Is it the people or the place? The remarkable 30-year period of integrative physiology research in the Carlson Gymnasium at the University of Colorado Boulder.

Historically, programs of physical education and sport were housed in gymnasium buildings on academic campuses. As physical education evolved to the more scientifically focused successor departments of exercise science and kinesiology, faculty specialization developed in the physiology of exercise. With time, some faculty broadened their research to study the integrative physiology of other biological states and stressors. Through this series of events, a small group of integrative physiologists was formed in the Carlson Gymnasium at the University of Colorado Boulder during the 1990s with the goal of conducting novel biomedical research. The challenges were daunting: no contemporary core laboratory facilities, lack of temperature control, piercing external noise, pests, regular flooding, electrical power outages, and lack of funds for renovation. Despite these obstacles, the group established an innovative program of translational physiological research ranging from high-throughput molecular analyses to cell models to rodent studies to clinical trials in humans. These investigators supported their work with grant awards from the National Institutes of Health (NIH), Department of Defense, National Aeronautics and Space Administration (NASA), American Heart Association, and private research foundations totaling ∼$80 M in direct costs from the late 1980s to 2020. Collectively, the faculty and their laboratory personnel published ∼950 articles in peer-reviewed scientific journals. Over that period, 379 undergraduate students, 340 graduate students, 84 postdoctoral fellows, and dozens of junior research faculty received scientific training in Carlson, supported by >$21 M in extramural funding. What was accomplished by this handful of integrative physiologists speaks to the importance of the qualities of the investigators rather than their research facilities in determining scientific success.

Physiological responses to exercise at altitude : an update.

Studies performed over the past decade have yielded new information related to the physiological and metabolic adjustments made in response to both short- and long-term high-altitude exposure. These investigations have examined the potential mechanisms responsible for the alterations observed in such key variables as heart rate, stroke volume, cardiac output, muscle blood flow, substrate utilization and mitochondrial function, both at rest and during exercise of varying intensities. Additionally, the occurrence and mechanisms related to the 'lactate paradox' continues to intrigue investigators. It is apparent that exposure to high altitude is an environmental stressor that elicits a robust sympathoadrenal response that contributes to many of the critical adjustments and adaptations mentioned above. Furthermore, as some of these important physiological adaptations are known to enhance performance, it has become popular to incorporate an aspect of altitude living/training into the training regimens of endurance athletes (e.g. 'live high-train low'). Finally, it is important to note that many factors influence the extent to which individuals adjust and adapt to the stress imposed by exposure to high altitude. Included among these are (i) the degree of hypoxia; (ii) the duration of exposure to hypoxic conditions; (iii) the exercise intensity (absolute vs relative workload); and (iv) the inter-individual variability in adapting to hypoxic environments ('responders' vs 'non-responders').

Activation of Akt as a potential mediator of adaptations that reduce muscle injury.

UNLABELLED: Contraction-induced injury occurs when a muscle is stretched while activated (lengthening contraction). Exposure to a bout of lengthening contractions results in protection from subsequent lengthening contraction-induced injury as well as an elevation in phosphorylated Akt and p70S6K. Whether Akt or p70S6K is involved in the protection from contraction-induced injury is unclear. To test for a specific role of Akt and/or p70S6K to induce protective adaptations, we used a conditioning protocol of passive stretches that reduces contraction-induced injury with minimal involvement of other cellular responses that have been associated with the Akt signaling pathway, such as increased metabolism, cell growth, and cell death. PURPOSE: To determine whether activation of Akt or p70S6K is necessary to induce protective adaptations. METHODS: Extensor digitorum longus muscles of anesthetized mice were administered 75 lengthening contractions in situ with or without previous exposure to 75 passive stretches 1 h, 24 h, 3 d, or 14 d prior to lengthening contractions. RESULTS: Compared with unconditioned muscles, the deficit in isometric force and number of injured fibers 3 d following lengthening contractions were smaller by half for passive-stretch-conditioned muscles from all time points. Phosphorylation of Akt and p70S6K were analyzed by Western blot 0 or 3 h following either lengthening contractions or passive stretches. Whereas lengthening contractions increased phosphorylation of Akt at 0 h and p70S6K at 3 h, passive stretches did not at any time increase phosphorylation of Akt or p70S6K despite reducing contraction-induced injury. CONCLUSION: Activation of neither Akt nor p70S6K is necessary to induce adaptations that reduce the severity of contraction-induced injury.

Cytokine responses at high altitude: effects of exercise and antioxidants at 4300 m.

