Key pointsr At the end of an incremental exercise to exhaustion a large functional reserve remains in the muscles to generate power, even at levels far above the power output at which task failure occurs, regardless of the inspiratory O 2 pressure during the incremental exercise.r Exhaustion (task failure) is not due to lactate accumulation and the associated muscle acidification; neither the aerobic energy pathways nor the glycolysis are blocked at exhaustion.r Muscle lactate accumulation may actually facilitate early recovery after exhaustive exercise even under ischaemic conditions. r Although the maximal rate of ATP provision is markedly reduced at task failure, the resynthesis capacity remaining exceeds the rate of ATP consumption, indicating that task failure during an incremental exercise to exhaustion depends more on central than peripheral mechanisms.Abstract To determine the mechanisms causing task failure during incremental exercise to exhaustion (IE), sprint performance (10 s all-out isokinetic) and muscle metabolites were measured before (control) and immediately after IE in normoxia (P IO 2 : 143 mmHg) and hypoxia (P IO 2 : 73 mmHg) in 22 men (22 ± 3 years). After IE, subjects recovered for either 10 or 60 s, with open circulation or bilateral leg occlusion (300 mmHg) in random order. This was followed by a 10 s sprint with open circulation. Post-IE peak power output (W peak ) was higher than the power output reached at exhaustion during IE (P < 0.05). After 10 and 60 s recovery in normoxia, W peak was reduced by 38 ± 9 and 22 ± 10% without occlusion, and 61 ± 8 and 47 ± 10% with occlusion (P < 0.05). Following 10 s occlusion, W peak was 20% higher in hypoxia than normoxia (P < 0.05), despite similar muscle lactate accumulation ([La]) and phosphocreatine and ATP reduction. Sprint performance and anaerobic ATP resynthesis were greater after 60 s compared with 10 s occlusions, despite the higher [La] and [H + ] after 60 s compared with 10 s occlusion recovery (P < 0.05). The mean rate of ATP turnover during the 60 s occlusion was 0.180 ± 0.133 mmol (kg wet wt) −1 s −1 , i.e. equivalent to 32% of leg peak O 2 uptake (the energy expended by the ion pumps). A greater degree of recovery is achieved, however, without occlusion. In conclusion, during incremental exercise task failure is not due to metabolite accumulation or lack of energy resources. Anaerobic metabolism, despite the accumulation of lactate and H + , facilitates early Abbreviations Cr, creatine; d.w., dry weight; F IO2 , inspired oxygen fraction; HR, heart rate; HR peak , peak heart rate; Hyp, hypoxia; IE, incremental exercise to exhaustion; La, lactate; Mb, myoglobin; Nx, normoxia; PCr, phosphocreatine; P ETCO2 , end-tidal CO 2 pressure; P ETO2 , end-tidal O 2 pressure; P IO2 , partial pressure of inspired O 2 ; RER, respiratory exchange ratio; S pO2 , haemoglobin oxygen saturation measured by pulse-oximetry; TOI, tissue oxygenation index;V CO2 , CO 2 production;V CO2peak , peak CO 2 production;V E , minute ventilation;V O2 , O 2 consumpt...

IntroductionRegular physical activity (PA) can reduce the risk of developing type 2 diabetes, but adherence to time-orientated (150 min week−1 or more) PA guidelines is very poor. A practical and time-efficient PA regime that was equally efficacious at controlling risk factors for cardio-metabolic disease is one solution to this problem. Herein, we evaluate a new time-efficient and genuinely practical high-intensity interval training (HIT) protocol in men and women with pre-existing risk factors for type 2 diabetes.Materials and methodsOne hundred eighty-nine sedentary women (n = 101) and men (n = 88) with impaired glucose tolerance and/or a body mass index >27 kg m−2 [mean (range) age: 36 (18–53) years] participated in this multi-center study. Each completed a fully supervised 6-week HIT protocol at work-loads equivalent to ~100 or ~125% V˙O2 max. Change in V˙O2 max was used to monitor protocol efficacy, while Actiheart™ monitors were used to determine PA during four, weeklong, periods. Mean arterial (blood) pressure (MAP) and fasting insulin resistance [homeostatic model assessment (HOMA)-IR] represent key health biomarker outcomes.ResultsThe higher intensity bouts (~125% V˙O2 max) used during a 5-by-1 min HIT protocol resulted in a robust increase in V˙O2 max (136 participants, +10.0%, p < 0.001; large size effect). 5-by-1 HIT reduced MAP (~3%; p < 0.001) and HOMA-IR (~16%; p < 0.01). Physiological responses were similar in men and women while a sizeable proportion of the training-induced changes in V˙O2 max, MAP, and HOMA-IR was retained 3 weeks after cessation of training. The supervised HIT sessions accounted for the entire quantifiable increase in PA, and this equated to 400 metabolic equivalent (MET) min week−1. Meta-analysis indicated that 5-by-1 HIT matched the efficacy and variability of a time-consuming 30-week PA program on V˙O2 max, MAP, and HOMA-IR.ConclusionWith a total time-commitment of <15 min per session and reliance on a practical ergometer protocol, 5-by-1 HIT offers a new solution to modulate cardio-metabolic risk factors in adults with pre-existing risk factors for type 2 diabetes while approximately meeting the MET min week−1 PA guidelines. Long-term randomized controlled studies will be required to quantify the ability for 5-by-1 HIT to reduce the incidence of type 2 diabetes, while strategies are required to harmonize the adaptations to exercise across individuals.

