High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation.

Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21-5% FiO2, 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy.

Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia.

Although it is well established that chronic hypoxia leads to an inexorable loss of skeletal muscle mass in healthy subjects, the underlying molecular mechanisms involved in this process are currently unknown. Skeletal muscle atrophy is also an important systemic consequence of chronic obstructive pulmonary disease (COPD), but the role of hypoxemia in this regulation is still debated. Our general aim was to determine the molecular mechanisms involved in the regulation of skeletal muscle mass after exposure to chronic hypoxia and to test the biological relevance of our findings into the clinical context of COPD. Expression of positive and negative regulators of skeletal muscle mass were explored 1) in the soleus muscle of rats exposed to severe hypoxia (6,300 m) for 3 wk and 2) in vastus lateralis muscle of nonhypoxemic and hypoxemic COPD patients. In rodents, we observed a marked inhibition of the mammalian target of rapamycin (mTOR) pathway together with a strong increase in regulated in development and DNA damage response 1 (REDD1) expression and in its association with 14-3-3, a mechanism known to downregulate the mTOR pathway. Importantly, REDD1 overexpression in vivo was sufficient to cause skeletal muscle fiber atrophy in normoxia. Finally, the comparative analysis of skeletal muscle in hypoxemic vs. nonhypoxemic COPD patients confirms that hypoxia causes an inhibition of the mTOR signaling pathway. We thus identify REDD1 as a negative regulator of skeletal muscle mass during chronic hypoxia. Translation of this fundamental knowledge into the clinical investigation of COPD shows the interest to develop therapeutic strategies aimed at inhibiting REDD1.

Cellular and molecular events controlling skeletal muscle mass in response to altered use.

Gain or loss of skeletal muscle mass occurs in situations of altered use such as strength training, aging, denervation, or immobilization. This review examines our current understanding of the cellular and molecular events involved in the control of muscle mass under conditions of muscle use and disuse, with particular attention to the effects of resistance exercise/training. The DNA content, which is a critical determinant of protein synthesis by providing the amount of DNA necessary to sustain gene transcription, can be either increased (activation of satellite cells) or decreased (apoptosis) depending on muscle activity and ongoing physiological processes. In addition, several transcription factors are sensitive to functional demand and may control muscle-specific protein expression to promote or repress myofiber enlargement. The control of skeletal muscle mass is also markedly mediated by the regulation of transduction pathways that promote the synthesis and/or the degradation of proteins. Insulin-like growth factor-I plays a key role in this balance by activating the Akt/tuberous sclerosis complex 2/mammalian target of rapamycin pathway. Stimulation of this pathway leads to the concomitant activation of initiation and elongation factors resulting in the elevation of protein translation and the downregulation of ubiquitin proteasome components through Forkhead-box O transcription factors.

Effect of hyperoxia on maximal O2 uptake in exercise-induced arterial hypoxaemic subjects.

This study focuses on the effect of hyperoxia on maximal oxygen uptake VO2max and maximal power (Pmax) in subjects exhibiting exercise-induced arterial hypoxemia (EIH) at sea level. Sixteen competing male cyclists VO2max > 60 ml.min(-1).kg(-1)) performed exhaustive ramp exercise (cycle-ergometer) under normoxia and moderate hyperoxia (FIO2 = 30%). After the normoxic trial, the subjects were divided into those demonstrating EIH during exercise [arterial O2 desaturation (delta SaO2) >5%; n = 9] and those who did not (n = 7). Under hyperoxia, SaO2 raised and the increase was greater for the EIH than for the non-EIH group (P<0.001). VO2max improved for both groups and to a greater extent for EIH (12.8 +/- 5.7% vs. 4.2 +/- 4.6%, P<0.01; mean+/-SD) and the increase was correlated to the gain in SaO2 for all subjects (r = 0.71, P<0.01). Pmax improved by 3.3 +/- 3.3% (P<0.01) regardless of the group. These data suggest that pulmonary gas exchange contributes to a limitation in VO2max and power for especially EIH subjects.

Effect of endurance training on the VO2-work rate relationship in normoxia and hypoxia.

