Evidence of thermoregulatory mechanisms in humans was reported as early as the 17th century when the Italian physician, Sanctorio Sanctorius (48), who designed the first clinical thermometer, demonstrated that human body temperature remains constant, except during illness when it rises. Experimentation on thermoregulation using heat chambers only began after the Fahrenheit, Celsius, and Reaumur clinical thermometers were developed (2). However, the characterization of integrative physiological reflexes and their control remained enigmatic until almost 200 yr later (26,45,46,58). The first references regarding heat acclimation are from the 18th century, coinciding with the emerging interest in tropical climate and diseases (e.g., Lind ); however, experimentation using humans and animals only began in the 20th century (Sumner in 1913 54 and Sundstroem in 1925 ). Comprehensive reviews on the physiology and biochemistry of heat acclimation were published in the mid-1990s when there was a basic understanding of thermoregulatory mechanisms. Since then, advances in thermoregulation and heat acclimation have been more rapid, and within 10 yr of the development of molecular biological techniques, they were included in the thermal biology repertoire. In 1995, Flanagan et al. (9) published the first in vivo model describing the effects of low and high heating rates on heat shock protein (HSP) synthesis in the liver, skeletal muscle, and other organs. In 1997, Moseley (43) hypothesized about the role of HSP70 in heat acclimation, and in that same year, the first study on HSP70 in heat-acclimating animals was published (23). The highlighted topic series on the molecular biology of thermoregulation in the Journal of Applied Physiology (May to June issues, e.g., Gabai and Sherman  and Sonna et al. ) promoted the need to integrate the molecular aspects of thermoregulatory processes with the function of the whole organism.
Despite the large number of articles on the molecular mechanisms of thermal responses, very few researchers used whole animal models that can provide detailed mechanistic explanations of integrative responses to environmental heat/exercise stress. Although there are some similarities in the phenomenology of cytoprotective and physiological processes between cultured cells and the whole organism, there are difficulties in translating results obtained from cultured cells, where single processes were perturbed, to the whole body where complex interplay occurs among many compensatory mechanisms. Currently, the functional complexity of adaptive responses and phenotypes can be dissected and understood using unbiased approaches such as global genomic and proteomic tools, allowing simultaneous analyses of concerted processes at the levels of the transcriptome/proteome, and if the model is adequate, results can be linked to physiological changes. Gene profiling analyses such as gene ontology (GO) and complementary bioinformatic tools enhance our understanding of the function of the genes responding to stressors as well as the pathways activated. However, changes in gene expression are not always translated into altered protein production. It is the gene products per se, the expressed proteins, that are the executors of the physiological change. Yet, our knowledge of the transcriptome is broader than that of the proteome. Our purposes in this mini review were to use the results of transcriptome profiling (and the changes in encoded proteins where data are available) and to highlight the molecular pathways underlying integrative thermoregulatory responses during chronic exposure to new environmental and/or internal heat loads.
THE CHOICE OF EXPERIMENTAL MODEL FOR UNRAVELING MOLECULAR PHYSIOLOGICAL LINKAGE DURING "WITHIN-LIFE PHENOTYPIC ADAPTATIONS"
Phenotypic adaptation is a chronic event in which reprogramming of gene expression is the keystone of the adaptive processes. Although microarrays have a huge potential for providing high-resolution analysis of molecular responses, most studies on gene profiling characterize "phenotype A" versus "phenotype B" under steady-state conditions. Species that have evolved to maintain homeostasis via physiological regulation display instability at the initial phases of exposure to novel environments or stressors such as training and acclimation (18,33). Hence, transient perturbations or adaptive gradients may be overlooked if microarrays are used only to examine the steady-state phase. To understand the phenotypic adaptive responses and their development, one must consider and study their kinetics, namely, changes over time. This has been elaborated by our group in the rat model of passive heat acclimation, which is a continuum of processes, where two distinct phases with variations in the excitability of the thermoregulatory controller are found (18,20). The first phase (short-term heat acclimation) is transient and is characterized by augmented autonomic signal/effector output ratio. The second phase (long-term heat acclimation) is stable, occurs when acclimatory homeostasis has been achieved, and shows enhanced physiological efficiency, during which the autonomic signal/effector output ratio decreases compared with nonacclimated animals (18). Short-term challenges from superimposed novel stressors (e.g., hypohydration) during acclimation revealed augmented thermoregulatory activity compared with basal thermoregulatory responses (in nonacclimated controls), leading to accentuated or diminished functions of the circuits involved (20,22), as well as providing information about them (50). Using this model, as well as the heat acclimation-aerobic training model, we will discuss the molecular-physiological architecture of integrative responses to heat and exercise.
