Contemporary exercise physiology: fifty years after the closure of Harvard Fatigue Laboratory.

The relationships between the discipline of exercise physiology and the activities of the Harvard Fatigue Laboratory were examined. Even though 5 decades have elapsed since the Laboratory's closure, its existence, leaders, and accomplishments continue to be revered by exercise physiologists. The Laboratory was unique because it was the first research facility of its type and because no single exercise physiology laboratory in the United States since 1947 has been able to attract the stature of the national and international investigators that conducted the interdisciplinary research published by the Laboratory. Despite the inference from its name, the Laboratory's purpose was not to advance the discipline of exercise physiology; rather, it was to advance our understanding and interactions of applied physiology, physiology, and sociology. Consequently, its contributions to the critical mass of exercise physiology literature were limited even though may of the publications were seminal in nature. As documented by the Horvaths, the closure resulted in the establishment of many different research laboratories by former Laboratory staff members and associates (R.E. Johnson at Illinois, Horvath at Santa Barbara, and Dill at Nevada); however, their impact on exercise physiology was delayed because Keys and Robinson had left for Minnesota and Indiana, respectively, well in advance of closing. Unfortunately, the administrative structure and organization of the Laboratory was not conducive to the training of Ph.D candidates with an interest in exercise physiology. Consequently, only two individuals graduated during its existence. Since departments of physiology or biology had limited faculty or interest in preparing students for such a future before and after closure, departments of physical education with specialization graduate programs in exercise physiology assumed this responsibility, which was facilitated by post-World War II funding that supported mass education, graduate training, health related research, and facility development. Today, the majority of the leaders in exercise physiology are the "products" of the specialization movement. Although undergraduates were encouraged to participate in the research activities, the talented faculty of the Laboratory did not offer formal courses in exercise physiology. Thus, the development of an academic discipline in exercise physiology was left to institutions that required a science-oriented curriculum in their undergraduate and graduate degree programs in physical education, exercise science, or kinesiology. The emergence of exercise physiology as a discipline in the United States was enhanced by the publications of the Journal of Applied Physiology in 1948 and by Medicine and Science in Sports in 1969. These were peer-reviewed journals that were interested in publishing research studies on exercise topics. Two other reasons contributed to its development. The first was the creation of an Applied Physiology Study Section at the National Institute of Health in 1964, whose purpose was to evaluate grant proposals in subject matter area intrinsic to exercise physiology, while the second reason was the formation of the American College of Sports Medicine in 1954. ACSM was an important for the establishment of the discipline because it had an organizational structure that encouraged exercise physiologists to join, provided opportunities for members to present at regional and national meetings, and would publish their findings. Although the American Physiological Society had been established more than a 100 years ago, only a limited number of its members were interested and active in exercise physiology at the time of the Laboratory's closure or at the beginning of the specialization era (1963). However, in 1977, APS created a membership section that included exercise physiology in its title. Currently, both APS and ACSM are effectively representing the professional interests of exercise ph

The hematological responses of rats exposed to conditions of simulated microgravity and acute exercise.

BACKGROUND: Although humans have experienced microgravity since 1961, it is unknown whether PaO2 or PaCO2 will change in humans or in animals exposed to similar conditions. Reports from subjects participating in long-term head down tilt studies indicate that PAO2 will decrease and PaCO2 will increase, presumably because of impairments in oxygen delivery and carbon dioxide transport. To investigate this topic with suspended (HDS) rats, we hypothesized that 14 d of HDS would lower resting PaO2 and elevate PaCO2 pressures when compared with control rats. Since returning astronauts, previously bed rested subjects, and suspended rats had exhibited decreases in maximum aerobic capacity, we predicted after 2 weeks of HDS, rats performing maximum exercise would demonstrate significant decreases in PaO2 and elevations in hydrogen ions. RESULTS: Blood gas results during HDS indicated PaO2 and PaCO2 partial pressures were significantly decreased during the first week of suspension. Maximal exercise significantly increased PaO2 pressures in both animal groups, but during exercise the suspended rats exhibited significant increases in lactic acid and hydrogen ion concentrations when compared with control animals. CONCLUSIONS: The suspended rat model effectively characterized PaO2 changes that have been reported for humans exposed to conditions of simulated microgravity. However, the decreases in VO2max reported for exercising humans and animals could not be explained by PaO2 changes and the rat model was not effective in predicting changes in blood PaCO2. RECOMMENDATIONS: NASA should encourage and support studies that characterize PaO2 and PaCO2 change in humans and animals, in space and after they return to a 1-G environment.

