The Metabolic Signature of Cardiorespiratory Fitness: A Systematic Review

Abstract

Background Cardiorespiratory fitness (CRF) is a potent health marker, the improvement of which is associated with a reduced incidence of non-communicable diseases and all-cause mortality. Identifying metabolic signatures associated with CRF could reveal how CRF fosters human health and lead to the development of novel health-monitoring strategies. Objective This article systematically reviewed reported associations between CRF and metabolites measured in human tissues and body fluids. Methods PubMed, EMBASE, and Web of Science were searched from database inception to 3 June, 2021. Metabolomics studies reporting metabolites associated with CRF, measured by means of cardiopulmonary exercise test, were deemed eligible. Backward and forward citation tracking on eligible records were used to complement the results of database searching. Risk of bias at the study level was assessed using QUADOMICS. Results Twenty-two studies were included and 667 metabolites, measured in plasma (n = 619), serum (n = 18), skeletal muscle (n = 16), urine (n = 11), or sweat (n = 3), were identified. Lipids were the metabolites most commonly positively (n = 174) and negatively (n = 274) associated with CRF. Specific circulating glycerophospholipids (n = 85) and cholesterol esters (n = 17) were positively associated with CRF, while circulating glycerolipids (n = 152), glycerophospholipids (n = 42), acylcarnitines (n = 14), and ceramides (n = 12) were negatively associated with CRF. Interestingly, muscle acylcarnitines were positively correlated with CRF (n = 15). Conclusions Cardiorespiratory fitness was associated with circulating and muscle lipidome composition. Causality of the revealed associations at the molecular species level remains to be investigated further. Finally, included studies were heterogeneous in terms of participants’ characteristics and analytical and statistical approaches. PROSPERO Registration Number CRD42020214375.

Ceramides as Mediators of Oxidative Stress and Inflammation in Cardiometabolic Disease

“…Aerobic exercise has been shown to modulate circulating ceramide levels [ 64 ]. In particular, cardiorespiratory fitness (CRF), a significant biomarker of health status, the improvement of which is related to a reduced incidence of non-communicable diseases and mortality, resulted as inversely associated to ceramide levels, after analysis in a systematic review reporting the association between CRF and metabolites measured in human tissues and body fluids, and including 22 studies [ 65 ]. In this context, additional therapies directed towards the inhibition of ceramide pathways (e.g., myriocin-inhibitor of serine palmitoyl-CoA transferase, an enzyme involved in up-regulation in de novo synthesis of ceramide), ceramide inhibitors (e.g., Fumonisin B1, fungin FTY720, etc.…”

Single and Joined Behaviour of Circulating Biomarkers and Metabolic Parameters in High-Fit and Low-Fit Healthy Females

“…We performed an elaborate analysis of 102 circulating biomarkers and metabolic parameters, previously studied in disease conditions such as diabetes type 2, obesity, and cardiovascular disease [ 24 , 25 , 26 , 27 ], but hardly in healthy individuals with different lifestyles. Analysis of a selection of these biomarkers and metabolic parameters across two platforms showed similar results, underpinning their reliability, and indicating the robustness of these platforms.…”

“…Our observation that all other biomarkers and metabolic parameters were similar between the two groups, while previous studies in high and low aerobically fit individuals found significant differences in e.g., lipid and protein metabolites [ 30 , 31 , 32 , 33 , 34 , 35 ], is likely related to our standardised experimental set-up, as compared to other studies. We studied healthy, young-adult females of similar age and BMI in a highly controlled setting, while previous studies were performed with metabolically impaired individuals [ 26 ], and individuals with substantially different BMIs [ 30 , 31 , 32 , 35 ], or wider age ranges [ 30 , 35 ] in experimental conditions that were less standardised [ 30 , 31 , 32 , 33 , 35 ], and these factors especially impact circulating metabolite levels [ 26 , 30 , 31 ]. Given that the levels of the analysed biomarkers and metabolic parameters were similar among the healthy females in our study, and multiple of these biomarkers and metabolic parameters showed dysregulation during disease, our findings imply that this biomarker and metabolic parameters set could be used to monitor progress from a healthy to an unhealthier state and may be used in health improvement interventions.…”

“…Here, we provided insight into which biomarkers and metabolic parameters were still not back to baseline after 22 h after exercise. Fourth, our study focused on a total of 102 biomarkers and metabolic parameters related to hormone signaling, inflammation and oxidative stress, and metabolism, while fitness level and single exercise stimulation have been associated with alterations in markers that were not included in our study, such as vitamins [ 32 , 33 ], ceramides [ 26 ], individual lysophosphatidylcholines [ 26 , 30 ] and bile acids, which could possibly have provided additional insights in these biomarkers and metabolic parameters in view of the homogeneity of our study subjects characteristics and high level of study standardisation.…”

Investigating the circulating sphingolipidome response to a single high-intensity interval training session within healthy females and males in their twenties (SphingoHIIT): Protocol for a randomised controlled trial

“…This hypothesis is supported by the fact that circulating sphingolipids have been reported to be negatively associated with cardiorespiratory fitness (CRF). 36 Two preliminary studies investigated the effect of exercise on the circulating sphingolipidome. A single bout of moderate-intensity continuous training (MICT) increased circulating sphingolipids in endurance athletes, sedentary obese individuals, and patients with T2DM.…”