HEAT ACCLIMATION: CHRONIC HEAT INDUCES A CONTINUUM OF ADAPTIVE SHIFTS IN GENE EXPRESSION
Heat acclimation (18,20) is a phenotypic adaptation achieved via prolonged exposure to heat and improves coping and fitness during periods of severely high ambient temperatures. The physiological criteria of the acclimated phenotype are decreased metabolic and HR and basal body temperature. Cardiovascular reserves and the capacity of the evaporative cooling system are increased. Leftward and rightward shifts in temperature thresholds for activating heat dissipation effectors and the onset of thermal injury, respectively, widen the dynamic thermoregulatory range (Fig. 1). Thus, an important acclimation signature is the transition from an inefficient to an efficient metabolic state (19,20).
The physiological basis of acclimatory homeostasis depends on temperature-adaptive shifts in gene expression (20). To screen for genes involved in heat acclimation, we undertook a time course analysis of transcript expression in the heart and the hypothalamus of heat-acclimating rats. In the heart, an immediate transient response was associated primarily with the up-regulation of genes linked with DNA maintenance/repair. The sustained response of the long-term acclimating phase correlated with changes in adaptive, long-lasting cytoprotective signaling networks (such as HSP, antiapoptosis, and antioxidative) (21). In the hypothalamus, the transcriptome map emphasized two phenomena: 1) a marked transient up-regulation in the transcript confined to genes encoding voltage-gated ion channels, ion pumps, or transporters, as well as hormone or transmitter receptors and cellular messengers, collectively implying enhanced membrane depolarization, release of transmitters, and neuronal excitability at this acclimation phase; and 2) a transient down-regulation of a group of genes suggesting perturbations in cellular maintenance (50). These transient responses are similar to those characterizing stressed or traumatic brain conditions (5). When acclimation has been achieved, a decrease in the expression of genes related to various metabolic activities, including those linked with mitochondrial energy metabolism and cellular maintenance processes, is noted. Resumption of preacclimation transcript levels of genes encoding proteins linked with ion movement and membrane or cellular signaling is noteworthy. Additional significant findings are the constitutive down-regulation of genes associated with energy metabolism and food intake and the marked up-regulation of a large group of genes linked with the immune response (Fig. 2) (50).
In the heart, during short-term acclimation, there is an up-regulation of transcripts linked with DNA integrity and hsps. After long-term acclimation, up-regulation of three major cytoprotective networks, namely, HSP, antioxidative, and antiapoptotic, was further enhanced (Fig. 2) (1,21,39,41), collectively producing the thermally protected and apoptosis-resistant phenotype (1). Notably, despite the high HSP70 transcript during short-term heat acclimation, almost no protein (HSP72) was detected, resulting in impaired cytoprotection (1,41), whereas on long-term heat acclimation, high constitutive levels of this protein, enhanced cytoprotection, and delayed thermotolerance were found (Fig. 2) (41,56).
There is no synchronization between the cellular fraction's adjustments during the process of heat acclimation. The lack of synchronization of each cellular fraction is highlighted, for example, by the evolution of the apoptosis-resistant phenotype (1). The changes in the mitochondrial outer membrane permeability attenuate the propagation of mitochondrial death signaling (intrinsic death signaling) and occur rapidly, appearing after short-term heat acclimation. In contrast, the adaptations in the sarcolemma (attenuating the propagation of extrinsic death signals) are slower and only brought into play after 1 month of acclimation, when homeostasis has been achieved (1).
To summarize, the delineated gene profiles indicate a two-tier defense strategy, correlating with our physiological understanding of the biphasic nature of heat acclimation (described above). The initial transient up-regulation of genes linked with DNA integrity and of transcripts encoding ion channels and neurotransmitters in the hypothalamus is congruent with the enhanced autonomic excitability seen at this acclimatory phase, where overactivation of heat defense mechanisms alleviates the initial heat strain. As acclimation progresses, these mechanisms are replaced with long-lasting ones, characterized by greater cytoprotective protein reserves (Fig. 2) and enhanced cellular efficiency.