Current issues in exercise metabolism: the crossover concept.

1. Since ancient times, athletes have consumed proteins because of the belief they were the necessary substrate for optimal performance. Even though this concept was proven to be incorrect before the beginning of the 19th century, the practice continued until several decades ago. 2. By 1939, careful metabolic investigations on the changes in the respiratory exchange ratio had demonstrated that the metabolic transformations of lipids and carbohydrates were the primary sources of energy for muscular exercise. 3. Metabolic investigations on the profile of energy transformations during exercise have indicated that aspects related to exercise intensity, state of training, the availability of circulating free fatty acids, the activity of the sympathetic nervous system, resting levels of muscle and liver glycogen and muscle triglyceride concentrations have to be considered to explain a specific response. 4. In 1994, Brooks and Mercier introduced the concept of 'crossover' in their review manuscript to explain the shift in substrate utilization from lipids to carbohydrates by trained subjects when the power output was increased. In addition, the concept was advanced to reconcile divergent results by different investigators. 5. In 1995, Coggan and associates investigated the glucose kinetics of non-trained and trained subjects performing power outputs equal to 80% VO2max and concluded that the crossover concept was unable to explain their metabolic results from trained subjects. 6. Because of the importance of the topic to exercise physiologists and the uncertainties the controversy has created for teachers and researchers, the American Physiological Society Section on Environmental and Exercise Physiology scheduled a Point-Counterpoint forum at the 1997 Experimental Biology Meeting. The subsequent manuscripts of Brooks and Coggan are a result of that forum.

Muscle adaptations to hindlimb suspension in mature and old Fischer 344 rats.

We examined skeletal and cardiac muscle responses of mature (8 mo) and old (23 mo) male Fischer 344 rats to 14 days of hindlimb suspension. Hexokinase (HK) and citrate synthase (CS) activities and GLUT-4 glucose transporter protein level, which are coregulated in many instances of altered neuromuscular activity, were analyzed in soleus (Sol), plantaris (PI), tibialis anterior (TA), extensor digitorum longus (EDL), and left ventricle. Protein content was significantly (P < 0.05) lower in all four hindlimb muscles after suspension compared with controls in both mature (21-44%) and old (17-43%) rats. Old rats exhibited significantly lower CS activities than mature rats for the Sol, Pl, and TA. HK activities were significantly lower in the old rats for the Pl (19%) and TA (33%), and GLUT-4 levels were lower in the old rats for the TA (38%) and EDL (24%) compared with the mature rats. Old age was also associated with a decrease in CS activity (12%) and an increase in HK activity (14%) in cardiac muscle. CS activities were lower in the Sol (20%) and EDL (18%) muscles from mature suspended rats and in the Sol (25%), Pl (27%), and EDL (25%) muscles from old suspended rats compared with corresponding controls. However, suspension was associated with significantly higher HK activities for all four hindlimb muscles examined, in both old (16-57%) and mature (10-43%) rats, and higher GLUT-4 concentrations in the TA muscles of the old rats (68%) but not the mature rats. These results indicate that old age is associated with decreased CS and HK activities and GLUT-4 protein concentration for several rat hindlimb muscles, and these variables are not coregulated during suspension. Finally, old rat skeletal muscle appears to respond to suspension to a similar or greater degree than mature rat muscle responds.

Sports medicine: a century of progress.

