Tom D Brutsaert - Academia.edu (original) (raw)

Papers by Tom D Brutsaert

Background: Tissue iron depletion may negatively affect endurance performance and muscle fatigabi... more Background: Tissue iron depletion may negatively affect endurance performance and muscle fatigability. Objective: We investigated tissue-level iron depletion and pro- gressive fatigue of the quadriceps during dynamic knee-extension exercise in young women. Design: Twenty iron-depleted (serum ferritin < 20 � g/L), nonane- mic (hemoglobin > 110 g/L) women (x - ± SEM age: 29.1 ± 1.2 y) received iron (iron

BMC physiology, Jan 19, 2002

Vascular endothelial growth factor (VEGF) mRNA levels increase in rat skeletal muscle after a sin... more Vascular endothelial growth factor (VEGF) mRNA levels increase in rat skeletal muscle after a single bout of acute exercise. We assessed regional differences in VEGF165 mRNA levels in rat gastrocnemius muscle using in situ hybridization after inducing upregulation of VEGF by treadmill running (1 hr) or electrical stimulation (1 hr). Muscle functional regions were defined as oxidative (primarily oxidative fibers, I and IIa), or glycolytic (entirely IIb or IId/x fibers). Functional regions were visualized on muscle cross sections that were matched in series to slides processed through in situ hybridization with a VEGF165 probe. A greater upregulation in oxidative regions was hypothesized. Total muscle VEGF mRNA (via Northern blot) was upregulated 3.5-fold with both exercise and with electrical stimulation (P = 0.015). Quantitative densitometry of the VEGF mRNA signal via in situ hybridization reveals significant regional differences (P <or= 0.01) and protocol differences (treadmill...

Respiratory Physiology & Neurobiology, 2004

To determine if hypoxia-inducible factor-1 (HIF-1) may regulate skeletal muscle vascular endothel... more To determine if hypoxia-inducible factor-1 (HIF-1) may regulate skeletal muscle vascular endothelial growth factor (VEGF) expression in response to exercise or hypoxia, rats underwent 1 h sciatic nerve electrical stimulation (ES), hypoxic exposure (H) or combined stimuli. HIF-1␣ protein levels increased six-fold with maximal (8 V) ES with or without H. Similar HIF-1␣ increases occurred with sub-maximal (6 V and 4 V) ES plus H, but not in sub-maximal ES or H alone. VEGF mRNA and protein levels increased three-fold in sub-maximal ES or H alone, six-fold in sub-maximal ES plus H, 6.3-fold with maximal ES, and 6.5-fold after maximal ES plus H. These data suggest: (1) intracellular hypoxia during normoxic exercise may exceed that during 8% oxygen breathing at rest and is more effective in stimulating HIF-1␣; (2) HIF-1 may be an important regulator of exercise-induced VEGF transcription; and (3) breathing 8% O 2 does not alter HIF-1␣ expression in skeletal muscle, implying that exercise-generated signals contribute to the regulation of HIF-1␣ and/or VEGF.

PLoS genetics, 2012

Most individuals throughout the Americas are admixed descendants of Native American, European, an... more Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four ...

Early Human Development, 2011

Poor fetal growth is associated with decrements in muscle strength likely due to changes during m... more Poor fetal growth is associated with decrements in muscle strength likely due to changes during myogenesis. We investigated the association of poor fetal growth with muscle strength, fatigue resistance, and the response to training in the isolated quadriceps femoris. Females (20.6 yrs) born to term but below the 10 th percentile of ponderal index (PI)-for-gestational-age (LOWPI, n=14) were compared to controls (HIGHPI, n=14), before and after an 8-week training. Muscle strength was assessed as grip-strength and as the maximal isometric voluntary contraction (MVC) of the quadriceps femoris. Muscle fatigue was assessed during knee extension eercise. Body composition and the maximal oxygen consumption (VO 2 max) were also measured. Controlling for fat free mass (FFM), LOWPI versus HIGHPI women had ~11% lower grip-strength (P=0.023), 9-24% lower MVC values (P=0.042 pre-trained; P=0.020 post-trained), a higher rate of fatigue (pre-and post-training), and a diminished training response (P=0.016). Statistical control for FFM increased rather than decreased strength differences between PI groups. The PI was not associated with VO 2 max or measures of body composition. Strength and fatigue decrements strongly suggest that poor fetal growth affects the pathway of muscle force generation. This could be due to neuromotor and/or muscle morphologic changes during development e.g., fiber number, fiber type, etc. Muscle from LOWPI women may also be less responsive to training. Indirectly, results also implicate muscle as a potential mediator between poor fetal growth and adult chronic disease, given muscle's direct role in determining insulin resistance, type II diabetes, physical activity, and so forth.

