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This study aimed to investigate the modulation of circulating exosome-like extracellular vesicles (ELVs) after 6 wk of sprint interval training (SIT) at sea level and at 2000, 3000, and 4000 m.Thirty trained endurance male athletes (18-35 yr) participated in a 6-wk SIT program (30-s all-out sprint, 4-min 30-s recovery; 4-9 repetitions, 2 sessions per week) at sea level ( n = 8), 2000 m (fraction of inspired oxygen (F io2 ) 0.167, n = 8), 3000 m (F io2 0.145, n = 7), or 4000 m (F io2 0.13, n = 7). Venous blood samples were taken before and after the training period. Plasma ELVs were isolated by size exclusion chromatography, counted by nanoparticle tracking analysis, and characterized according to international standards. Candidate ELV microRNAs (miRNAs) were quantified by real-time polymerase chain reaction.When the three hypoxic groups were analyzed separately, only very minor differences could be detected in the levels of circulating particles, ELV markers, or miRNA. However, the levels of circulating particles increased (+262%) after training when the three hypoxic groups were pooled, and tended to increase at sea level (+65%), with no difference between these two groups. A trend to an increase was observed for the two ELV markers, TSG101 (+65%) and HSP60 (+441%), at sea level, but not in hypoxia. Training also seemed to decrease the abundance of miR-23a-3p and to increase the abundance of miR-21-5p in hypoxia but not at sea level.A 6-wk SIT program tended to increase the basal levels of circulating ELVs when performed at sea level but not in hypoxia. In contrast, ELV miRNA cargo seemed to be modulated in hypoxic conditions only. Further research should explore the potential differences in the origin of ELVs between normoxic and local and systemic hypoxic conditions.

PURPOSE: Toll-like receptors 2 and 4 (TLR2, TLR4) are found in the membrane of skeletal muscle cells. A variety of molecular components can activate TLR2 and TLR4, among others, long-chain fatty acids. The subsequent downstream signaling triggers the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways. Therefore, the purpose of this study was to test whether an elevation of extracellular nonesterified fatty acids (NEFA) observed during endurance exercise may activate the MAPK and NF-κB pathways via TLR2 and TLR4. METHODS: tlr2 and tlr4 mice and wild-type C57BL/6J animals (WT) were submitted to a standardized endurance exercise. RESULTS: Immediately after exercise, the phosphorylation state of p38 MAPK, c-Jun NH2-terminal kinase (JNK), and c-Jun was increased in the tibialis anterior (TA) and soleus (SOL) muscles of WT (P < 0.05). The phosphorylation state of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and IκB kinase α/β and the DNA-binding of NF-κB remained unchanged. The activation of p38 MAPK, JNK, and c-Jun was completely blunted in TA of tlr2 and tlr4 mice, whereas in SOL, it represented only 25% of the increase observed in WT mice. The causal relationship between NEFA concentration and MAPK activation was evaluated by injecting mice with heparin. A similar increase in plasma NEFA was observed after heparin injection than after endurance exercise. JNK and p38 MAPK were activated under heparin in TA and SOL of WT (P < 0.05) but not in muscles of tlr2 and tlr4 mice. CONCLUSIONS: The present study supports the idea that during endurance exercise, TLR2 and TLR4 mediate a signal linking the elevated plasma NEFA concentration to the activation of p38 MAPK and JNK. ispartof: Medicine and Science in Sports and Exercise vol:44 issue:8 pages:1463-1472 ispartof: location:United States status: published