According to the international Olympic Committee, it is the responsibility of the sports medicine profession to care for the health and welfare of Olympic athletes, treat and prevent injuries, conduct medical examinations, evaluate performance capacity, provide nutritional advice, prescribe and supervise training programs, and to monitor substance use. Implicit in these functions is to assist Olympic athletes in achieving the objectives of the Olympic Motto (Citius, Altius, Fortius), which is to become faster, higher, and stronger. During the past Olympiads, athletic performance has increased, as indicated by times for the men's marathon (-28%) or by the distance covered in the women's javelin throw (+80%). However, the fulfillment of these responsibilities was a slow and protracted process, as demonstrated by the facts that medical examinations were not required until 1920, that 28 years elapsed before an official team physician was appointed, and that women had to wait until 1984 before sanction was given to compete in the marathon race. Doping was not defined until 1964, and monitoring of substance abuse did not materialize until after 1972. Although individuals have prepared for athletic competition since the ancient Olympics, the scientific foundations for various training prescriptions were not firmly established until the 1960s and 1970s. It was speculated that performance records will continue to improve in the next century because more scientific sports medicine information would be available and because such information would be better disseminated to athletes.

Dobutamine as a countermeasure for reduced exercise performance of rats exposed to simulated microgravity.

Post-spaceflight results and findings from humans and rodents after conditions of bed rest or simulated microgravity indicate maximum exercise performance is significantly compromised. However, the chronic administration of dobutamine (a synthetic adrenomimetic) to humans in relevant experiments improves exercise performance by mechanisms that prevent the decline in peak O2 consumption (VO2peak) and reduce the concentration of lactic acid measured in the blood. Although dobutamine restores maximum VO2 values in animals participating in simulated microgravity studies, it is unknown whether injections of this alpha 1-, beta 1-, and beta 2-adrenoceptor agonist in rats will enhance exercise performance. To investigate this, adult male rats were assigned to three experimental groups: caged control receiving saline; head-down, tail-suspended (HDS) receiving saline (HDS-S); and an HDS group receiving dobutamine hydrochloride injections (1.8 mg/kg twice daily per rat). Treadmill tests were performed before suspension, at 14 days, and after 21 days. VO2peak, run time, and the rate of rise in colonic temperature (heating index) were evaluated after 14 days, whereas at 21 days, hemodynamic responses (heart rate, systolic blood pressure, and double product) were determined during submaximal exercise with blood pH, blood gases, and lactic acid concentration values obtained during maximal exercise. In contrast to the results for the HDS-S rats, dobutamine administration did restore VO2peak and "normalized" lactic acid concentrations during maximal exercise. However, daily injections were unable to enhance exercise performance aspects associated with treadmill run time, the mechanical efficiency of running, the heating index, or the retention of muscle and body mass. These simulated microgravity findings suggest that dobutamine's potential value as a countermeasure for postflight maximal performance or for egress emergencies is limited and that other countermeasures must be considered.

Influence of simulated microgravity on the sympathetic response to exercise.

Rats exposed to simulated conditions of microgravity exhibit reductions in aerobic exercise capacity that may be due to an impaired ability of the sympathetic nervous system (SNS) to mediate an increase in cardiac output and to redistribute blood flow. The purpose of this study was to quantify the sympathetic response to exercise in rats after exposure to 14 days of simulated microgravity or control conditions. To achieve this aim, rats were exposed to 14 days of head-down suspension (HDS) or cage control (CC) conditions. On day 14, norepinephrine (NE) synthesis was blocked with alpha-methyl-p-tyrosine, and the rate of NE depletion after synthesis blockade was used to estimate SNS activity in the left ventricle, spleen, and soleus muscle during treadmill exercise at 75% of maximal oxygen uptake. When compared with CC rats, the sympathetic response to exercise in HDS rats was characterized by a lower rate of NE depletion in the left ventricle (-82%) and spleen (-42%). The rate of NE depletion in the soleus muscle was 47% higher. These differences could contribute to the decrement in aerobic capacity of HDS rats by impairing their ability to augment cardiac output and to redirect blood flow to actively contracting skeletal muscle during exercise.

Animal models and their importance to human physiological responses in microgravity.