-AMPactivated protein kinase (AMPK) is a major mediator of the exercise response and a molecular target to improve insulin sensitivity. To determine if the anaerobic component of the exercise response, which is exaggerated when sprint is performed in severe acute hypoxia, influences sprint exercise-elicited Thr 172 -AMPK␣ phosphorylation, 10 volunteers performed a single 30-s sprint (Wingate test) in normoxia and in severe acute hypoxia (inspired PO2: 75 mmHg). Vastus lateralis muscle biopsies were obtained before and immediately after 30 and 120 min postsprint. Mean power output and O2 consumption were 6% and 37%, respectively, lower in hypoxia than in normoxia. O2 deficit and muscle lactate accumulation were greater in hypoxia than in normoxia. Carbonylated skeletal muscle and plasma proteins were increased after the sprint in hypoxia. Thr 172 -AMPK␣ phosphorylation was increased by 3.1-fold 30 min after the sprint in normoxia. This effect was prevented by hypoxia. The NAD ϩ -to-NADH.H ϩ ratio was reduced (by 24-fold) after the sprints, with a greater reduction in hypoxia than in normoxia (P Ͻ 0.05), concomitant with 53% lower sirtuin 1 (SIRT1) protein levels after the sprint in hypoxia (P Ͻ 0.05). This could have led to lower liver kinase B1 (LKB1) activation by SIRT1 and, hence, blunted Thr 172 -AMPK␣ phosphorylation. Ser 485 -AMPK␣1/Ser 491 -AMPK␣2 phosphorylation, a known negative regulating mechanism of Thr 172 -AMPK␣ phosphorylation, was increased by 60% immediately after the sprint in hypoxia, coincident with increased Thr 308 -Akt phosphorylation. Collectively, our results indicate that the signaling response to sprint exercise in human skeletal muscle is altered in severe acute hypoxia, which abrogated Thr 172 -AMPK␣ phosphorylation, likely due to lower LKB1 activation by SIRT1.sprint; AMP-activated protein kinase; signaling; muscle; metabolism AMP-ACTIVATED PROTEIN KINASE (AMPK) is a metabolic energy sensor activated by Thr 172 phosphorylation of the ␣-subunit, mainly in response to an increase of the AMP-to-ATP ratio (25). AMPK is involved in the regulation of feeding and body weight (42), lipid metabolism (26), glucose homeostasis (62), and mitochondrial biogenesis (69) and is a key player in the adaptation to exercise training (48). AMPK␣ phosphorylation of Thr 172 increases markedly in response to sprint exercise (22), most likely due to the elevation of the AMP-to-ATP ratio (11). Whether free radicals may also play a role in contractionmediated Thr 172 -AMPK␣ phosphorylation in skeletal muscle remains controversial (41,52). In cell cultures, hypoxia and anoxia increase Thr 172 -AMPK␣ phosphorylation more through the release of free radicals than through an increase in the AMP-to-ATP ratio (15). In contrast, chronic hypoxia (5 and 12 days of exposure to 5,500 m above sea level) did not increase skeletal muscle Thr 172 -AMPK␣ phosphorylation in rats (10). The influence of the inspired O 2 fraction (FI O 2 ) on exerciseinduced Thr 172 -AMPK␣ phosphorylation has been scarcely studied in humans (63)....

