by the Swiss National Science Foundation (108 258 and 102 544 to M.B.) and Fondi d’Ateneo Grants from Università Cattolica, Rome (to C.C.).
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
