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.

Fig. 1

Preferred Reporting Items for Systematic and Meta-Analysis (PRISMA) 2020 flow diagram. CPET cardiopulmonary exercise test, CRF cardiorespiratory fitness

Fig. 2

Included metabolites on the super class level. a Metabolites super classes positively associated with cardiorespiratory fitness. b Metabolites super classes negatively associated with cardiorespiratory fitness. n number of metabolite species. Figure was created with the Mind the Graph platform (www.mindthegraph.com) and Adobe Illustrator 2021 (Adobe Inc., San Jose, CA, USA)

Fig. 3

Included lipid and lipid-like molecules. a Lipids and lipid-like molecules positively associated with cardiorespiratory fitness, by class level. b Lipids and lipid-like molecules negatively associated with cardiorespiratory fitness, by class level. c Glycerophospholipids positively associated with cardiorespiratory fitness, by direct parent level. d Glycerophospholipids negatively associated with cardiorespiratory fitness, by direct parent level. LPC lyso-acylglycerophosphocholines, LPC-O lyso-alkylglycerophosphocholines, LPC-P lyso-alkenylglycerophosphocholines, LPE lyso-acylglycerophosphoethanolamines, n number of metabolite species, PC diacylglycerophosphocholines, PC-P alkenyl-acylglycerophosphocholines, PE diacylglycerophosphoethanolamines, PE-O alkyl-acylglycerophosphoethanolamines, PE-P alkenyl-acylglycerophosphoethanolamines, PI diacylglycerophosphoinositol. Figure was created with the Mind the Graph platform (www.mindthegraph.com) and Adobe Illustrator 2021 (Adobe Inc., San Jose, CA, USA)

Fig. 4

Included organic acids and derivatives on the class level. a Organic acids and derivatives positively associated with cardiorespiratory fitness. b Organic acids and derivatives negatively associated with cardiorespiratory fitness. n number of metabolite species. Figure was created with the Mind the Graph platform (www.mindthegraph.com) and Adobe Illustrator 2021 (Adobe Inc., San Jose, CA, USA)

Fig. 5

Metabolites associated with cardiorespiratory fitness (CRF) as potential driving forces of cardiometabolic health. Figure was created with the Mind the Graph platform (www.mindthegraph.com) and Adobe Illustrator 2021 (Adobe Inc., San Jose, CA, USA). BCAA branched-chain amino acids, LPCs lyso-acylglycerophosphocholines