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      The Effect of High-Altitude on Human Skeletal Muscle Energetics: 31P-MRS Results from the Caudwell Xtreme Everest Expedition

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          Many disease states are associated with regional or systemic hypoxia. The study of healthy individuals exposed to high-altitude hypoxia offers a way to explore hypoxic adaptation without the confounding effects of disease and therapeutic interventions. Using 31P magnetic resonance spectroscopy and imaging, we investigated skeletal muscle energetics and morphology after exposure to hypobaric hypoxia in seven altitude-naïve subjects (trekkers) and seven experienced climbers. The trekkers ascended to 5300 m while the climbers ascended above 7950 m. Before the study, climbers had better mitochondrial function (evidenced by shorter phosphocreatine recovery halftime) than trekkers: 16±1 vs. 22±2 s (mean ± SE, p<0.01). Climbers had higher resting [Pi] than trekkers before the expedition and resting [Pi] was raised across both groups on their return (PRE: 2.6±0.2 vs. POST: 3.0±0.2 mM, p<0.05). There was significant muscle atrophy post-CXE (PRE: 4.7±0.2 vs. POST: 4.5±0.2 cm 2, p<0.05), yet exercising metabolites were unchanged. These results suggest that, in response to high altitude hypoxia, skeletal muscle function is maintained in humans, despite significant atrophy.

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          Most cited references 46

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          Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.

          Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine), whereas cycloheximide blocked induction of glycolytic RNAs and HIF-1 activity. Oligonucleotides from the ALDA, PGK1, enolase 1, lactate dehydrogenase A, and phosphofructokinase L (PFKL) genes, containing sequences similar to the HIF-1 binding site in the erythropoietin enhancer, specifically bound HIF-1 present in crude nuclear extracts or affinity-purified preparations. Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. These results support the role of HIF-1 as a mediator of adaptive responses to hypoxia that underlie cellular and systemic oxygen homeostasis.
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            This article describes a Java-based graphical user interface for the magnetic resonance user interface (MRUI) quantitation package. This package allows MR spectroscopists to easily perform time-domain analysis of in vivo/medical MR spectroscopy data. We have found that the Java programming language is very well suited for developing highly interactive graphical software applications such as the MRUI system. We also have established that MR quantitation algorithms, programmed in the past in other languages, can easily be embedded into the Java-based MRUI by using the Java native interface (JNI).
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              Muscle tissue adaptations to hypoxia.

              This review reports on the effects of hypoxia on human skeletal muscle tissue. It was hypothesized in early reports that chronic hypoxia, as the main physiological stress during exposure to altitude, per se might positively affect muscle oxidative capacity and capillarity. However, it is now established that sustained exposure to severe hypoxia has detrimental effects on muscle structure. Short-term effects on skeletal muscle structure can readily be observed after 2 months of acute exposure of lowlanders to severe hypoxia, e.g. during typical mountaineering expeditions to the Himalayas. The full range of phenotypic malleability of muscle tissue is demonstrated in people living permanently at high altitude (e.g. at La Paz, 3600-4000 m). In addition, there is some evidence for genetic adaptations to hypoxia in high-altitude populations such as Tibetans and Quechuas, who have been exposed to altitudes in excess of 3500 m for thousands of generations. The hallmark of muscle adaptation to hypoxia in all these cases is a decrease in muscle oxidative capacity concomitant with a decrease in aerobic work capacity. It is thought that local tissue hypoxia is an important adaptive stress for muscle tissue in exercise training, so these results seem contra-intuitive. Studies have therefore been conducted in which subjects were exposed to hypoxia only during exercise sessions. In this situation, the potentially negative effects of permanent hypoxic exposure and other confounding variables related to exposure to high altitude could be avoided. Training in hypoxia results, at the molecular level, in an upregulation of the regulatory subunit of hypoxia-inducible factor-1 (HIF-1). Possibly as a consequence of this upregulation of HIF-1, the levels mRNAs for myoglobin, for vascular endothelial growth factor and for glycolytic enzymes, such as phosphofructokinase, together with mitochondrial and capillary densities, increased in a hypoxia-dependent manner. Functional analyses revealed positive effects on V(O(2)max) (when measured at altitude) on maximal power output and on lean body mass. In addition to the positive effects of hypoxia training on athletic performance, there is some recent indication that hypoxia training has a positive effect on the risk factors for cardiovascular disease.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                19 May 2010
                : 5
                : 5
                [1 ]Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, Oxfordshire, United Kingdom
                [2 ]The Oxford Centre for Clinical Magnetic Resonance Research, John Radcliffe Hospital, Oxford, Oxfordshire, United Kingdom
                [3 ]School of Clinical Sciences, University of Liverpool, Liverpool, Merseyside, United Kingdom
                [4 ]Centre for Altitude, Space, and Extreme Environment Medicine, University College London, London, United Kingdom
                [5 ]Institute for Human Health and Performance, University College London, London, United Kingdom
                Pennington Biomedical Research Center, United States of America
                Author notes

                Conceived and designed the experiments: LME AJM DT GJK CJH DL HEM MPWG KC. Performed the experiments: LME AJM CJH DL MPWG. Analyzed the data: LME GJK CJH KC. Wrote the paper: LME AJM DT GJK CJH PAR SN DL HEM MPWG KC.


                Current address: Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia


                Current address: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom

                Edwards et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 8
                Research Article
                Physiology/Integrative Physiology
                Physiology/Muscle and Connective Tissue
                Physiology/Respiratory Physiology



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