Bartlett JD, Louhelainen J, Iqbal Z, Cochran AJ, Gibala MJ, Gregson W, Close GL, Drust B, Morton JP. Reduced carbohydrate availability enhances exercise-induced p53 signaling in human skeletal muscle: implications for mitochondrial biogenesis. Am J Physiol Regul Integr Comp Physiol 304: R450 -R458, 2013. First published January 30, 2013 doi:10.1152/ajpregu.00498.2012The mechanisms that regulate the enhanced skeletal muscle oxidative capacity observed when training with reduced carbohydrate (CHO) availability are currently unknown. The aim of the present study was to test the hypothesis that reduced CHO availability enhances p53 signaling and expression of genes associated with regulation of mitochondrial biogenesis and substrate utilization in human skeletal muscle. In a repeated-measures design, muscle biopsies (vastus lateralis) were obtained from eight active males before and after performing an acute bout of high-intensity interval running with either high (HIGH) or low CHO availability (LOW). Resting muscle glycogen (HIGH, 467 Ϯ 19; LOW, 103 Ϯ 9 mmol/kg dry wt) was greater in HIGH compared with LOW (P Ͻ 0.05). Phosphorylation (P-) of ACC Ser79 (HIGH, 1.4 Ϯ 0.4; LOW, 2.9 Ϯ 0.9) and p53 Ser15 (HIGH, 0.9 Ϯ 0.4; LOW, 2.6 Ϯ 0.8) was higher in LOW immediately postexercise and 3 h postexercise, respectively (P Ͻ 0.05). Before and 3 h postexercise, mRNA content of pyruvate dehydrogenase kinase 4, mitochondrial transcription factor A, cytochrome-c oxidase IV, and PGC-1␣ were greater in LOW compared with HIGH (P Ͻ 0.05), whereas carnitine palmitoyltransferase-1 showed a trend toward significance (P ϭ 0.09). However, only PGC-1␣ expression was increased by exercise (P Ͻ 0.05), where three-fold increases occurred independently of CHO availability. We conclude that the exerciseinduced increase in p53 phosphorylation is enhanced in conditions of reduced CHO availability, which may be related to upstream signaling through AMPK. Given the emergence of p53 as a molecular regulator of mitochondrial biogenesis, such nutritional modulation of contraction-induced p53 activation has implications for both athletic and clinical populations.AMPK; PGC-1␣; glycogen; high-intensity interval running SKELETAL MUSCLE MITOCHONDRIAL biogenesis is one of the most prominent adaptations induced by endurance exercise training (20). At a molecular level, mitochondrial adaptations to exercise are thought to be due to the cumulative effects of the transient increases in the transcripts of mRNA that encode the upregulation of mitochondrial proteins (37). In considering possible contractile induced stressors for activating the acute cell signaling pathways associated with regulation of mitochondrial biogenesis, reductions in carbohydrate (CHO) availability is now emerging as one of the most potent signals (41). For example, in healthy subjects, the acute exercise-induced activation of the signaling kinases AMPK (60, 62) and p38MAPK (8, 12) are greater when preexercise glycogen availability is low. Transcription of several metabolic related genes ...
The aim of the present study was to test the hypothesis that acute high-intensity interval (HIT) running induces greater activation of signaling pathways associated with mitochondrial biogenesis compared with moderate-intensity continuous (CONT) running matched for work done. In a repeated-measures design, 10 active men performed two running protocols consisting of HIT [6 × 3-min at 90% maximal oxygen consumption (Vo(2max)) interspersed with 3-min recovery periods at 50% Vo(2max) with a 7-min warm-up and cool-down period at 70% Vo(2max)] or CONT (50-min continuous running at 70% Vo(2max)). Both protocols were matched, therefore, for average intensity, duration, and distance run. Muscle biopsies (vastus lateralis) were obtained preexercise, postexercise, and 3 h postexercise. Muscle glycogen decreased (P < 0.05) similarly in HIT and CONT (116 ± 11 vs. 111 ± 17 mmol/kg dry wt, respectively). Phosphorylation (P-) of p38MAPK(Thr180/Tyr182) (1.9 ± 0.1- vs. 1.5 ± 0.2-fold) and AMPK(Thr172) (1.5 ± 0.3- vs. 1.5 ± 0.1-fold) increased immediately postexercise (P < 0.05) in HIT and CONT, respectively, and returned to basal levels at 3 h postexercise. P-p53(Ser15) (HIT, 2.7 ± 0.8-fold; CONT, 2.1 ± 0.8-fold), PGC-1α mRNA (HIT, 4.2 ± 1.7-fold; CONT, 4.5 ± 0.9-fold) and HSP72 mRNA (HIT, 4.4 ± 2-fold; CONT, 3.5 ± 1-fold) all increased 3 h postexercise (P < 0.05) although neither parameter increased (P > 0.05) immediately postexercise. There was no difference between trials for any of the above signaling or gene expression responses (P > 0.05). We provide novel data by demonstrating that acute HIT and CONT running (when matched for average intensity, duration, and work done) induces similar activation of molecular signaling pathways associated with regulation of mitochondrial biogenesis. Furthermore, this is the first report of contraction-induced p53 phosphorylation in human skeletal muscle, thus highlighting an additional pathway by which exercise may initiate mitochondrial biogenesis.
The aim of the present study was to test the hypothesis that consuming protein does not attenuate AMPK signalling when exercise is commenced in a glycogen-depleted state. After performing a glycogen-depleting protocol the evening before, the subsequent morning ten active men performed 45 min steady-state cycling at 50 % of peak power output (PPO) followed by an exercise capacity test (1-min intervals at 80 % PPO interspersed with 1-min periods at 40 % PPO). In a repeated measures design, subjects consumed 20 g of a casein hydrolysate solution (PRO) 45 min before exercise, 10 g during and a further 20 g immediately post-exercise, or an equivalent volume of a non-calorie taste matched placebo (PLA). Resting (PRO = 134 ± 29; PLA = 136 ± 28 mmol kg(-1)) and post-exercise muscle glycogen (PRO = 43 ± 16; PLA = 47 ± 18 mmol kg(-1)) was not different (P > 0.05) between trials nor was exercise capacity (PRO = 26 ± 9; PLA = 25 ± 10 min, P > 0.05). Phosphorylation of AMPK(Thr172) increased threefold immediately post-exercise (P < 0.05) and PGC1-mRNA increased sixfold at 3 h post-exercise (P < 0.05), though there were no differences between conditions (P > 0.05). In contrast, there was a trend (P = 0.08) for a divergent response in eEF2(Thr56) phosphorylation such that 1.5 fold increases post- and 3 h post-exercise in PLA were blunted with PRO, thus indicative of greater eEF2 activation. We conclude that athletes who deliberately incorporate training phases with reduced muscle glycogen into their training programmes may consume protein before, during and after exercise without negating signalling through the AMPK cascade.
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