Key pointsr Heavy-intensity exercise causes a progressive increase in energy demand that contributes to exercise limitation.r This inefficiency arises within the locomotor muscles and is thought to be due to an increase in the ATP cost of power production; however, the responsible mechanism is unresolved.r We measured whole-body O 2 uptake and skeletal muscle ATP turnover by combined pulmonary gas exchange and magnetic resonance spectroscopy during moderate and heavy exercise in humans.r Muscle ATP synthesis rate increased throughout constant-power heavy exercise, but this increase was unrelated to the progression of whole-body inefficiency.r Our data indicate that the increased ATP requirement is not the sole cause of inefficiency during heavy exercise, and other mechanisms, such as increased O 2 cost of ATP resynthesis, may contribute.Abstract During constant-power high-intensity exercise, the expected increase in oxygen uptake (V O 2 ) is supplemented by aV O 2 slow component (V O 2 sc ), reflecting reduced work efficiency, predominantly within the locomotor muscles. The intracellular source of inefficiency is postulated to be an increase in the ATP cost of power production (an increase in P/W). To test this hypothesis, we measured intramuscular ATP turnover with 31 P magnetic resonance spectroscopy (MRS) and whole-bodyV O 2 during moderate (MOD) and heavy (HVY) bilateral knee-extension exercise in healthy participants (n = 14). Unlocalized 31 P spectra were collected from the quadriceps throughout using a dual-tuned ( 1 H and 31 P) surface coil with a simple pulse-and-acquire sequence. Total ATP turnover rate (ATP tot ) was estimated at exercise cessation from direct measurements of the dynamics of phosphocreatine (PCr) and proton handling. Between 3 and 8 min during MOD, there was no discernableV O 2 sc (mean ± SD, 0.06 ± 0.12 l min −1 ) or change in [PCr] (30 ± 8 vs. 32 ± 7 mM) or ATP tot (24 ± 14 vs. 17 ± 14 mM min −1 ; each P = n.s.). During HVY, theV O 2 sc was 0.37 ± 0.16 l min −1 (22 ± 8%), [PCr] decreased (19 ± 7 vs. 18 ± 7 mM, or 12 ± 15%; P < 0.05) and ATP tot increased (38 ± 16 vs. 44 ± 14 mM min −1 , or 26 ± 30%; P < 0.05) between 3 and 8 min. However, the increase in ATP tot ( ATP tot ) was not correlated with theV O 2 sc during HVY (r 2 = 0.06; P = n.s.

Non-technical summary The mechanisms determining exercise intolerance are poorly understood. A reduction in work efficiency in the form of an additional energy cost and oxygen requirement occurs during high-intensity exercise and contributes to exercise limitation. Muscle fatigue and subsequent recruitment of poorly efficient muscle fibres has been proposed to mediate this decline. These data demonstrate in humans, that muscle fatigue, generated in the initial minutes of exercise, is correlated with the increasing energy demands of high-intensity exercise. Surprisingly, however, while muscle fatigue reached a plateau, oxygen uptake continued to increase throughout 8 min of exercise. This suggests that additional recruitment of inefficient muscle fibres may not be the sole mechanism contributing to the decline in work efficiency during high-intensity exercise.Abstract During constant work rate (CWR) exercise above the lactate threshold (LT), the exponential kinetics of oxygen uptake (V O 2 ) are supplemented by aV O 2 slow component (V O 2 sc ) which reduces work efficiency. This has been hypothesised to result from 'fatigue and recruitment' , where muscle fatigue during supra-LT exercise elicits recruitment of additional, but poorly efficient, fibres to maintain power production. To test this hypothesis we characterised changes in the power-velocity relationship during sub-and supra-LT cycle ergometry in concert withV O 2 kinetics. Eight healthy participants completed a randomized series of 18 experiments consisting of: (1) a CWR phase of 3 or 8 min followed immediately by; (2) a 5 s maximal isokinetic effort to characterize peak power at 60, 90 and 120 rpm. CWR bouts were: 20 W (Con); 80% LT (Mod); 20% (H); 60% (VH); where is the difference between the work rate at LT andV O 2 max . TheV O 2 sc was 238 ± 128 and 686 ± 194 ml min −1 during H and VH, with no discernibleV O 2 sc during Mod. Peak power in Con was 1025 ± 400, 1219 ± 167 and 1298 ± 233 W, at 60, 90 and 120 rpm, respectively, and was not different after Mod (P > 0.05). Velocity-specific peak power was significantly reduced (P < 0.05) by 3 min of H (−103 ± 46 W) and VH (−216 ± 60 W), with no further change by 8 min. TheV O 2 sc was correlated with the reduction in peak power (R 2 = 0.49; P < 0.05). These results suggest that muscle fatigue is requisite for theV O 2 sc . However, the maintenance of velocity-specific peak power between 3 and 8 min suggests that progressive muscle recruitment is not obligatory. Rather, a reduction in mechanical efficiency in fatigued fibres is implicated.