-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 extremely high energy demand elicited by sprint exercise is satisfied by an increase in O2 consumption combined with a high glycolytic rate, leading to a marked lactate accumulation, increased AMP-to-ATP ratio, and reduced NAD(+)/NADH.H(+) and muscle pH, which are accompanied by marked Thr(172) AMP-activated protein kinase (AMPK)-α phosphorylation during the recovery period by a mechanism not fully understood. To determine the role played by reactive nitrogen and oxygen species (RNOS) on Thr(172)-AMPKα phosphorylation in response to cycling sprint exercise, nine voluntary participants performed a single 30-s sprint (Wingate test) on two occasions: one 2 h after the ingestion of placebo and another after the intake of antioxidants (α-lipoic acid, vitamin C, and vitamin E) in a double-blind design. Vastus lateralis muscle biopsies were obtained before, immediately postsprint, and 30 and 120 min postsprint. Performance and muscle metabolism were similar during both sprints. The NAD(+)-to-NADH.H(+) ratio was similarly reduced (84%) and the AMP-to-ATP ratio was similarly increased (×21-fold) immediately after the sprints. Thr(286) Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and Thr(172)-AMPKα phosphorylations were increased after the control sprint (with placebo) but not when the sprints were preceded by the ingestion of antioxidants. Ser(485)-AMPKα1/Ser(491)-AMPKα2 phosphorylation, a known inhibitory mechanism of Thr(172)-AMPKα phosphorylation, was increased only with antioxidant ingestion. In conclusion, RNOS play a crucial role in AMPK-mediated signaling after sprint exercise in human skeletal muscle. Antioxidant ingestion 2 h before sprint exercise abrogates the Thr(172)-AMPKα phosphorylation response observed after the ingestion of placebo by reducing CaMKII and increasing Ser(485)-AMPKα1/Ser(491)-AMPKα2 phosphorylation. Sprint performance, muscle metabolism, and AMP-to-ATP and NAD(+)-to-NADH.H(+) ratios are not affected by the acute ingestion of antioxidants.
To determine if there is a sex dimorphism in the skeletal muscle signaling response to sprint exercise, 17 men and ten women performed a 30-s Wingate test. Muscle biopsies were taken before, immediately after the exercise and at 30 and 120 min during the recovery period. Thr(172)-AMPKα, Ser(221)-ACCβ, Thy(705)-STAT3, Thr(202)/Thy(204)-ERK1/2 and Thr(180)/Thy(182)-p38MAPK phosphorylation responses to sprint exercise were not statistically different between men and women. AMPKα phosphorylation was enhanced fourfold 30 min after the sprint exercise in males and females (P < 0.01). ACCβ phosphorylation was enhanced by about threefold just after the sprint test exercise and 30 min into the recovery period in males and females (P < 0.01). STAT3 phosphorylation was increased 2 h after the Wingate test compared to the value observed right after the end of the exercise (P < 0.05), and 30 min after the Wingate test there was a 2.5-fold increase in ERK1/2 phosphorylation, compared to both the pre-exercise and to the value observed right after the Wingate test (both, P < 0.05). In conclusion, the skeletal muscle signaling response to a single bout of sprint exercise mediated by AMPK, ACC, STAT3, ERK and p38MAPK is not statistically different between men and women. Marked increases in AMPKα, ACCβ, STAT3 and ERK phosphorylation were observed after a single 30-s all-out sprint (Wingate test) in the vastus lateralis.
Androgen receptor (AR) CAG n (polyglutamine) and GGN n (polyglycine) repeat polymorphisms determine part of the androgenic effect and may influence adiposity. The association of fat mass, and its regional distribution, with the AR CAG n and GGN n polymorphisms was studied in 319 and 78 physically active nonsmoker men and women (mean 6 SD: 28.3 6 7.6 and 24.8 6 6.2 years old, respectively). The length of CAG and GGN repeats was determined by polymerase chain reaction and fragment analysis, and confirmed by DNA sequencing of selected samples. Men were grouped as CAG short (CAG S ) if harboring repeat lengths #21, the rest as CAG long (CAG L ). The corresponding cutoff CAG number for women was 22. GGN was considered short (GGN S ) if GGN #23, the rest as GGN long (GGN L ). No association between AR polymorphisms and adiposity or the hormonal variables was observed in men. Neither was there a difference in the studied variables between men harboring CAG L + GGN L , CAG S + GGN S , CAG S + GGN L , and CAG L + GGN S combinations. However, in women, GGN n was linearly related to the percentage of body fat (r 5 0.30, P , .05), the percentage of fat in the trunk (r 5 0.28, P , .05), serum leptin concentration (r 5 0.40, P , .05), and serum osteocalcin concentration (r 5 0.32, P , .05). In men, free testosterone was inversely associated with adiposity and serum leptin concentration, and positively with osteocalcin, even after accounting for differences in CAG n , GGN n , or both. In summary, this study shows that the AR repeat polymorphism has little influence on absolute and relative fat mass or its regional distribution in physically active men. In young women, GGN length is positively associated with adiposity, leptin, and osteocalcin.
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