Importance. High physical fitness is associated with a reduction in risk of cardiovascular diseases and death, but the underlying mechanisms are insufficiently understood.

Objective. To determine how aerobic fitness and muscular strength are associated with serum metabolome measures.

Design, Setting, and Participants. This cross-sectional study included Finnish men receiving military refresher training from May 5, 2015, to November 28, 2015, representing partly overlapping groups of individuals with the lowest vs highest aerobic fitness and the lowest vs highest muscular strength. Data analyses were conducted from January 1, 2018, to May 31, 2019.

Main Outcomes and Measures. The associations of aerobic fitness (determined with maximum oxygen consumption in milliliters per minute per kilogram, measured with maximal cycle ergometer test) and muscular strength (determined with a maximal strength test for lower extremities in kilograms) with 66 metabolome measures from fasting serum samples (nuclear magnetic resonance–based metabolomics) were analyzed.

Results. Participants included 580 Finnish men (mean [SD] age, 26.1 [6.5] years). Including overlap between groups, there were 196 men in the lowest aerobic fitness group and 197 men in the highest aerobic fitness group as well as 196 men in the lowest muscular strength group and 197 men in the highest muscular strength group. Of 66 studied metabolome measures, 48 differed between high vs low aerobic fitness groups, including small very low-density lipoprotein (standardized median difference, −0.67; 95% CI, −0.83 to −0.49), large high-density lipoprotein (standardized median difference, 0.89; 95% CI, 0.69-1.15), total triglyceride levels (standardized median difference, −0.52; 95% CI, −0.65 to −0.34), isoleucine (standardized median difference, −0.37; 95% CI, −0.55 to −0.16), leucine (standardized median difference, −0.55; 95% CI, −0.72 to −0.34), phenylalanine (standardized median difference, −0.54; 95% CI, −0.71 to −0.32), glycerol (standardized median difference, −0.64; 95% CI, −0.81 to −0.48), and glycoprotein (standardized median difference, −0.78; 95% CI, −0.95 to −0.62) concentration, a high unsaturation degree of fatty acids (standardized median difference, 0.59; 95% CI, 0.42-0.81), and apolipoprotein B to apolipoprotein A1 ratio (standardized median difference, −0.88; 95% CI, −1.08 to −0.67). Adding aerobic fitness into the regression model after age, education, smoking, use of alcohol, and dietary factors accounted for more than an additional 5% of variation for 25 metabolome measures (R2 range, 5.01%-15.90% by measure). With these 2 criteria, maximal muscular strength was not associated with any metabolome measures. Aerobic fitness was associated with high large high-density lipoprotein particle concentration (R2, 14.97%; 95% CI, 10.65%-20.85%), low apolipoprotein B to apolipoprotein A1 ratio (R2, 14.49%; 95% CI, 10.58%-19.51%), and low glycoprotein concentration (R2, 15.90%; 95% CI, 11.22%-21.51%). Aerobic fitness was also associated with low very low-density lipoprotein, triglyceride, isoleucine, leucine, phenylalanine, glycerol, and glycoprotein concentrations and with a high unsaturation degree of fatty acids. Adjusting for recent physical activity influenced the results minimally. Adjusting for body fat percentage showed that some of the associations were mechanistically associated with body fat percentage.

Conclusions and Relevance. This study provides data on the association of high aerobic fitness with underlying oxidative lipid metabolism associated with a reduction in cardiometabolic risk. High maximal muscular strength is not similarly associated with these benefits.