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Integrated Physiological Mechanisms of Exercise Performance, Adaptation, and Maladaptation to Heat Stress

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Abstract

This article emphasizes significant recent advances regarding heat stress and its impact on exercise performance, adaptations, fluid electrolyte imbalances, and pathophysiology. During exercise‐heat stress, the physiological burden of supporting high skin blood flow and high sweating rates can impose considerable cardiovascular strain and initiate a cascade of pathophysiological events leading to heat stroke. We examine the association between heat stress, particularly high skin temperature, on diminishing cardiovascular/aerobic reserves as well as increasing relative intensity and perceptual cues that degrade aerobic exercise performance. We discuss novel systemic (heat acclimation) and cellular (acquired thermal tolerance) adaptations that improve performance in hot and temperate environments and protect organs from heat stroke as well as other dissimilar stresses. We delineate how heat stroke evolves from gut underperfusion/ischemia causing endotoxin release or the release of mitochondrial DNA fragments in response to cell necrosis, to mediate a systemic inflammatory syndrome inducing coagulopathies, immune dysfunction, cytokine modulation, and multiorgan damage and failure. We discuss how an inflammatory response that induces simultaneous fever and/or prior exposure to a pathogen (e.g., viral infection) that deactivates molecular protective mechanisms interacts synergistically with the hyperthermia of exercise to perhaps explain heat stroke cases reported in low‐risk populations performing routine activities. Importantly, we question the “traditional” notion that high core temperature is the critical mediator of exercise performance degradation and heat stroke. Published 2011 This article is a U.S. Government work and is in the public domain in the USA. Compr Physiol 1:1883‐1928, 2011.

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Figure 1. Figure 1.

Active (vastus medialis) and inactive (triceps brachii) muscle temperatures relative to core and mean skin temperature changes during exercise.

Reprinted (with permission) from Jay et al.
Figure 2. Figure 2.

Core (rectal and esophageal) temperature during rest and aerobic exercise in the heat.

Reprinted (with permission) from Sawka and Wenger
Figure 3. Figure 3.

Possible core temperatures steady‐state during aerobic exercise at metabolic rates of 200, 350, 500, and 1000 W at different environmental conditions.

Reprinted (with permission) from Sawka et al.
Figure 4. Figure 4.

Schematic diagram of the thermoregulatory control system. Tsk represents skin temperature and Tc represents core temperature.

Reprinted (with permission) from Sawka et al.
Figure 5. Figure 5.

Schematic diagram of thermoregulatory effector (e.g., sweating rate and skin blood flow) responses (forcing function analysis with linear plots) to: (A) increased load error (LE), (B) parallel shift in threshold temperature suggesting change in “set point,” and (C) slope or sensitivity changes suggesting peripheral modifications. LE, load error; D, decrease; and I, increase.

Reprinted (with permission) from Gisolfi and Wenger
Figure 6. Figure 6.

Differences between the elevation of core temperature in fever and during exercise.

Reprinted (with permission) from Sawka and Wenger ; redrawn (with permission) from Stitt and Gisolfi and Wenger
Figure 7. Figure 7.

Schematic description of the thermoregulatory control of skin blood flow as modified by moderately intense exercise.

Reprinted (with permission) from Gonzalez‐Alonso et al.
Figure 8. Figure 8.

Cardiovascular responses during sustained moderate intensity (70% ) exercise in temperate and hot conditions. BF, blood flow; PV, plasma volume; SV, stroke volume; CO, cardiac output; Tsk, skin temperature; Tes, esophageal temperature; and Ta, ambient temperature. Drawn (with permission) from data presented by Nadel et al. .

Figure 9. Figure 9.

The impact of high skin temperature on elevating heart rate during light‐intensity exercise.

Reprinted (with permission) from Cheuvront et al.
Figure 10. Figure 10.

The impact of graded exercise intensity on cardiovascular responses during hot (triangle) and temperate (circle) conditions.

Reprinted (with permission) from Rowell
Figure 11. Figure 11.

Nomogram examining the potential performance decrement (y‐axis) based on projected marathon finishing time (x‐axis) with increasing Wet Bulb Globe Temperature.

Reprinted (with permission) from Ely et al.
Figure 12. Figure 12.

Maximum aerobic power values for the pre‐ and postacclimation tests in both environments.

