Phenyllactic Acid is Physiologically Released from Skeletal Muscle and Contributes to the Beneficial Effects of Physical Exercise in Humans

Aims/hypothesisWhile physical activity is clearly beneficial in combating type 2 diabetes, the underlying molecular mechanisms are incompletely understood. Moreover, there is a considerable degree of variability in the individual response to exercise-based lifestyle interventions that remains to be explained. We aimed to identify novel exercise-induced metabolites that could mediate the improvement in glycemic control and reduction of obesity and contribute to individual differences in the response to exercise interventions. MethodsWe studied acute exercise- and training-induced changes in plasma metabolites in sedentary subjects with overweight (8 male, 14 female) participating in an eight-week supervised training program flanked by two acute endurance exercise sessions. Plasma metabolites were quantified using LC- and CE-MS. In a separate study (n=9 lean males), we assessed metabolite fluxes over the leg using arterial and venous catheters. Functional analyses were performed in primary blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) or the saturated fatty acid palmitate. ResultsThe amino acid breakdown products 3-phenyllactic acid (PLA), 4-hydroxyphenyllactic acid and indolelactic acid were increased after both acute exercise and training. All three aromatic lactic acids, which so far mainly received attention as bacterial metabolites, exhibited an efflux from the leg. PLA showed the largest increase after both acute exercise and training, of 57% and 20% respectively. The magnitude of the acute exercise-induced increase in PLA correlated with a decrease in subcutaneous adipose tissue volume and an improvement in insulin sensitivity over the course of the intervention. Furthermore, both isomers, D- and L-PLA, counteracted inflammatory cytokine production in PBMCs. Conclusions/interpretationOur findings indicate that PLA is physiologically released from skeletal muscle and can contribute to the anti-inflammatory effects of exercise as well as to individual difference in the response to lifestyle interventions in humans. PLA and potentially, aromatic lactic acids in general may be particularly relevant metabolic regulators because they can be produced both endogenously and by the microbiome. Trial registrationClinicalTrials.gov NCT03151590