Purinergic P2X7 Receptor Antagonism Impairs Aerobic Capacity without Detectable Effect on Cardiac Adaptation to Exercise in Mice.

Adenosine triphosphate (ATP) signaling through the P2X7 receptor is an emerging determinant of mitochondrial energy metabolism and physical fitness, and the receptor is increasingly targeted pharmacologically for its role in inflammation. Whether systemic P2X7 antagonism affects aerobic capacity and the structural adaptation of the heart to exercise is unknown. Adult male Swiss mice were studied in a 2 × 2 factorial design crossing physical conditioning (sedentary or exercised) with treatment (saline or the P2X7 antagonist Brilliant Blue G, BBG; 50 mg/kg). Exercised animals trained on a treadmill on alternate days over approximately 4 weeks; maximal oxygen uptake (V̇O2max) and power were measured by incremental treadmill ergospirometry, and myocardial cardiomyocyte volume density (Vv) was quantified by design-based stereology. Aerobic training increased V̇O2max and cardiomyocyte Vv. BBG reduced V̇O2max and peak power independently of training and produced a deficit that widened progressively with workload across the incremental test, indicating a demand-dependent limitation of oxidative performance. Critically, BBG did not detectably alter the exercise-induced increase in cardiomyocyte Vv and showed no interaction with training; motor coordination, locomotor and exploratory behavior, blood lactate, and body mass were also unaffected. P2X7 antagonism thus impairs aerobic capacity without detectable blunting of the structural response of the heart to exercise. This functional-structural dissociation points to a metabolic process, plausibly mitochondrial, rather than to cardiac remodeling, although the present sample size bounds rather than excludes an effect on cardiac adaptation, and indicates that P2X7-directed therapies may reduce exercise capacity without producing overt cardiac structural change.