COMBINED HEAT ACCLIMATION AND EXERCISE TRAINING-A CASE OF POSSIBLE CONFLICT/COMPETITION WHEN ADJUSTING TO ENVIRONMENTAL DEMANDS
Adaptation to either heat or aerobic exercise training involves changes at all levels of body organization to enhance effector performance (19). Opposing metabolic features are required to adapt to each of these stressors (Fig. 3). Aerobic exercise training boosts muscle performance; consequently, biochemical adaptations enhance aerobic and anaerobic energy metabolism to meet the need for greater ATP generation. Increased basal metabolic rate and lean body mass have also been documented (13,53). These alterations seem to be in conflict with critical adaptive features occurring after heat acclimation such as decreased basal metabolic rate (e.g., Sawka et al. ) found in humans and animals (17) to counteract excessive heat production.
An additional "clash" while exercising in the heat may stem from competition between the skin (for heat dissipation) and muscles for blood flow, compromising the redistribution of cardiac output to these vascular beds and, in turn, decreasing cardiac output and performance during hyperthermia (14,46). Francesconi et al. (10), using a rat model, demonstrated that long-term heat acclimation under sedentary conditions enhances thermoregulatory mechanisms but limits exercise endurance in the heat. This phenomenon was accompanied by a shut down of the thermoregulatory tail blood flow, implying that the demands of exercise were overriding. In humans, prolonged passive heating produces a heat-acclimated phenotype but does not improve exercising in the heat (3,37). Considering that the primary goal of any "acclimatory process" is stress-specific and given that the probability of the occurrence of heat exhaustion is negatively correlated with aerobic power (59), combined heat acclimation and exercise training protocols are required if we are to enhance exercise performance and meet thermoregulatory demands. Along these lines, Rowell (46) and Rowell et al. (47) measured increased stroke volume and exercise endurance in humans acclimated to heat and exercise. We found that the cardiovascular system, after acclimation to both stressors, individually and combined, shows increased stroke volume and cardiac efficiency (25,42). However, to the specific adaptive requirements of each stressor (described above), it is likely that these seemingly similar cardiac adjustments are achieved by different mechanisms. Evidence from our rat models confirmed that both heat acclimation and exercise training decreased double product index (i.e., increased cardiac work efficiency) during exercise in the heat. The decrease was more pronounced in the acclimated groups, suggesting significant climate (heat) effect. Heat acclimation reduces cardiac index by expanding stroke volume, whereas exercise alone predominantly affected the HR (42).
Animals and humans commonly encounter combined environmental/metabolic heat stresses, yet the weighted adaptations required to cope with the dual stress have rarely been dissected. Adaptive processes may involve exclusions or compromising elements (7,16) and may be considered as a stress in their own right. Collectively, physiological features and the reprogramming of stress-specific genes bring about these changes. The combined heat acclimation and exercise training produces a greater effect (15,35) on both the heart and the skeletal (soleus) muscle mechanical and metabolic performance (32,33,35) than either stress alone. Notably, these responses support the concept of acclimatory "trade-offs/compromises" (efficient force generation at the expanse of, e.g., relaxation velocity) and implicate different adaptive mechanisms. These issues are discussed below.
Figure 4 depicts the physiological characteristics of (i) force generation in the soleus, which is predominantly composed of oxidative fibers and is a model commonly used to study adaptations of slow-twitch postural skeletal muscle (including changes in gene expression) after acute and repeatedbouts of exercise (52) (Fig. 4A) and (ii) heart muscles of rats acclimated to heat and exercise, individually or combined (Fig. 4B). The amplitude of the isometric force generated by paced isolated soleus from rats subjected to combined heat and exercise training was 45% higher than untrained controls. Given that the ability to sustain peak isometric power with increasing stimulation frequency (Fig. 4A, upper panel) is analogous to endurance, we demonstrated that heat acclimation, both under sedentary and exercising conditions, attenuated the drop in power found in the normothermic groups. The soleus muscles exposed to the combined stressors demonstrated markedly longer relaxation times compared with sedentary or normothermic exercising groups (32). In the heart, heat acclimation and exercise training, individually, lead to greater cardiac pressure generation (35), suggesting that each of these stressors induces similar outcomes. However, combined heat acclimation and exercise training greatly enhance the capacity for pressure generation compared with acclimation or training under normothermic conditions alone (Fig. 4B) (15,35). Hearts from heat-acclimated rats also demonstrate decreased contractile and relaxation velocities because of the sustained low thyroxine levels, which augment slow myosin isoform predominance and phosphorylation levels of several Ca2+-regulatory proteins and are typical of the heat-acclimated phenotype (4,6,19). The negative lusitropic (myocardial relaxation) effect was more pronounced at high beating frequencies. Differences were less pronounced in the exercising animals, but collectively, the trade-off to enhanced endurance when heat acclimation contributes is the negative lusitropic effect in both the heart and the skeletal muscle. We demonstrated that in heat-acclimated hearts, negative lusitropy stems from the effect of thyroxine on the control of the pump returning calcium to its sarcoplasmic stores during the relaxation phase (4,6). It is not known whether the Ca2+ pump is similarly controlled during exposure to combined heat acclimation and exercise training. However, humans subjected to heat acclimation also demonstrate decreased thyroxine levels (12), implying a similar outcome.