Andean high altitude natives show higher arterial oxygen saturation (Sao2) during exercise in hyp... more Andean high altitude natives show higher arterial oxygen saturation (Sao2) during exercise in hypoxia, compared to acclimatized sojourners. In order to evaluate the effects of life-long exposure to high altitude on Sao2, we studied two groups of well-matched, self-identified Peruvian Quechua natives who differed in their developmental exposure to hypoxia before and after a 2-month training period. Male and female volunteers (18-35 years) were recruited in Lima, Peru (150 m). The two groups were: a) Individuals who were born and raised at sea-level (BSL, n=34) and b) Individuals who were born and raised at high altitude (BHA, n=32), but who migrated to sea-level as adults (>16 years old). Exercise testing was conducted using a submaximal exercise protocol in normobaric hypoxia in Lima (BP=750 mmHg, Fio2=0.12), in order to measure Sao2 (%), ventilation (VE L/min) and oxygen consumption (Vo2, L/min). Repeated-measures ANOVA, controlling for VE/VO2 (L/min) and sex during the submaximal protocol showed that BHA maintained higher Sao2 (%) compared to BSL at all workloads before (p=0.005) and after training (p=0.017). As expected, both groups showed a decrease in Sao2 (%) (p<0.001), as workload increased. Resting Sao2 levels were not found to be different between groups. The results suggest that developmental exposure to altitude contributes to the maintenance of higher Sao2 levels during submaximal exercise at hypoxia.

Medicine and sport science, 2009

This chapter provides an overview of the truism that both nature and nurture determine human athl... more This chapter provides an overview of the truism that both nature and nurture determine human athletic ability. The major thesis developed is that environmental effects work through the process of growth and development and interact with an individual's genetic background to produce a specific adult phenotype, i.e. an athletic or nonathletic phenotype. On the nature side (genetics), a brief historical review is provided with emphasis on several areas that are likely to command future attention including the rise of genome-wide association as a mapping strategy, the problem of false positives using association approaches, as well as the relatively unknown effects of gene-gene interaction(epistasis), gene-environment interaction, and genome structure on complex trait variance. On the nurture side (environment), common environmental effects such as training-level and sports nutrition are largely ignored in favor of developmental environmental effects that are channeled through growt...

High altitude natives have enlarged vital capacities and residual volumes (RV). Because pulmonary... more High altitude natives have enlarged vital capacities and residual volumes (RV). Because pulmonary volumes are an indication of functionally relevant traits, such as diffusion capacity, the understanding of the factors (genetic/developmental) that influence lung volumes provides insight into the adaptive responses of highlanders. In order to test for the effect of growth and development at high altitude on lung volumes, we obtained forced vital capacities (FVC), RV, and total lung capacities (TLC) for a sample of 65 Peruvian females of mostly Quechua origins (18-34 years) who were subdivided into two well-matched groups: 1) sea-level born and raised females (BSL, n 5 34) from Lima, Peru (150 m), and 2) high-altitude born and raised females (BHA, n 5 31) from Cerro de Pasco, Peru (4,338 m). To determine Quechua origins, Native American ancestry proportion (NAAP) for each This article was published online on 3 May 2012. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected on 14 June 2012.

Advances in Experimental Medicine and Biology, 2006

The complete sequencing the human genome and recent analytical advances have provided the opportu... more The complete sequencing the human genome and recent analytical advances have provided the opportunity to perform genome-wide studies of human variation. There is substantial potential for such population-genomic approaches to assist efforts to uncover the historical and demographic histories of human populations. Additionally, these genome-wide datasets allow for investigations of variability among genomic regions. Although all genomic regions in a population have experienced the same demographic events, they have not been affected by these events in precisely the same way. Much of the variability among genomic regions is simply the result of genetic drift (i.e., gene frequency changes resulting from the effects of small breeding-population size), but some is also the result of genetic adaptation, which will only affect the gene under selection and nearby regions. We have used a new DNA typing assay that allows for the genotyping of thousands of SNPs on hundreds of samples to identify regions most likely to have been affected by genetic adaptation. Populations that have inhabited different niches ( high-altitude regions) can be used to identify genes underlying the physiological differences. We have used two methods (admixture mapping and genome scans for genetic adaptation) founded on the populationgenomic paradigms to search for genes underlying population differences in response to chronic hypoxia. There is great promise that together these methods will facilitate