PURPOSE: This study tested the hypothesis that antioxidant supplementation would attenuate plasma cytokine (IL-6, tumor necrosis factor (TNF)-alpha), and C-reactive protein (CRP) concentrations at rest and in response to exercise at 4300-m elevation. METHODS: A total of 17 recreationally trained men were matched and assigned to an antioxidant (N = 9) or placebo (N = 8) group in a double-blinded fashion. At sea level (SL), energy expenditure was controlled and subjects were weight stable. Then, 3 wk before and throughout high altitude (HA), an antioxidant supplement (10,000 IU beta-carotene, 200 IU alpha-tocopherol acetate, 250 mg ascorbic acid, 50 microg selenium, 15 mg zinc) or placebo was given twice daily. At HA, energy expenditure increased approximately 750 kcal.d(-1) and energy intake decreased approximately 550 kcal.d, resulting in a caloric deficit of approximately 1200-1500 kcal.d(-1). At SL and HA day 1 (HA1) and day HA13, subjects exercised at 55% of VO2peak until they expended approximately 1500 kcal. Blood samples were taken at rest, end of exercise, and 2, 4, and 20 h after exercise. RESULTS: No differences were seen between groups in plasma IL-6, CRP, or TNF-alpha at rest or in response to exercise. For both groups, plasma IL-6 concentration was significantly higher at the end of exercise, 2, 4, and 20 h after exercise at HA1 compared with SL and HA13. Plasma CRP concentration was significantly elevated 20 h postexercise for both groups on HA1 compared to SL and HA13. TNF-alpha did not differ at rest or in response to exercise. CONCLUSION: Plasma IL-6 and CRP concentrations were elevated following exercise at high altitude on day 1, and antioxidant supplementation did not attenuate the rise in plasma IL-6 and CRP concentrations associated with hypoxia, exercise, and caloric deficit.

Endocrine responses to acute and chronic high-altitude exposure (4,300 meters): modulating effects of caloric restriction.

High-altitude anorexia leads to a hormonal response pattern modulated by both hypoxia and caloric restriction (CR). The purpose of this study was to compare altitude-induced neuroendocrine changes with or without energy imbalance and to explore how energy sufficiency alters the endocrine acclimatization process. Twenty-six normal-weight, young men were studied for 3 wk. One group [hypocaloric group (HYPO), n = 9] stayed at sea level and consumed 40% fewer calories than required to maintain body weight. Two other groups were deployed to 4,300 meters (Pikes Peak, CO), where one group (ADQ, n = 7) was adequately fed to maintain body weight and the other [deficient group (DEF), n = 10] had calories restricted as above. HYPO experienced a typical CR-induced reduction in many hormones such as insulin, testosterone, and leptin. At altitude, fasting glucose, insulin, and epinephrine exhibited a muted rise in DEF compared with ADQ. Free thyroxine, thyroid-stimulating hormone, and norepinephrine showed similar patterns between the two altitude groups. Morning cortisol initially rose higher in DEF than ADQ at 4,300 meters, but the difference disappeared by day 5. Testosterone increased in both altitude groups acutely but declined over time in DEF only. Adiponectin and leptin did not change significantly from sea level baseline values in either altitude group regardless of energy intake. These data suggest that hypoxia tends to increase blood hormone concentrations, but anorexia suppresses elements of the endocrine response. Such suppression results in the preservation of energy stores but may sacrifice the facilitation of oxygen delivery and the use of oxygen-efficient fuels.

Altitude, exercise and immune function.

Little is known with regard to how acute and chronic high altitude exposure effects immune function. Hypoxia is an environmental stressor that is known to elicit alterations in both the autonomic nervous system and endocrine function. Alterations in these systems can have an immediate as well as a longer lasting impact on immune function. Studies from the summit of Pikes Peak (4300 m) have indicated a strong alpha- & beta-adrenergic component in the regulation of immune function at altitude that can persist weeks after initial exposure. Specifically, interleukin (IL)-6 is elevated with acute altitude exposure primarily mediated via beta-adrenergic stimulation and remains elevated for several weeks as a result of alpha-adrenergic activation. When the added stress of physical exercise is combined with that of hypoxia, a more pronounced impact on immune function is observed compared to that of either exercise or hypoxia alone. A popular training paradigm currently employed by endurance athletes to enhance performance involves living at high altitude while training at low altitude. The concept entails incorporating the physiologic and metabolic adaptations associated with chronic high altitude exposure (increase in RBC, mitochondrial oxidative capacity, capillary density, etc) while training at a lower altitude allowing for the maintenance of a high absolute training intensity. Others have demonstrated that a short-term application (18 days) of the live high-train low paradigm results in suppression of the mucosal immune system as indicated by a cumulative decline in salivary IgA levels. Taken together, the majority of evidence suggests a potential additive effect of combined hypoxia and exercise in transiently suppressing immune function, at least in the short-term. Implications for the athletes and training are addressed.

No effect of menstrual cycle phase on lactate threshold.