The global genomic approach allows partial integration of the heat-acclimated, exercise-trained physiological phenotype and the underlying molecular mechanisms via (i) highlighting possible pathways leading to greater muscular force generation and (ii) determining genomic responses that are heat- or training-specific. In the soleus, a large number of genes assigned to Ca2+ signaling were upregulated similarly in the acclimated and the normothermic exercising groups. However, after heat acclimation combined with aerobic training (32), profound elevations in the expression of genes linked with energy metabolism (e.g., 6-phosphofructokinase, a rate-limiting enzyme in glycolysis and mitochondrial carnitine O-palmitoyltransferase (enhances lipid metabolism)) together with the specifically overexpressed genes associated with Ca2+ regulatory proteins (the sarcoplasmic reticulum (SR) Ca2+ ATPase and inositol triphosphate both involved in sarcoplasmic-cytosolic Ca2+ turnover (inositol triphosphate activates the ryanodine receptor to release calcium to the cytosol [8,57], whereas the SR Ca2+ ATPase pump is responsible for reuptake of calcium to the SR 7) seem to be the unique changes that underlie the improved performance of this treatment group. Further details on the genomic changes after acclimation or training in the soleus are presented in Figure 5. Genes, altered only by heat or training, were also identified (Fig. 5). Interestingly, there are differences in the acclimation/training profiles of the soleus and the heart. In the heart, up-regulation of genes specifically linked to excitation-contraction coupling (Ca2+-induced Ca2+ release mechanism, e.g., up-regulation of L-type Ca2+ channels and Na+/Ca2+ exchanger) and stress-specific genes was very pronounced. Unlike the soleus (studied in the same rats), the share of the changing metabolic-associated transcripts to the better performance of the heart was relatively minor (Kodesh E. and Horowitz M., personal communication) (33). Collectively, our data provide evidence of (i) differences in the adaptive responses of cardiac and skeletal muscle and (ii) the specific effect of exposure to combined exercise and heat acclimation that did not induce the same changes as exposure to each of these stressors independently, i.e., combined heat acclimation and exercise training did not induce a simple additive response. Further experiments are required to substantiate this concept.
In accordance with our concept of the importance of the dynamics/kinetics of our adaptive models, we characterized the genomic responses to short (2-3 d) and long-term (30 d) acclimation to heat and aerobic exercise in the soleus muscle and the heart. Different genes were recruited during the two periods of exposure. In the soleus, heat and exercise, individually and combined, affected the expression of genes associated with transport after short-term exposure, whereas after long-term exposure, genes involved mostly with metabolism and signal transduction changed their expression. Similar response was detected in the metabolic-associated genes of the heart. This slowly developing metabolic effect agrees with the concept (on the basis of both physiological data [19,27,46,49] and signal transduction data ) that acclimation enhances performance efficiency. A similar genomic profile was observed in our previous studies on the heart and the hypothalamus of rats undergoing passive heating (21,50). In addition, in both the soleus and the heart, acclimation induced temporal changes in genes linked with maintenance (via remodeling) of membrane integrity. The changes observed were specific to the stressor and the exposure time. For example, long-term exposure to passive heat acclimation was needed to induce notable changes in soleus membrane integrity genes, whereas after exercise training, normothermic as well as combined with heat, only 2 d were required to induce changes in these genes. In contrast, in the heart, long-term subjection to combined heat acclimation and training upregulated transcripts linked to sarcolemmal voltage-gated ion channels. From these examples, we can conclude that the molecular machinery of each muscle is challenged differently and responds specifically to each stressor (33).