Journal of applied physiology (Bethesda, Md. : 1985), 2003

Quechua in the Andes may be genetically adapted to altitude and able to resist decrements in maxi... more Quechua in the Andes may be genetically adapted to altitude and able to resist decrements in maximal O2 consumption in hypoxia (DeltaVo2 max). This hypothesis was tested via repeated measures of Vo2 max (sea level vs. 4338 m) in 30 men of mixed Spanish and Quechua origins. Individual genetic admixture level (%Spanish ancestry) was estimated by using ancestry-informative DNA markers. Genetic admixture explained a significant proportion of the variability in DeltaVo2 max after control for covariate effects, including sea level Vo2 max and the decrement in arterial O2 saturation measured at Vo2 max (DeltaSpO2 max) (R2 for admixture and covariate effects approximately 0.80). The genetic effect reflected a main effect of admixture on DeltaVo2 max (P = 0.041) and an interaction between admixture and DeltaSpO2 max (P = 0.018). Admixture predicted DeltaVo2 max only in subjects with a large DeltaSpO2 max (P = 0.031). In such subjects, DeltaVo2 max was 12-18% larger in a subgroup of subjects ...

High altitude natives are reported to have outstanding work capacity in spite of the challenge of... more High altitude natives are reported to have outstanding work capacity in spite of the challenge of oxygen transport and delivery in hypoxia. To evaluate the developmental effect of lifelong exposure to hypoxia on aerobic capacity, VO2peak was measured on two groups of Peruvian Quechua subjects (18-35 years), who differed in their developmental exposure to altitude. Male and female volunteers were recruited in Lima, Peru (150 m), and were divided in two groups, based on their developmental exposure to hypoxia, those: a) Born at sea-level individuals (BSL), with no developmental exposure to hypoxia (n = 34) and b) Born at high-altitude individuals (BHA) with full developmental exposure to hypoxia (n = 32), but who migrated to sea-level as adults (>16-years-old). Tests were conducted both in normoxia (BP = 750 mm Hg) and normobaric hypoxia at sea-level (BP = 750 mm Hg, FiO2 = 0.12, equivalent to 4,449 m), after a 2-month training period (in order to control for initial differences in physical fitness) at sea-level. BHA had a significantly higher VO2peak at hypoxia (40.31 ± 1.0 ml/min/kg) as compared to BSL (35.78 ± 0.96 ml/min/kg, P = 0.001), adjusting for sex. The decrease of VO2peak at HA relative to SL (ΔVO2peak ) was not different between groups, controlling for baseline levels (VO2peak at sea-level) and sex (BHA = 0.35 ± 0.04 l/min, BSL = 0.44 ± 0.04 l/min; P = 0.12). Forced vital capacity (controlling for height) and the residuals of VO2peak (controlling for weight) had a significant association in the BHA group only (r = 0.155; P = 0.031). In sum, results indicate that developmental exposure to altitude constitutes an important factor to determine superior exercise performance.

Human genomics, 2005

Understanding the distribution of human genetic variation is an important foundation for research... more Understanding the distribution of human genetic variation is an important foundation for research into the genetics of common diseases. Some of the alleles that modify common disease risk are themselves likely to be common and, thus, amenable to identification using gene-association methods. A problem with this approach is that the large sample sizes required for sufficient statistical power to detect alleles with moderate effect make gene-association studies susceptible to false-positive findings as the result of population stratification. Such type I errors can be eliminated by using either family-based association tests or methods that sufficiently adjust for population stratification. These methods require the availability of genetic markers that can detect and, thus, control for sources of genetic stratification among populations. In an effort to investigate population stratification and identify appropriate marker panels, we have analysed 11,555 single nucleotide polymorphisms...

