Endurance training lowers heart rate and blood pressure responses to exercise, but the mechanisms and consequences remain unclear. To determine the role of skeletal muscle for the cardioventilatory response to exercise, 8 healthy young men were studied before and after 5 weeks of 1-legged knee-extensor training and 2 weeks of deconditioning of the other leg (leg cast). Hemodynamics and muscle interstitial nucleotides were determined during exercise with the (1) deconditioned leg, (2) trained leg, and (3) trained leg with atrial pacing to the heart rate obtained with the deconditioned leg. Heart rate was ≈ 15 bpm lower during exercise with the trained leg (P<0.05), but stroke volume was higher (P<0.05) and cardiac output was similar. Arterial and central venous pressures, rate-pressure product, and ventilation were lower during exercise with the trained leg (P<0.05), whereas pulmonary capillary wedge pressure was similar. When heart rate was controlled by atrial pacing, stroke volume decreased (P<0.05), but cardiac output, peripheral blood flow, arterial pressures, and pulmonary capillary wedge pressure remained unchanged. Circulating [norepinephrine], [lactate] and [K(+)] were lower and interstitial [ATP] and pH were higher in the trained leg (P<0.05). The lower cardioventilatory response to exercise with the trained leg is partly coupled to a reduced signaling from skeletal muscle likely mediated by K(+), lactate, or pH, whereas the lower cardiac afterload increases stroke volume. These results demonstrate that skeletal muscle training reduces the cardioventilatory response to exercise without compromising O2 delivery, and it can therefore be used to reduce the load on the heart during physical activity.