Two prominent theories to explain the physiological effects of microgravity relate to the cascade of changes associated with the cephalic shifts of fluids and the absence of tissue deformation forces. One-g experiments for humans used bed rest and the head-down tilt (HDT) method, while animal experiments have been conducted using the tail-suspended, head-down, and hindlimbs non-weightbearing model. Because of the success of the HDT approach with rats to simulate the gravitational effects on the musculoskeletal system exhibited by humans, the same model has been used to study the effects of gravity on the cardiopulmonary systems of humans and other vertebrates. Results to date indicate the model is effective in producing comparable changes associated with blood volume, erythropoiesis, cardiac mass, baroreceptor responsiveness, carbohydrate metabolism, post-flight VO2max, and post-flight cardiac output during exercise. Inherent with these results is the potential of the model to be useful in investigating responsible mechanisms. The suspension model has promise in understanding the capillary blood PO2 changes in space as well as the arterial PO2 changes in subjects participating in a HDT experiment. However, whether the model can provide insights on the up-or-down regulation of adrenoreceptors remains to be determined, and many investigators believe the HDT approach should not be followed to study gravitational influences on pulmonary function in either humans or animals. It was concluded that the tail-suspended animal model had sufficient merit to study in-flight and post-flight human physiological responses and mechanisms.

Physiological adaptations and countermeasures associated with long-duration spaceflights.

Since 1961, there have been more than 165 flights involving several hundred individuals who have remained in a space environment from 15 min to more than a year. In addition, plans exist for humans to explore, colonize, and remain in microgravity for 1000 d or more. This symposium will address the current state of knowledge in select aspects associated with the cardiovascular, fluid and electrolytes, musculoskeletal, and the neuroendocrine and immune systems. The authors will focus on responses, mechanisms, and the appropriate countermeasures to minimize or prevent the physiological and biochemical consequences of a microgravity environment. Since exercise is frequently cited as a generic countermeasure, this topic will be covered in greater detail. Models for simulated microgravity conditions will be discussed in subsequent manuscripts, as will future directions for ground-based research.

Neuroendocrine and immune system responses with spaceflights.

Despite the fact that the first human was in space during 1961 and individuals have existed in a microgravity environment for more than a year, there are limited spaceflight data available on the responses of the neuroendocrine and immune systems. Because of mutual interactions between these respective integrative systems, it is inappropriate to assume that the responses of one have no impact on functions of the other. Blood and plasma volume consistently decrease with spaceflight; hence, blood endocrine and immune constituents will be modified by both gravitational and measurement influences. The majority of the in-flight data relates to endocrine responses that influence fluids and electrolytes during the first month in space. Adrenocorticotropin (ACTH), aldosterone, and anti-diuretic hormone (ADH) appear to be elevated with little change in the atrial natriuretic peptides (ANP). Flight results longer than 60 d show increased ADH variability with elevations in angiotensin and cortisol. Although post-flight results are influenced by reentry and recovery events, ACTH and ADH appear to be consistently elevated with variable results being reported for the other hormones. Limited in-flight data on insulin and growth hormone levels suggest they are not elevated to counteract the loss in muscle mass. Post-flight results from short- and long-term flights indicate that thyroxine and insulin are increased while growth hormone exhibits minimal change. In-flight parathyroid hormone (PTH) levels are variable for several weeks after which they remain elevated. Post-flight PTH was increased on missions that lasted either 7 or 237 d, whereas calcitonin concentrations were increased after 1 wk but decreased after longer flights. Leukocytes are elevated in flights of various durations because of an increase in neutrophils. The majority of post-flights data indicates immunoglobulin concentrations are not significantly changed from pre-flight measurements. However, the numbers of T-lymphocytes and natural killer cells are decreased with post-flight conditions. Of the lymphokines, interleukin-2 production, lymphocyte responsiveness, and the activity of natural killer cells are consistently reduced post-flight. Limited head-down tilt (HDT) data suggest it is an effective simulation model for microgravity investigations. Neuroendocrine and pharmacological countermeasures are virtually nonexistent and should become high priority items for future research. Although exercise has the potential to be an effective countermeasure for various neuroendocrine-immune responses in microgravity, this concept must be tested before flights to Mars are scheduled.

Influence of simulated microgravity on cardiac output and blood flow distribution during exercise.