Placenta, 2004

A long and productive history of studies at high altitude has demonstrated that chronic hypoxia p... more A long and productive history of studies at high altitude has demonstrated that chronic hypoxia plays a key role in the aetiology of intrauterine growth restriction (IUGR) and pre-eclampsia. Susceptibility to altitude-associated IUGR varies among high-altitude populations in relation to their duration of altitude exposure, with multigenerational residents demonstrating one-third the birth weight fall present in shorter-resident groups. Higher uteroplacental blood flow during pregnancy in multigenerational high-altitude residents suggests that such population differences are due, at least in part, to differences in maternal vascular responses to pregnancy. We hypothesize that natural selection acting on hypoxia-inducible factor (HIF)-targeted or -regulatory genes has enabled maternal vascular adaptation to pregnancy in long-resident high-altitude groups. Preliminary evidence in support of this hypothesis demonstrates that the potent HIF-targeted vasoconstrictor, endothelin-1 (ET-1), is differentially regulated by pregnancy and chronic hypoxia in Andean vs European residents of high altitude. Andeans show the normal, pregnancy-associated fall in ET-1 levels previously reported at low altitude, whereas Europeans have higher ET-1 levels and little pregnancy-associated change, like pre-eclamptic women. Single nucleotide polymorphisms (SNPs) in the ET-1 gene also differ in Andeans compared with low-altitude populations. We conclude that high altitude serves as an experiment of nature for elucidating genetic factors underlying susceptibility to complications of pregnancy and fetal life. Such studies may be important for identifying persons at risk for these complications at any altitude.

Respiratory Physiology & Neurobiology, 2004

To determine if hypoxia-inducible factor-1 (HIF-1) may regulate skeletal muscle vascular endothel... more To determine if hypoxia-inducible factor-1 (HIF-1) may regulate skeletal muscle vascular endothelial growth factor (VEGF) expression in response to exercise or hypoxia, rats underwent 1h sciatic nerve electrical stimulation (ES), hypoxic exposure (H) or combined stimuli. HIF-1alpha protein levels increased six-fold with maximal (8V) ES with or without H. Similar HIF-1alpha increases occurred with sub-maximal (6V and 4V) ES plus H, but not in sub-maximal ES or H alone. VEGF mRNA and protein levels increased three-fold in sub-maximal ES or H alone, six-fold in sub-maximal ES plus H, 6.3-fold with maximal ES, and 6.5-fold after maximal ES plus H. These data suggest: (1) intracellular hypoxia during normoxic exercise may exceed that during 8% oxygen breathing at rest and is more effective in stimulating HIF-1alpha; (2) HIF-1 may be an important regulator of exercise-induced VEGF transcription; and (3) breathing 8% O(2) does not alter HIF-1alpha expression in skeletal muscle, implying that exercise-generated signals contribute to the regulation of HIF-1alpha and/or VEGF.

Respiratory Physiology & Neurobiology, 2006

Variation in human athletic performance is determined by a complex interaction of socio-cultural,... more Variation in human athletic performance is determined by a complex interaction of socio-cultural, psychological, and proximate physiological factors. Human physiological trait variance has both an environmental and genetic basis, although the classic gene-environment dichotomy is clearly too simplistic to understand the full range of variation for most proximate determinants of athletic performance, e.g., body composition. In other words, gene and environment interact, not just over the short term, but also over the lifetime of an individual with permanent effects on the adult phenotype. To further complicate matters, gene and environment may also be correlated. That is, genetically gifted individuals may be identified as children and begin training pulmonary, cardiovascular, and muscle systems at an early critical age. This review covers evidence in support of a genetic basis to human athletic performance, with some emphasis on the recent explosion of candidate gene studies. In addition, the review covers environmental influences on athletic performance with an emphasis on irreversible environmental effects, i.e., developmental effects that may accrue during critical periods of development either before conception (epigenetic effects), during fetal life (fetal programming), or during childhood and adolescence. Throughout, we emphasize the importance of gene-environment interaction (G × E) as a means of understanding variation in human physiological performance and we promote studies that integrate genomics with developmental biology.

PLoS Genetics, 2010

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exer... more High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.

