Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions (original) (raw)
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European Journal of Applied Physiology, 2009
Intermittent hypoxic exposure with exercise training is based on the assumption that brief exposure to hypoxia is suYcient to induce beneWcial muscular adaptations mediated via hypoxia-inducible transcription factors (HIF). We previously demonstrated (Mounier et al. Med Sci Sports Exerc 38:1410-1417) that leukocytes respond to hypoxia with a marked inter-individual variability in HIF-1 mRNA. This study compared the eVects of 3 weeks of intermittent hypoxic training on hif gene expression in both skeletal muscle and leukocytes. Male endurance athletes (n = 19) were divided into an Intermittent Hypoxic Exposure group (IHE) and a Normoxic Training group (NT) with each group following a similar 3-week exercise training program. After training, the amount of HIF-1 mRNA in muscle decreased only in IHE group (¡24.7%, P < 0.05) whereas it remained unchanged in leukocytes in both groups. The levels of vEGF 121 and vEGF 165 mRNA in skeletal muscle increased signiWcantly after training only in the NT group (+82.5%, P < 0.05 for vEGF 121 ; +41.2%, P < 0.05 for vEGF 165 ). In leukocytes, only the IHE group showed a signiWcant change in vEGF 165 (¡28.2%, P < 0.05). The signiWcant decrease in HIF-1 mRNA in skeletal muscle after hypoxic training suggests that transcriptional and post-transcriptional regulations of the hif-1 gene are diVerent in muscle and leukocytes.
Acta Physiologica, 2017
Aim. To determine whether repeated maximal-intensity hypoxic exercise induces larger beneficial adaptations on the hypoxia inducible factor-1α pathway and its target genes than similar normoxic exercise, when combined with chronic hypoxic exposure. Methods. Lowland elite male team-sport athletes underwent 14 days of passive normobaric hypoxic exposure (≥14 h.day-1 at F i O 2 14.5-14.2%) with the addition of six maximal-intensity exercise sessions either in normobaric hypoxia (F i O 2 ~14.2%) (LHTLH; n = 9) or in normoxia (F i O 2 20.9%) (LHTL; n = 11). A group living in normoxia with no additional maximalintensity exercise (LLTL; n = 10) served as control. Before (Pre), immediately after (Post-1), and 3 weeks after (Post-2) the intervention, muscle biopsies were obtained from the vastus lateralis. Results. Hypoxia inducible factor-1α subunit, vascular endothelial growth factor, myoglobin, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha and mitochondrial transcription factor A mRNA levels increased at Post-1 (all P≤0.
Journal of Applied Physiology, 2005
We hypothesized that specific muscular transcript level adaptations participate in the improvement of endurance performances following intermittent hypoxia training in endurance-trained subjects. Fifteen male high-level, long-distance runners integrated a modified living low-training high program comprising two weekly controlled training sessions performed at the second ventilatory threshold for 6 wk into their normal training schedule. The athletes were randomly assigned to either a normoxic (Nor) (inspired O2 fraction = 20.9%, n = 6) or a hypoxic group exercising under normobaric hypoxia (Hyp) (inspired O2 fraction = 14.5%, n = 9). Oxygen uptake and speed at second ventilatory threshold, maximal oxygen uptake (V̇o2 max), and time to exhaustion (Tlim) at constant load at V̇o2 max velocity in normoxia and muscular levels of selected mRNAs in biopsies were determined before and after training. V̇o2 max (+5%) and Tlim (+35%) increased specifically in the Hyp group. At the molecular le...