In this study, we compared the effect of sprint interval training (SIT) in normoxia versus hypoxia on muscle glycolytic and oxidative capacity, monocarboxylate transporter content, and endurance exercise performance.Healthy male volunteers (18-30 yr) performed 6 wk of SIT on a cycling ergometer (30-s sprints vs 4.5-min rest intervals; 3 d · wk(-1)) in either normobaric hypoxia (HYP, FiO2 = 14.4%, n = 10) or normoxia (NOR, FiO2 = 20.9%, n = 9). The control group did not train (CON, n = 10). Training load was increased from four sprints per session in week 1 to nine sprints in week 6. Before and after SIT, subjects performed a maximal incremental exercise test plus a 10-min simulated time trial on a cycle ergometer in both normoxia (MAX nor and TT nor) and hypoxia (MAX hyp and TT hyp). A needle biopsy was taken from musculus vastus lateralis at rest 5-6 d after the last exercise session.SIT increased muscle phosphofructokinase activity more in HYP (+59%, P0.05) than that in NOR (+17%), whereas citrate synthase activity was similar between groups. Compared with the pretest, power outputs corresponding to 4 mmol blood lactate in HYP during MAX nor (+7%) and MAX hyp (+9%) were slightly increased (P0.05), whereas values were constant in NOR. V·O 2max in MAX nor and TT performance in TT nor and TT hyp were increased by ≈ 6%-8% (P0.05) in either group. The training elevated monocarboxylate transporter 1 protein content by ≈ 70% (P0.05). In CON, all measurements were constant throughout the study.SIT in hypoxia up-regulated muscle phosphofructokinase activity and the anaerobic threshold more than SIT in normoxia but did not enhance endurance exercise performance.

This study investigated whether a 200-km run modulates signaling pathways implicated in cellular stress in skeletal muscle, with special attention paid to the endoplasmic reticulum (ER) stress and to the activation of the ubiquitin-proteasome pathway.Eight men ran 200 km (28 h 03 min ± 2 h 01 min). Two muscle biopsies were obtained from the vastus lateralis muscle 2 wk before and 3 h after the race. Mitogen-activated protein kinase, ubiquitin-proteasome pathway, ER stress, inflammation, and oxidative stress markers were assayed by Western blot analysis or by quantitative real-time polymerase chain reaction. Chymotrypsin-like activity of the proteasome was measured by a fluorimetric assay.Phosphorylation states of extracellular signal-related kinase 1/2 (+401% ± 173.8%, P = 0.027) and c-Jun N-terminal (+149% ± 61.9%, P = 0.023) increased after the race, whereas p38 phosphorylation remained unchanged. Increases in BiP (+235% ± 94.7%, P = 0.021) and in the messenger RNA level of total (+138% ± 31.2%, P = 0.002) and spliced X-box binding protein 1 (+241% ± 53.3%, P = 0.001) indicated the presence of ER stress. Transcripts of inflammatory markers interleukin-6 (+403% ± 96.1%, P = 0.002) and tumor necrosis factor-α (+233% ± 58.4%, P = 0.003) as well as oxidative stress markers metallothionein 1F (+519% ± 258.3%, P = 0.042), metallothionein 1H (+666% ± 157.5%, P = 0.002), and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) (+162% ± 60.5%, P = 0.016) were increased. The messenger RNA level of the ubiquitin ligases muscle-specific RING finger 1 (+583% ± 244.3%, P = 0.024) and muscle atrophy F-box (+249% ± 83.8%, P = 0.011) and the C2 proteasome subunit (+116% ± 40.6%, P = 0.012) also increased. Surprisingly, the amount of ubiquitin-conjugated proteins and the chymotrypsin-like activity of the proteasome were decreased by 20% ± 8.3% (P = 0.025) and 21% ± 4.4% (P = 0.001), respectively. The expression of ubiquitin-specific protease 28 deubiquitinase was increased (+81% ± 37.9%, P = 0.034).In the skeletal muscle, a 200-km run activates the expression of ubiquitin ligases muscle-specific RING finger 1 and muscle atrophy F-box as well as various cellular stresses, among which are ER stress, oxidative stress, and inflammation. Meanwhile, compensatory mechanisms seem also triggered: the unfolded protein response is up-regulated, and the chymotrypsin-like activity of the proteasome is repressed.