High Altitude Medicine & Biology, 2008

Bigham, Abigail W., . Angiotensin-converting enzyme genotype and arterial oxygen saturation at hi... more Bigham, Abigail W., . Angiotensin-converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quechua. High Alt. Med. Biol. 9:167-178, 2008.-The I-allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with performance benefits at high altitude (HA). In n ϭ 142 young males and females of largely Quechua origins in Peru, we evaluated 3 specific hypotheses with regard to the HA benefits of the I-allele: (1) the I-allele is associated with higher arterial oxygen saturation (Sa O 2 ) at HA, (2) the I-allele effect depends on the acclimatization state of the subjects, and (3) the putative I-allele effect on Sa O 2 is mediated by the isocapnic hypoxic ventilatory response (HVR, l/min Ϫ1 /%Sa O 2 Ϫ1 ). The subject participants comprised two different study groups including BLA subjects (born at low altitude) who were lifelong sea-level residents transiently exposed to hypobaric hypoxia (Ͻ24 h) and BHA subjects (born at HA) who were lifelong residents of HA. To control for the possibility of population stratification, Native American ancestry proportion (NAAP) was estimated as a covariate for each individual using a panel of 70 ancestry-informative molecular markers (AIMS). At HA, resting and exercise Sa O 2 was strongly associated with the ACE genotype, p ϭ 0.008 with ϳ4% of the total variance in Sa O 2 attributed to ACE genotype. Moreover, I/I individuals maintained ϳ2.3 percentage point higher Sa O 2 compared to I/D and D/D. This I-allele effect was evident in both BLA and BHA groups, suggesting that acclimatization state has little influence on the phenotypic expression of the ACE gene. Finally, ACE genotype was not associated with the isocapnic HVR, although HVR had a strong independent effect on Sa O 2 (p ϭ 0.001). This suggests that the I-allele effect on Sa O 2 is not mediated by the peripheral control of breathing, but rather by some other central cardiopulmonary effect of the ACE gene on the renin-angiotensin-aldosterone system (RAAS).

High Altitude Medicine & Biology, 2004

This study tested the hypothesis that Andean natives are adapted to high altitude (HA) via high w... more This study tested the hypothesis that Andean natives are adapted to high altitude (HA) via high work efficiency during exercise in hypoxia. A total of 186 young males and females were tested in Bolivia, comprising eight different subject groups. Groups were identified based on gender, ancestry (Aymara vs. European), altitude of birth (highlands vs. lowlands), and the altitude where tested (420, 3600, 3850 m). This design allows partitioning of ancestral (i.e., genetic) and developmental effects. To minimize measurement error, subjects were given two submaximal exercise tests on a cycle ergometer (on separate days). Each test consisted of four 5-min work bouts (levels), each separated by a 5-min rest period. For all groups, the oxygen consumption (V(O2))-work rate relationship was not different from the sea-level reference. Gross and net efficiencies (GE and NE) were not different between groups at any work level, with the exception of European men born in the lowlands and acclimatized and tested at 3600 m. These men showed slightly lower V(O2) at high work output, but this may be due to a nonsteady-state V(O2) kinetic, rather than to an altered steady-state V(O2)-work rate relationship per se. There were no significant group differences in delta efficiency (DE). In sum, these results provide no support for the hypothesis of energetic advantage during submaximal work in Andean HA natives. A review and analysis of the literature suggest that the same is true for HA natives in the Himalayas.

BMC physiology, Jan 19, 2002

Respiratory Physiology & Neurobiology, 2004

PLoS genetics, 2012

Early Human Development, 2011

Medicine and sport science, 2009

Advances in Experimental Medicine and Biology, 2006

Journal of applied physiology (Bethesda, Md. : 1985), 2003

Human genomics, 2005

Placenta, 2004

Respiratory Physiology & Neurobiology, 2004

To determine if hypoxia-inducible factor-1 (HIF-1) may regulate skeletal muscle vascular endothel... more To determine if hypoxia-inducible factor-1 (HIF-1) may regulate skeletal muscle vascular endothelial growth factor (VEGF) expression in response to exercise or hypoxia, rats underwent 1h sciatic nerve electrical stimulation (ES), hypoxic exposure (H) or combined stimuli. HIF-1alpha protein levels increased six-fold with maximal (8V) ES with or without H. Similar HIF-1alpha increases occurred with sub-maximal (6V and 4V) ES plus H, but not in sub-maximal ES or H alone. VEGF mRNA and protein levels increased three-fold in sub-maximal ES or H alone, six-fold in sub-maximal ES plus H, 6.3-fold with maximal ES, and 6.5-fold after maximal ES plus H. These data suggest: (1) intracellular hypoxia during normoxic exercise may exceed that during 8% oxygen breathing at rest and is more effective in stimulating HIF-1alpha; (2) HIF-1 may be an important regulator of exercise-induced VEGF transcription; and (3) breathing 8% O(2) does not alter HIF-1alpha expression in skeletal muscle, implying that exercise-generated signals contribute to the regulation of HIF-1alpha and/or VEGF.

Respiratory Physiology & Neurobiology, 2006

PLoS Genetics, 2010

High Altitude Medicine & Biology, 2008

High Altitude Medicine & Biology, 2004