No previous exercise studies in women have assessed the effects of the normal menstrual cycle on the lactate threshold (LT) measured during a graded, maximal exercise test. This is relevant to our understanding of exercise training and metabolism in eumenorrheic women. The present study, therefore, examined the effect of menstrual cycle phase on the LT. Eight moderately active, eumenorrheic women performed three maximal exercise tests with simultaneous determination of LT. Tests were performed in the early follicular (low estrogen and progesterone), midfollicular (elevated estrogen and low progesterone), and midluteal (elevated estrogen and progesterone) phases of the menstrual cycle. No significant differences were observed in LT measured across phases of the menstrual cycle whether data were expressed in absolute terms (1299 +/- 70, 1364 +/- 80, and 1382 +/- 71 ml O(2)/min, respectively) or relative to maximal oxygen uptake (V(o2 max); 52.1 +/- 1.7, 54.7 +/- 1.7, and 55.7 +/- 1.6%, respectively). In addition, there were no significant cycle phase differences in V(o2 max), maximal heart rate, heart rate at LT, or final lactate concentration. With data combined across all phases of the menstrual cycle, there was a significant correlation between the LT and the epinephrine breakpoint (r = 0.91, P < 0.0002) and norepinephrine breakpoint (r = 0.94, P < 0.0001). For epinephrine only, there was close correspondence between the epinephrine breakpoint (ml O(2)/min) and the LT. In conclusion, LT as well as V(o2 max) and other measures of cardiorespiratory fitness are not significantly affected by the changing sex steroid levels observed across the normal menstrual cycle. Data suggest that the onset of the steep increase in epinephrine determines the LT during graded exercise.

Influence of alpha-adrenergic blockade on the catecholamine response to exercise at 4,300 meters.

This investigation examined the influence of alpha-adrenergic blockade on plasma and urinary catecholamine responses to both exercise and high-altitude exposure. Sixteen nonsmoking, eumenorrheic women (age 23.2 +/- 1.4 years, 68.7 +/- 1.0 kg) were studied at sea level and during 12 days of high-altitude exposure (4,300 m). Subjects received either alpha-blockade (prazosin 3 mg/d) or a placebo in a double-blinded, randomized fashion. Resting plasma and 24-hour urine samples were collected periodically throughout the duration of the study. Further, subjects participated in submaximal exercise tests (50 minutes at 50% sea level maximum oxygen consumption [Vo2max]) at Sea level and on days 1 and 12 at altitude. Urinary norepinephrine (NE) excretion rates increased significantly over time at altitude, with blocked subjects having greater values compared to controls. Plasma NE levels increased significantly with chronic altitude exposure compared to sea level and acute hypoxia both at rest and during exercise. NE levels at rest were greater for blocked compared to control subjects during all conditions. Urinary and plasma epinephrine (EPI) levels increased dramatically, with acute altitude exposure returning to sea level values by day 12 of altitude exposure. EPI levels were greater for blocked compared to placebo both at rest and during exercise for all conditions studied. Changes in alpha-adrenergic activity over time at altitude were associated with select metabolic and physiologic adjustments. The presence of alpha-blockade significantly affected these responses during chronic altitude exposure. It was concluded that: (1) alpha-adrenergic blockade elicited a potentiated sympathoadrenal response to the stress of both exercise as well as high-altitude exposure, and (2) the sympathetics, via alpha-adrenergic stimulation, contribute to a number of key adaptations associated with acclimatization to high altitude.

Adrenergic contribution during acclimatization to high altitude: perspectives from Pikes Peak.

We have examined the sympathoadrenal responses to both acute and chronic high-altitude exposure at the summit of Pikes Peak, CO, in both men and women. A dissociation between the adrenal medullary response (acute) with that of the sympathetic nervous system (chronic) is observed. Both alpha- and beta-adrenergic contributions to key metabolic and physiologic adjustments to high-altitude exposure are evident.

High altitude residence during pregnancy alters cytokine and catecholamine levels.

This study assessed the impact of high altitude residence during pregnancy on parameters of maternal immune and endocrine system function. Urinary catecholamines, and serum cytokines, estriol, and cortisol were assessed during pregnancy in women living at moderate or high altitude. Women residing at high altitude exhibited elevated levels of proinflammatory cytokines only during pregnancy, and tended to have higher levels of catecholamines during pregnancy than women living at lower altitude. These data suggest that the combination of high altitude and pregnancy alters the maternal neural-immune axis in a manner that may predispose women to suboptimal birth outcomes.

Exercicio e atividade fisica para pessoas idosas / Exercise and physical activity for older adults

No ano 2030,o numero de individuos acima de 65 anos pode alcancar 70 milhoes somente no Estados Unidos;o segmento populacional que mais cresce e o de pessoas com 85 anos e mais.Como mais individuos vivem mais e necessario detreminar a amplitude e os mecanismos em que o exrecicio e a atividade fisica podem melhorar a saude,capacidade funcional,qualidade de vida e independencia nesta populacao.O envelhecimento e um processo complexo que envolve muitas variacoes(por exemplo,genetica,estilo de vida,doencas cronicas)que integram entre si e influenciam significativamente o modo que alcacamos detremnada idade.A participacao em atividade fisica regular (exercicios aerobicos e de forca)fornecem um numero de respostas favoraveis que contribuem para o envelhecimento saudavel.Muito tem sido aprendido recentemente em relacao a adaptabi;idade dos varios sistemas biologicos,assim como os meios em que o exercicio regular pode influencia-los.A participacao em um programa de exercicio regular e uma modalidade de intervencao efetiva para reduzir/prevenir um numero de declineos funcionais associados ao envehecimento.Adicionalmente,a treinabilidade dos individuos idosos(incluindo octo e nonagenarios)e evidenciada pela habilidade de se adaptarem e responderem a ambos tipos de treinamento,endurance e forca