Rats exposed to simulated conditions of microgravity by head-down suspension (HDS) exhibit reductions in aerobic capacity. This may be due to an impaired ability to augment cardiac output and to redistribute blood flow during exercise. The purpose of this investigation was to measure cardiac output and blood flow distribution in rats that were exposed to 14 days of HDS or cage control conditions. Measurements were obtained at rest and during light-intensity (15 m/min) and heavy-intensity (25 m/min; 10% grade) treadmill exercise. Cardiac output was similar in HDS and cage control rats at rest and light exercise but was significantly lower in HDS rats (-33%) during heavy exercise. Soleus muscle blood flow (ml/min) was lower at rest and during exercise in HDS rats; however, when expressed relative to muscle mass (ml.min-1.100 g-1), soleus blood flow was lower only during light exercise. Plantaris muscle blood flow was lower in HDS rats during heavy exercise. Blood flow to the ankle flexor, knee extensor, and knee flexor muscles was not altered by HDS. Blood flow to the spleen and kidney was significantly higher in HDS rats. It was concluded that the reduction in aerobic capacity associated with HDS is due in part to an impaired ability to augment cardiac output during exercise.

Influence of simulated microgravity on the exercise performance of Fischer 344 rats.

Measurements from mission specialists after space flights or from subjects subjected to head down tilt experiments have demonstrated a decrease in exercise performance. Similar decreases have been reported for rats that have participated in simulated microgravity studies using the head down-tail suspended method of Morey-Holton (HDS). Because it is unclear whether older animal populations would exhibit similar responses, we undertook a HDS study with Fischer 344 male rats.

Hormonal and metabolic responses of hypophysectomized rats with head-down suspension.

The primary purpose of this investigation was to secure select anatomical and physiological measurements from hypophysectomized rats and their sham-operated control to determine how various endocrine influences could be modified by conditions of simulated microgravity. The focal point of the study was the exercise responses after head-down suspension; however, we were also interested in obtaining insights on nonexercise-related mechanisms. Since more details and information concerning this study will be published elsewhere, we will highlight those findings which warrant further research.

Metabolic responses to head-down suspension in hypophysectomized rats.

Rats exposed to head-down suspension (HDS) exhibit reductions in maximal O2 consumption (VO2max) and atrophy of select hindlimb muscles. This study tested the hypothesis that an endocrine-deficient rat exposed to HDS would not exhibit reductions in VO2max or hindlimb muscle mass. Hypophysectomized (HYPX) and sham-operated (SHAM) rats were tested for VO2max before and after 28 days of HDS or cage control (CC) conditions. No significant reductions in VO2max were observed in HYPX rats. In contrast, SHAM-HDS rats exhibited a significant reduction in absolute (-16%) and relative (-29%) measures of aerobic capacity. Time course experiments revealed a reduction in VO2max in SHAM-HDS rats within 7 days, suggesting that cardiovascular adjustments to HDS occurred in the 1st wk. HDS was associated with atrophy of the soleus (-42%) in SHAM rats, whereas HYPX rats exhibited atrophy of the soleus (-36%) and plantaris (-13%). SHAM-HDS rats had significantly lower (-38%) soleus citrate synthase activities per gram muscle mass than SHAM-CC, but no significant differences existed between HYPX-HDS and -CC rats. HDS rats had an impaired ability to thermoregulate, as indicated by significantly greater temperature increases per unit run time, compared with their CC counterparts. Pretreatment plasma epinephrine levels were significantly lower in HYPX than in SHAM rats. Norepinephrine concentration was similar for all groups except HYPX-HDS, in which it was significantly higher. HDS had no significant effect on thyroxine or triiodothyronine. SHAM-HDS rats had significantly lower concentrations of testosterone and growth hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Histone H4 stimulates glucose transport activity in rat skeletal muscle.