HSP72-A HALLMARK ADAPTIVE RESPONSE TO HEAT AND TRAINING: A LINK TO INTEGRATIVE AUTONOMIC FUNCTIONS
The 72-kDa heat shock protein, HSP72, is a consensus marker of thermal injury. At high physiological temperatures, its level is tissue-specific and may identify a susceptibility to early thermal damage (9). In addition, to the consensus function of HSP in cytoprotection, there is accruing evidence of HSP participation in integrative physiological systems during stress (24). The scope of the current review is too narrow to review the cytoprotective role of HSP; therefore, we will only discuss the less known functions of these proteins with respect to thermal stress and heat acclimation. Briefly, the HSP are among the functional class of molecular chaperones; they are ubiquitous in nature, present in cells under normal conditions, and their accumulation increases, transiently, after a wide variety of insults. HSP assist in the correct noncovalent assembly of other polypeptide containing structures in vivo but are not components of these assembled structures while performing their biological functions. In addition to their cytoprotective role per se, the HSP provide cytoprotection via mediating antiapoptosis, antioxidative activity, neuroprotection, immunoprotection, reduced epithelial/endothelial permeability, etc. For further details on the cytoprotective activities of HSP, please see Horowitz et al. (22) and Kregel (34). Among the large body of publications on HSP and heat stress, Flanagan et al. (9), in a pioneering study, showed, using in vivo experiments, a direct relationship between animals' exercise performance under conditions of heat stress and the HSP level in various tissues. Flanagan et al. (9) showed that levels of HSP72 increase during stress in a dose-dependent manner. Considering the lack of correlation between internal strain, expressed as heat storage, and HSP72 transcript levels, but the positive correlation between HSP72 mRNA and the ambient temperature (17,18), Maloyan et al. (41) advanced our understanding of the regulatory role of the autonomic nervous system in HSP induction during heat stress, suggesting that external environmental heat stimuli use the thermal receptor efferent pathway of the thermoregulatory loop and mediate the HSP elevation (Fig. 6). Heat acclimation in the presence of propranolol, a β-antagonistic drug that inhibits HSP production, hastens the development of heat stroke syndrome in rats subjected to heat stress and significantly increases tissue damage (24,40). In contrast, in intact acclimated rats, in which basal HSP72 reserves are augmented, heating rate as well as the onset of thermal injury is markedly delayed (reviewed in Horowitz and Robinson ). Li et al. (36), questioning whether HSP70 potentiates the baroreflex response by acting on the nucleus tractus solitarius (NTS), the recipient "relay station" of baroreceptor afferent fibers, demonstrated that increased HSP70 levels in the NTS enhanced the sensitivity of both sympathetic and parasympathetic arms of the autonomic nervous system and thus attenuated heat stroke-induced cerebral ischemia and hypotension. Microinjection of anti-HSP antibodies to the NTS before thermal preconditioning abolished this effect. Interestingly, a certain level of HSP is required in the NTS at the onset of the baroreflex response. The preservation of synaptic transmission after thermal preconditioning shown by Kelty et al. (31) in the brain stem of mice fits well with this model. Extensive electrophysiological-molecular studies on heat stress-induced protection of synaptic transmission in the neuromuscular junction of Drosophila mutant larvae demonstrated that whereas HSP70 affects presynaptic vesicles (44), HSP83 and HSP40 seem to protect postsynaptic mechanisms (28,29). In both sites, presynaptic and postsynaptic domains, protection is achieved via the chaperoning actions of the HSP, namely, correct protein folding and trafficking. Similarly, the involvement of HSP in signaling homeostatic physiological systems during heat stress is likely to rely on their chaperoning and cytoprotective functions and their involvement is signal transduction.
Global genomic responses in tandem with an appropriate physiological experimental model are a good experimental design strategy to unravel the molecular mechanisms underlying integrative thermoregulatory responses. In this way, dynamic adaptation models, with accentuated or diminished regulatory circuits, triggered by superimposition of novel stressors sharing similar protective pathways, have significant benefits. Applying this concept to thermoregulation in conditions of heat stress, heat acclimation, and heat acclimation combined with training, we affirmed stress specificity of gene expression during "within-lifetime" phenotypic adaptations. We have demonstrated stress-specific gene reprogramming including genes associated with the metabolic and mechanical performance of the heart and skeletal muscle and thus emphasized the underlying molecular mechanisms of integrative adaptive responses under hyperthermic conditions. Many of these genes were not previously considered as part of the acclimatory repertoire. Although the molecular data discussed are derived from animal models, there is a similarity in basic acclimatory and physiological responses between these mammalian model and humans; hence, our data are pertinent to human acclimatory responses.
This work did not receive funding from National Institutes of Health, Wellcome Trust, Howard Hughes Medical Institute, or any other source requiring deposit. The authors' research of this article was supported over the years by the ISF, Israel Science Foundation, founded by the Israel Academy of Sciences and Humanities, BSF, US-Israel Binational Fund, and German Israeli Foundation Research Grants.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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