Skeletal muscle hypoxia-inducible factor-1 and exercise
Experimental physiology, 2016
Reduced oxygen levels in skeletal muscle during exercise are a consequence of increased oxygen consumption. The cellular response to hypoxia is conferred to a large extent by activation of the hypoxia-sensitive transcription factor hypoxia-inducible factor-1 (HIF-1). The target genes of HIF-1 increase oxygen transport through mechanisms such as erythropoietin-mediated erythropoiesis and vascular endothelial growth factor-induced angiogenesis and improve tissue function during low oxygen availability through increased expression of glucose transporters and glycolytic enzymes, which makes HIF-1 an interesting candidate as a mediator of skeletal muscle adaptation to endurance training. However, HIF-1 may also inhibit cellular oxygen consumption and mitochondrial oxidative metabolism, features discordant with the phenotype of a trained muscle. Skeletal muscle readily adjusts to altered functional demands. Adaptation of skeletal muscle to long-term aerobic training enables better aerobic...
Physiological activation of hypoxia inducible factor-1 in human skeletal muscle
The FASEB Journal, 2005
The human hypoxia inducible factor 1 (HIF-1) system is activated under various pathological conditions, yet less is known about its physiological regulation in healthy human tissue. We have studied the effect of exercise on the activation of HIF-1 in human skeletal muscle. Employing a model where oxygen consumption increases and oxygen tension can be manipulated, nine healthy male subjects performed 45 min of one-legged knee-extension exercise. Biopsies were taken before, directly after, and 30, 120, and 360 min after exercise. Exercise led to elevated HIF-1α protein levels and a more prevalent nuclear staining of HIF-1α. Interestingly, a concurrent decrease in von Hippel-Lindau tumor suppressor protein (VHL) levels was detected in some subjects. Moreover, exercise induced an increase in the DNA binding activity of HIF-1α. Characterization of gene expression by real-time PCR demonstrated that the HIF-1 target genes VEGF and EPO were activated. VEGF mRNA was further increased when blood flow to the exercising leg was restricted. In conclusion, these data clearly demonstrate that physical activity induces the HIF-1-mediated signaling pathway in human skeletal muscle, providing the first evidence that human HIF-1α can be activated during physiologically relevant conditions.
Pfl�gers Archiv European Journal of Physiology, 2003
To test the hypothesis that severe hypoxia during low-resistance/high-repetition strength training promotes muscle hypertrophy, 19 untrained males were assigned randomly to 4 weeks of low-resistance/highrepetition knee extension exercise in either normoxia or in normobaric hypoxia (FiO 2 0.12) with recovery in normoxia. Before and after the training period, isokinetic strength tests were performed, muscle cross-sectional area (MCSA) measured (magnetic resonance imaging) and muscle biopsies taken. The significant increase in strength endurance capacity observed in both training groups was not matched by changes in MCSA, fibre type distribution or fibre cross-sectional area. RT-PCR revealed considerable inter-individual variations with no significant differences in the mRNA levels of hypoxia markers, glycolytic enzymes and myosin heavy chain isoforms. We found significant correlations, in the hypoxia group only, for those hypoxia marker and glycolytic enzyme mRNAs that have previously been linked to hypoxia-specific muscle adaptations. This is interpreted as a small, otherwise undetectable adaptation to the hypoxia training condition. In terms of strength parameters, there were, however, no indications that low-resistance/high-repetition training in severe hypoxia is superior to equivalent normoxic training.
A hypoxia complement differentiates the muscle response to endurance exercise
Experimental Physiology, 2010
Metabolic stress is believed to constitute an important signal for training-induced adjustments of gene expression and oxidative capacity in skeletal muscle. We hypothesized that the effects of endurance training on expression of muscle-relevant transcripts and ultrastructure would be specifically modified by a hypoxia complement during exercise due to enhanced glycolytic strain. Endurance training of untrained male subjects in conditions of hypoxia increased subsarcolemmal mitochondrial density in the recruited vastus lateralis muscle and power output in hypoxia more than training in normoxia, i.e. 169 versus 91% and 10 versus 6%, respectively, and tended to differentially elevate sarcoplasmic volume density (42 versus 20%, P = 0.07). The hypoxia-specific ultrastructural adjustments with training corresponded to differential regulation of the muscle transcriptome by single and repeated exercise between both oxygenation conditions. Fine-tuning by exercise in hypoxia comprised gene ontologies connected to energy provision by glycolysis and fat metabolism in mitochondria, remodelling of capillaries and the extracellular matrix, and cell cycle regulation, but not fibre structure. In the untrained state, the transcriptome response during the first 24 h of recovery from a single exercise bout correlated positively with changes in arterial oxygen saturation during exercise and negatively with blood lactate. This correspondence was inverted in the trained state. The observations highlight that the expression response of myocellular energy pathways to endurance work is graded with regard to metabolic stress and the training state. The exposed mechanistic relationship implies that the altitude specificity of improvements in aerobic performance with a 'living low-training high' regime has a myocellular basis.