We investigated the effects of purified histone H4 on glucose transport activity in rat soleus and flexor digitorum brevis muscles. Histone H4, at concentrations up to 11.8 microM, increased 2-deoxyglucose (2-DG) uptake in a dose-dependent fashion. However, at concentrations higher than 11.8 microM, H4 caused a decrease in 2-DG uptake from the maximum, suggesting a secondary inhibitory action of this compound. The maximal effect of H4 on 2-DG uptake was not additive to the maximal effect of insulin. Moreover, 2-DG uptake in the presence of both H4 and insulin was significantly lower than the 2-DG uptake in the presence of insulin alone. The maximal effect of H4 on stimulation of 2-DG uptake was neither additive nor inhibitory to the maximal effects of the intracellularly acting insulin mimetics sodium vanadate or H2O2. It was, on the other hand, additive to the maximal effects of muscle contractions. Also, in contrast with the effects of H4 on insulin-stimulated 2-DG uptake, H4 did not inhibit insulin-like growth factor-I (IGF-I)-stimulated 2-DG uptake, as the maximal effects of H4 and IGF-I were additive. Scatchard analysis of the binding of 125I-insulin in the absence or presence of histone H4 revealed that H4 increased the specific binding of insulin without affecting receptor affinity. These data suggest that H4 interacts with the insulin, rather than the hypoxia/contraction, pathway for activation of glucose transport in muscle tissue, and that H4 acts either directly or indirectly to increase the number of insulin receptors at the surface of the muscle cell. This interaction does not appear to occur with the similar, although distinct, IGF-I receptor. These studies may provide additional insight into the complex signal-transduction systems of insulin action.

Muscle glucose uptake in the rat after suspension with single hindlimb weight bearing.

This study was designed to examine the effect of non-weight-bearing conditions and the systemic influences of simulated microgravity on rat hindlimb muscles. For this purpose, rats were suspended (SUS) in a head-down position (45 degrees) with the left hindlimb non-weight bearing (NWB) and the right hindlimb bearing 20% of presuspension body mass (WB). Weight bearing by the SUS-WB limb was accomplished by using a platform connected to a rod in sleeve, cable, and pulley apparatus to which weight could be added. Rats (250-325 g) were assigned to SUS or cage control (CC) conditions for 14 days. The angle between the foot and leg for SUS-WB and CC remained similar (20-30 degrees) throughout the experiment while the SUS-NWB hindlimbs extended to approximately 140 degrees by day 12. On day 14, the soleus, plantaris, and gastrocnemius muscles from the SUS-NWB limbs exhibited significantly lower (P < or = 0.05) masses than presuspension mass values (29, 11, and 21%, respectively). Weight bearing by the SUS-WB limbs prevented the loss of mass by these muscles. In separate groups of SUS and CC rats, 2-deoxyglucose uptake during hindlimb perfusion was significantly higher in both SUS-NWB and SUS-WB hindlimbs at 24,000 microU/ml of insulin compared with CC for all the muscles examined (21-80%). In addition, extracellular space (ml/g) was significantly greater in the soleus muscles from both the SUS-NWB and SUS-WB hindlimbs (64%) compared with CC muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of simulated microgravity on the VO2 max of nontrained and trained rats.

Head-down suspension (HDS) of rats has evolved as a useful model for the simulation of a microgravity environment. Previous HDS experiments with rats have shown an impaired capacity to perform aerobic exercise as demonstrated by reductions in maximum oxygen consumption (VO2 max), treadmill run time (RT), and mechanical efficiency (ME) of treadmill running at submaximal conditions. To determine whether endurance training (TR) before HDS would modify exercise performance, male Sprague-Dawley rats were assigned to nontrained (NT) or TR groups for 6 wk and exposed to HDS or cage control (CC) conditions for 29 days. The rats were tested for VO2 max, RT, and ME before treatment and on days 7, 14, 21, and 28. In addition, water and electrolyte excretion was measured on days 1 and 21 of the experimental period. Before HDS, the TR rats had significantly higher measures of VO2 max (15%) and RT (22%) than the NT rats. On day 28, HDS was associated with significant reductions in absolute VO2 max (ml/min) in TR (-30%) and NT (-14%) rats. Relative VO2 max (ml.min-1.kg-1) was significantly reduced in TR (-15%) but not NT rats. Similar reductions in RT occurred in TR (-37%) and NT (-35%) rats by day 28. ME was reduced 22% in both TR and NT rats after 28 days of suspension. HDS elicited diuresis, natriuresis, and kaliuresis in TR rats after 21 days but not after 24 h. In contrast, HDS-NT rats exhibited no diuretic, natriuretic, or kaliuretic responses.(ABSTRACT TRUNCATED AT 250 WORDS)