PURPOSE: We postulated that the relationship between VO2 and work rate (VO2-WR relationship) during incremental exercise is dependent on O2 availability, and that training-induced adaptations alter this relationship. We therefore studied the effect of endurance training on VO2 response during incremental exercise in normoxia and hypoxia (FIO2=0.134). METHODS: Before and after training (6 d.wk, 4 wk), eight subjects performed incremental exercises under normoxia and hypoxia and one constant-work rate exercise in normoxia at 80% of pretraining VO2max. The slopes of the VO2-WR relationship during incremental exercise were calculated using all the points (whole slope) or only points before the lactate threshold (pre-LT slope). The difference between VO2max measured and VO2max expected from the pre-LT slope (DeltaVO2) was determined, as was the difference between VO2 at minute 10 and VO2 at minute 4 during the constant-work rate exercise (DeltaVO2(10'-4')). RESULTS: In normoxia, training induced a significant decrease in the whole slope (11.0+/-1.0 vs 9.9+/-0.4 mL.min.W, P<0.05). In hypoxia, training induced a significant increase in the pre-LT slope (8.7+/-1.2 vs 9.8+/-0.7 mL.min.W; P<0.05) and the whole slope (8.5+/-1.2 vs 9.4+/-0.5 mL.min.W; P<0.05). A significant correlation between the decrease of DeltaVO2 and the decrease of DeltaVO2(10'-4') with training was found in normoxia (P<0.01, r=0.79). CONCLUSIONS: Taken together, these results indicate that adaptations induced by endurance training are associated with more efficient incremental and constant-workload exercise performed in normoxia. Moreover, training contributes to improved O2 delivery during moderate exercise performed in hypoxia, and to enhanced near-maximal exercise tolerance.

Decrease in peak heart rate with acute hypoxia in relation to sea level VO(2max).

The aim of this study was to evaluate the influence of arterial oxygen saturation ( SaO(2)) on maximal heart rate during maximal exercise under conditions of acute hypoxia compared with normoxia. Forty-six males were divided into three groups depending on their sea level maximal oxygen consumption ( VO(2max)): high [GH, VO(2max)=64.2 (3.3) ml x min(-1) x kg(-1)], medium [GM, 50.8 (3.9) ml x min(-1) x kg(-1)] and low [GL, 41.0 (1.9) ml x min(-1) x kg(-1)]. All subjects performed a maximal exercise test in two conditions of inspired oxygen tension ( PIO(2), (149 mmHg and 70 mmHg). Among the GM group, seven subjects performed five supplementary incremental exercise tests at PIO(2) 136, 118, 104, 92, and 80 mmHg. Measurements of VO(2max) and SaO(2) using an ear-oxymeter were carried out at all levels of PIO(2). The decrease in SaO(2 )and peak heart rate (HR(peak)) with PIO(2) became significant from 104 and 92 mmHg. SaO(2) correlated with the decrease in HR(peak). For PIO(2)=70 mmHg, the decrease in VO(2max), SaO(2) and HR(peak) was, respectively, 44%, 62%, and 17.0 bpm for GH, 38%, 68%, and 14.7 bpm for GM, and 34%, 68%, and 11.8 bpm for GL. During maximal exercise in hypoxia, SaO(2) was lower for GH than GM and GL ( p<0.01). Among subjects in GH, five presented exercise-induced hypoxemia (EIH) when exercising in normoxia. The EIH group exhibited a greater decrement in HR(peak) than the non-EIH group at maximal hypoxic exercise (21.2 bpm vs. 15.0 bpm; p<0.05). When subjects are exposed to acute hypoxia, the lower SaO(2), due either to lower PIO(2) or to training status, is associated with lower HR(peak).

Effects of training frequency on the dynamics of performance response to a single training bout.

The aim of this study was to analyze the effect of an increase in training frequency on exercise-induced fatigue by using a systems model with parameters free to vary over time. Six previously untrained subjects undertook a 15-wk training experiment composed of 1) an 8-wk training period with three sessions per week (low-frequency training), 2) 1 wk without training, 3) a 4-wk training period with five sessions per week [high frequency training (HFT)], and 4) 2 wk without training. The systems input ascribed to training loads was computed from interval exercises and expressed in arbitrary units. The systems output ascribed to performance was evaluated three times each week using maximal power sustained over 5 min. The time-varying parameters of the model were estimated by fitting modeled performances to the measured ones using a recursive least squares method. The variations over time in the model parameters showed an increase in magnitude and duration of fatigue induced by a single training bout. The time needed to recover performance after a training session increased from 0.9 +/- 2.1 days at the end of low-frequency training to 3.6 +/- 2.0 days at the end of HFT. The maximal gain in performance for a given training load decreased during HFT. This study showed that shortening recovery time between training sessions progressively yielded a more persistent fatigue induced by each training.