HIF-1α in endurance training: suppression of oxidative metabolism
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2007
During endurance training, exercising skeletal muscle experiences severe and repetitive oxygen stress. The primary transcriptional response factor for acclimation to hypoxic stress is hypoxia-inducible factor-1α (HIF-1α), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1α in endurance training, we have created mice specifically lacking skeletal muscle HIF-1α and subjected them to an endurance training protocol. We found that only wild-type mice improve their oxidative capacity, as measured by the respiratory exchange ratio; surprisingly, we found that HIF-1α null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1α null mice have an increased capillary to fiber ratio and elevated oxidative enzyme activities. These changes correlate with constitutively activated AMP-activated protein kinase in the HIF-1α null muscles. Additionally, HIF-1α null muscles have decreased expre...
Journal of Applied Physiology, 2015
The present study investigated the effects of acute and chronic eccentric exercise on the hypoxia-inducible factor (HIF)-1α activation response and the concomitant modulation of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression in rat skeletal muscle. Twenty-four male Wistar rats were randomly assigned to three experimental groups: rested control group, acutely exercised group after an intermittent downhill protocol for 90 min, and acutely exercise group with a previous eccentric training of 8 wk. HIF-1α activation, VEGF and eNOS gene expression, protein content, and promoter activation were assessed in vastus lateralis muscle biopsies. Acute eccentric exercise induced a marked activation of HIF-1α and resulted in increased VEGF and eNOS mRNA level and protein concentration. The binding of HIF-1α to the VEGF and eNOS promoters, measured by a chromatin immunoprecipitation assay, was undetectable in rested rats, whereas it was evident in...
AJP: Regulatory, Integrative and Comparative Physiology, 2011
Le Moine CMR, Morash AJ, McClelland GB. Changes in HIF-1␣ protein, pyruvate dehydrogenase phosphorylation, and activity with exercise in acute and chronic hypoxia. Exercise under acute hypoxia elicits a large increase in blood lactate concentration ([La] b) compared with normoxic exercise. However, several studies in humans show that with the transition to chronic hypoxia, exercise [La] b returns to normoxic levels. Although extensively examined over the last decades, the muscle-specific mechanisms responsible for this phenomenon remain unknown. To assess the changes in skeletal muscle associated with a transition from acute to chronic hypoxia, CD-1 mice were exposed for 24 h (24H), 1 wk (1WH), or 4 wk (4WH) to hypobaric hypoxia (equivalent to 4,300 m), exercised under 12% O 2, and compared with normoxic mice (N) at 21% O2. Since the enzyme pyruvate dehydrogenase (PDH) plays a major role in the metabolic fate of pyruvate (oxidation vs. lactate production), we assessed the changes in its activity and regulation. Here we report that when run under hypoxia, 24H mice exhibited the highest blood and intramuscular lactate of all groups, while the 1WH group approached N group values. Concomitantly, the 24H group exhibited the lowest PDH activity, associated with a higher phosphorylation (inactive) state of the Ser 232 residue of PDH, a site specific to PDH kinase-1 (PDK1). Furthermore, protein levels of PDK1 and its regulator, the hypoxia inducible factor-1␣ (HIF-1␣), were both elevated in the 24H group compared with N and 1WH groups. Overall, our results point to a novel mechanism in muscle where the HIF-1␣ pathway is desensitized in the transition from acute to chronic hypoxia, leading to a reestablishment of PDH activity and a reduction in lactate production by the exercising muscles.