-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
The aim was to test the hypothesis that 7 days of bed rest reduces mitochondrial number and expression and activity of oxidative proteins in human skeletal muscle but that exercise-induced intracellular signaling as well as mRNA and microRNA (miR) responses are maintained after bed rest. Twelve young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies taken before and after bed rest. In addition, muscle biopsies were obtained from six of the subjects prior to, immediately after, and 3 h after 45 min of one-legged knee extensor exercise performed before and after bed rest. Maximal oxygen uptake decreased by 4%, and exercise endurance decreased nonsignificantly, by 11%, by bed rest. Bed rest reduced skeletal muscle mitochondrial DNA/nuclear DNA content 15%, hexokinase II and sirtuin 1 protein content ∼45%, 3-hydroxyacyl-CoA dehydrogenase and citrate synthase activity ∼8%, and miR-1 and miR-133a content ∼10%. However, cytochrome c and vascular endothelial growth factor (VEGF) protein content as well as capillarization did not change significantly with bed rest. Acute exercise increased AMP-activated protein kinase phosphorylation, peroxisome proliferator activated receptor-γ coactivator-1α, and VEGF mRNA content in skeletal muscle before bed rest, but the responses were abolished after bed rest. The present findings indicate that only 7 days of physical inactivity reduces skeletal muscle metabolic capacity as well as abolishes exercise-induced adaptive gene responses, likely reflecting an interference with the ability of skeletal muscle to adapt to exercise.
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.
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