A newly identified lipidated amino acid, NPG, may help explain how aerobic exercise improves cardiorespiratory fitness and long-term health. This study, published in Circulation, investigated molecular signatures of fitness using large human cohorts and mechanistic validation.

The analysis examined 654 adults in the HERITAGE Family Study, all of whom completed 20 weeks of supervised endurance training and underwent cardiopulmonary exercise testing. Untargeted liquid chromatography–mass spectrometry plasma profiling identified an unknown peak later confirmed as NPG, which showed the strongest positive association with VO₂max (β = 1.29, q = 5.3 × 10⁻⁶).

This relationship replicated in 408 participants from the Framingham Heart Study (β = 1.2, P = 3.8 × 10⁻⁵). NPG levels also increased after training (log fold change = 0.22, q = 5.3 × 10⁻¹²). Higher NPG concentrations were inversely associated with all-cause mortality in the Jackson Heart Study and the Multi-Ethnic Study of Atherosclerosis (hazard ratios 0.91 and 0.65, P = 0.029 and 0.028, respectively).

To explore potential mechanisms, investigators conducted experimental studies in C2C12 myotubes, where NPG increased the mitochondrial-to-nuclear DNA ratio by 15% and 20% at 6.5 nM and 26 nM (P = 0.04 and 0.02). NPG also improved mitochondrial bioenergetics, increasing the phosphate-to-oxygen ratio across ADP concentrations (ANOVA P = 0.0027).

These findings identify NPG as a previously unrecognized molecule that rises with exercise, correlates with aerobic fitness, and associates with lower mortality, suggesting a potential role as an exercise-responsive molecular transducer.