Metabolic basis to Sherpa altitude adaptation

Horscroft, James A.; Kotwica, Aleksandra; Laner, Verena; West, James A.; Hennis, P. J.; Levett, Denny; Howard, David; Fernandez, Bernadette; Burgess, Sarah; Ament, Zsuzsanna; Gilbert‐Kawai, Edward; Vercueil, André; Landis, Blaine; Mitchell, Kay; Mythen, Monty; Branco, Cristina; Johnson, Randall S.; Feelisch, Martin; Montgomery, Hugh; Griffin, Julian L.; Grocott, Michael P.W.; Gnaiger, Erich; Martin, Daniel S.; Murray, Andrew J.

doi:10.1073/pnas.1700527114

Cited by 164 publications

(227 citation statements)

References 55 publications

(55 reference statements)

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“…Further, greater mitochondrial efficiency has recently been demonstrated in skeletal muscle of Sherpa compared to lowlanders (Horscroft et al . ), which if such a phenomenon is present in cerebral tissue may be related to the differential flow regulation observed in the present study. However, if the difference in CDO 2 is unrelated to metabolic differences between lowlander and Sherpa (i.e.…”

Section: Discussionsupporting

confidence: 66%

“…), increased skeletal muscle capillary density (Beall, ), and improved muscle energetics in Sherpa (Horscroft et al . ), little is known relative to potential adaptations in cerebral oxygen delivery/utilization (for reviews see Jansen & Basnyat, ; Gilbert‐Kawai et al . ).…”

Section: Introductionmentioning

confidence: 99%

“…While several examples of phenotypical adaptations distinct from those in lowlanders have been observed in the oxygen cascade of Tibetans, such as a higher nitric oxide bioavailability (Beall et al 2001;Erzurum et al 2007), increased skeletal muscle capillary density (Beall, 2007), and improved muscle energetics in Sherpa (Horscroft et al 2017), little is known relative to potential adaptations in cerebral oxygen delivery/utilization (for reviews see Jansen & Basnyat, 2011;Gilbert-Kawai et al 2014). Tibetans may display a 'high flow' phenotype to maintain oxygen delivery to various peripheral tissues in the presence of relatively normal arterial oxyhaemoglobin saturation (S aO 2 ) and haemoglobin concentrations [Hb] that are comparable to lowlanders at altitude (Beall, 2007).…”

Section: Introductionmentioning

confidence: 99%

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UBC‐Nepal expedition: phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude

Hoiland

Howe

Carter

et al. 2019

The Journal of Physiology

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Key points Sherpa have lived in the Nepal Himalaya for 25–40 thousand years and display positive physiological adaptations to hypoxia. Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery to the brain compared to lowland natives. We demonstrate that Sherpa have lower brain blood flow during ascent to and acclimatization at high altitude compared to lowlanders and that this difference in flow is not attributable to factors such as mean arterial pressure, blood viscosity and pH. The observed lower cerebral oxygen delivery in Sherpa likely represents a positive adaptation that may indicate a cerebral hypometabolic conservation of energy at altitude and/or decreased risk of other cerebral consequences such as vasogenic oedema. Abstract Debilitating side effects of hypoxia manifest within the central nervous system; however, high‐altitude natives of the Tibetan plateau, the Sherpa, experience negligible cerebral effects compared to lowland natives at extreme altitude. Phenotypical optimization of the oxygen cascade has been demonstrated in the systemic circulation of Tibetans and Sherpa, likely underscoring their adapted capacity to thrive at altitude. Yet, little is known as to how the cerebral circulation of Sherpa may be adapted. To examine potential differences in cerebral oxygen delivery in Sherpa compared to lowlanders we measured arterial blood gases and global cerebral blood flow (duplex ultrasound) during a 9 day ascent to 5050 m. Although cerebral oxygen delivery was maintained during ascent in lowlanders, it was significantly reduced in the Sherpa at 3400 m (−30.3 ± 21.6%; P < 0.01) and 4371 m (−14.2 ± 10.7%; P = 0.03). Furthermore, linear mixed effects modelling indicated that independent of differences in mean arterial pressure, pH and blood viscosity, race accounts for an approximately 100 mL min−1 (∼17–34%) lower cerebral blood flow in Sherpa compared to lowlanders across ascent to altitude (P = 0.046). To ascertain the role of chronic hypoxia independent of the ascent, Sherpa who had not recently descended were also examined at 5050 m. In these Sherpa, cerebral oxygen delivery was also lower compared to lowlanders (∼22% lower; P < 0.01). We highlight new information about the influence of race and genetic adaptation in the regulation of cerebral oxygen delivery. The lower cerebral oxygen delivery in the Sherpa potentially represents a positive adaptation considering Sherpa endure less deleterious cerebral consequences than lowlanders at altitude.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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UBC‐Nepal expedition: phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude

Hoiland

Howe

Carter

et al. 2019

The Journal of Physiology

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“…Assay 1 was based on a previously described protocol (38) with the concentrations optimized for permeabilized cardiac fibers and was designed to investigate β-oxidation of fatty acids. Assay 2 was adapted from a previously described protocol (39) and aimed to characterize control of different substrate-supported pathways over oxidative phosphorylation (oxphos).…”

Section: Methodsmentioning

confidence: 99%

Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration—probing the role of PPARα

et al. 2019

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Dietary inorganic nitrate prevents aspects of cardiac mitochondrial dysfunction induced by hypoxia, although the mechanism is not completely understood. In both heart and skeletal muscle, nitrate increases fatty acid oxidation capacity, and in the latter case, this involves up-regulation of peroxisome proliferator-activated receptor (PPAR)α expression. Here, we investigated whether dietary nitrate modifies mitochondrial function in the hypoxic heart in a PPARα-dependent manner. Wild-type (WT) mice and mice without PPARα ( Ppara −/− ) were given water containing 0.7 mM NaCl (control) or 0.7 mM NaNO 3 for 35 d. After 7 d, mice were exposed to normoxia or hypoxia (10% O 2 ) for the remainder of the study. Mitochondrial respiratory function and metabolism were assessed in saponin-permeabilized cardiac muscle fibers. Environmental hypoxia suppressed mass-specific mitochondrial respiration and additionally lowered the proportion of respiration supported by fatty acid oxidation by 18% ( P < 0.001). This switch away from fatty acid oxidation was reversed by nitrate treatment in hypoxic WT but not Ppara −/− mice, indicating a PPARα-dependent effect. Hypoxia increased hexokinase activity by 33% in all mice, whereas lactate dehydrogenase activity increased by 71% in hypoxic WT but not Ppara −/− mice. Our findings indicate that PPARα plays a key role in mediating cardiac metabolic remodeling in response to both hypoxia and dietary nitrate supplementation.—Horscroft, J. A., O’Brien, K. A., Clark, A. D., Lindsay, R. T., Steel, A. S., Procter, N. E. K., Devaux, J., Frenneaux, M., Harridge, S. D. R., Murray, A. J. Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration—probing the role of PPARα.

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“…This likely reflects the complex interplay of factors known to influence metabolic substrate supply and demand in hypoxic environments (7), and emphasizes that changes in selected "marker" enzymes or transcriptional regulators might not fully represent adaptive metabolic responses. More recent application of "omics" approaches and high-resolution mitochondrial respirometry have begun to shed light on the complexity of muscle metabolic adjustments to hypoxia (23)(24)(25). However, the integrated responses that balance energy demands and stress signals to maintain muscle homeostasis remain unclear, particularly in the absence of additional energetic stress that often accompanies studies of human hypoxia adaptation (i.e.…”

mentioning

confidence: 99%

Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: Lessons from AltitudeOmics

Chicco

Gnaiger

et al. 2018

Journal of Biological Chemistry

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Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress.

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Metabolic basis to Sherpa altitude adaptation

Cited by 164 publications

References 55 publications

UBC‐Nepal expedition: phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude

UBC‐Nepal expedition: phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude

Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration—probing the role of PPARα

Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: Lessons from AltitudeOmics

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