Key pointsr Severe acute hypoxia reduces sprint performance. r MuscleV O 2 during sprint exercise in normoxia is not limited by O 2 delivery, O 2 offloading from haemoglobin or structure-dependent diffusion constraints in the skeletal muscle of young healthy men.r A large functional reserve in muscle O 2 diffusing capacity exists and remains available at exhaustion during exercise in normoxia; this functional reserve is recruited during exercise in hypoxia.r During whole-body incremental exercise to exhaustion in severe hypoxia, legV O 2 is primarily dependent on convective O 2 delivery and less limited by diffusion constraints than previously thought.r The kinetics of O 2 offloading from haemoglobin does not limitV O 2 peak in hypoxia. r Our results indicate that the limitation toV O 2 during short sprints resides in mechanisms regulating mitochondrial respiration.Abstract To determine the contribution of convective and diffusive limitations toV O 2 peak during exercise in humans, oxygen transport and haemodynamics were measured in 11 men (22 ± 2 years) during incremental (IE) and 30 s all-out cycling sprints (Wingate test, WgT), in normoxia (Nx, P IO 2 : 143 mmHg) and hypoxia (Hyp, P IO 2 : 73 mmHg). Carboxyhaemoglobin (COHb) was increased to 6-7% before both WgTs to left-shift the oxyhaemoglobin dissociation curve. Leġ V O 2 was measured by the Fick method and leg blood flow (BF) with thermodilution, and muscle O 2 diffusing capacity (D MO 2 ) was calculated. In the WgT mean power output, leg BF, leg O 2 delivery and legV O 2 were 7, 5, 28 and 23% lower in Hyp than Nx (P < 0.05); however, peak WgT D MO 2 was higher in Hyp (51.5 ± 9.7) than Nx (20.5 ± 3.0 ml min −1 mmHg −1 , P < 0.05). Despite a similar P aO 2 (33.3 ± 2.4 and 34.1 ± 3.3 mmHg), mean capillary P O 2 (16.7 ± 1.2 and 17.1 ± 1.6 mmHg), and peak perfusion during IE and WgT in Hyp, D MO 2 and legV O 2 were 12 and 14% higher, respectively, during WgT than IE in Hyp (both P < 0.05). D MO 2 was insensitive to COHb (COHb: 0.7 vs. 7%, in IE Hyp and WgT Hyp). At exhaustion, the Y equilibration index was well above 1.0 in both conditions, reflecting greater convective than diffusive limitation to the O 2 transfer in both Nx and Hyp. In conclusion, muscleV O 2 during sprint exercise is not limited by O 2 delivery, O 2 offloading from haemoglobin or structure-dependent diffusion constraints in

Aim/hypothesis: The aim of this study was to investigate mitochondrial function, fibre-type distribution and substrate oxidation during exercise in arm and leg muscles in male postobese (PO), obese (O) and age-and body mass index (BMI)-matched control (C) subjects. The hypothesis of the study was that fat oxidation during exercise might be differentially preserved in leg and arm muscles after weight loss. Methods: Indirect calorimetry was used to calculate fat and carbohydrate oxidation during both progressive arm-cranking and leg-cycling exercises. Muscle biopsy samples were obtained from musculus deltoideus (m. deltoideus) and m. vastus lateralis muscles. Fibre-type composition, enzyme activity and O 2 flux capacity of saponin-permeabilized muscle fibres were measured, the latter by high-resolution respirometry. Results: During the graded exercise tests, peak fat oxidation during leg cycling and the relative workload at which it occurred (FatMax) were higher in PO and O than in C. During arm cranking, peak fat oxidation was higher in O than in C, and FatMax was higher in O than in PO and C. Similar fibre-type composition was found between groups. Plasma adiponectin was higher in PO than in C and O, and plasma leptin was higher in O than in PO and C. Conclusions: In O subjects, maximal fat oxidation during exercise and the eliciting relative exercise intensity are increased. This is associated with higher intramuscular triglyceride levels and higher resting non esterified fatty acid (NEFA) concentrations, but not with differences in fibre-type composition, mitochondrial function or muscle enzyme levels compared with Cs. In PO subjects, the changes in fat oxidation are preserved during leg, but not during arm, exercise.