Reprinted (with permission) from Sawka et al.
Figure 13. Figure 13.

The percent decrement in time trial performance from euhydration at each skin temperature.

Reprinted (with permission) from Kenefick et al.
Figure 14. Figure 14.

A comparison of the benefits from an aerobic training program with a heat acclimation program on reducing physiological strain and improving performance during exercise‐heat stress.

Reprinted (with permission) from Sawka and Young . Original data adapted (with permission) from Cohen and Gisolfi
Figure 15. Figure 15.

Cardiorespiratory and performance changes as a percent change from the preacclimation trials in both environmental conditions.

Reprinted (with permission) from Lorenzo et al. . *P < .05 vs. the preacclimation trials in both environments
Figure 16. Figure 16.

(A) Comparison of baseline heat shock protein (HSP) values between day 1 and day 10 of heat acclimation (HA). (B) Quantification of Western blot analysis in densitometry units representing ratio of HSP:β‐tubulin. Values are means and standard deviation with correlation between post‐HA (day 10 vs. day 1) increase in HSP72 and HSP90 expression.

Reprinted (with permission) from McClung et al.
Figure 17. Figure 17.

Predictions of daily water requirements as function of daily energy expenditure and air temperature. Figure adapted (with permission) from Institute of Medicine .

Figure 18. Figure 18.

Predictions of daily sodium requirements as function of daily energy expenditure and air temperature. Figure adapted (with permission) from Institute of Medicine .

Figure 19. Figure 19.

Predicted body mass loss (due to water deficit; left panel) for two 70‐kg people of different body composition, running at 8.5 km·h−1 in temperate weather (18°C), and drinking water at three rates [400 ml·h−1 (solid line), 600 ml·h−1 (broken line), 800 ml·h−1 (broken dotted line)]. The yellow‐shaded areas indicate when water loss would be sufficient to modestly degrade performance, and when water loss would substantially degrade performance (red). Also predicted are plasma sodium concentrations for three rates sweat sodium loss. Two lines sharing the same line style are the predicted outcomes for people of two different body compositions; with total body water accounting for 50% and 63% (leaner) of body mass. The hatched shaded areas denote the presence of hyponatremia (plasma sodium concentration <130 mEq·liter−1) into the range where symptoms develop.

Figure 20. Figure 20.

Distribution of relative risk among male Marine Corps recruits and distribution of exertional heat stroke at Parris Island, SC, for years 1988 to 1992. High risk = body mass index (BMI) ≥22 kg·m−2, 1.5 mi run time ≥12 min; medium risk = BMI ≥26 kg·m−2, 1.5 mi run time <12 min or BMI <22 kg·m−2, 1.5 mi run time ≥12 min; low risk = BMI <26 kg·m−2, 1.5 mi run time <12 min. Adapted (with permission) from Gardner et al. .

Figure 21. Figure 21.

Core temperature of a male Marine Corp recruit during normal physical training and when incurring exertional heat stroke, conducted on two different days. Note the rapid development of hyperthermia on the day of heat stroke despite performing the same activity as the day that heat stroke was not observed. Wenger et al. (unpublished data).

Figure 22. Figure 22.

Summary of exertional heat stroke pathophysiological responses that culminate in multiorgan system failure. During exercise heat stress, there is an increase in cutaneous blood flow and decrease in splanchnic blood flow. Gut epithelial membrane ischemia induces oxidative and nitrosative stress that increases tight junction permeability and allows endotoxin to leak into the systemic and portal circulation. Toll‐like receptors (e.g., TLR4) detect pattern‐associated molecular patterns (PAMPs) on the cell membrane of endotoxin and stimulate pro‐ and anti‐inflammatory cytokine production. Heat is toxic to several organs and stimulates the secretion of heat shock proteins (HSPs) that interact with cytokines and other proteins to mediate the systemic inflammatory response syndrome of the host. A shift of the cytokine milieu from anti‐inflammatory (Th2) to a pro‐inflammatory (Th1) balance (a process known as anergy) is thought to mediate many of the adverse consequences of the heat stroke syndrome that lead to multiorgan system failure and death.

Figure 23. Figure 23.

Representative light micrographs of histological damage (hematoxylin and eosin stain) to inverted rat small‐intestinal sac tissue exposed to 41.5 to 42°C over a 60‐min time course. Villi appear normal at 15 min compared with the initial sloughing of epithelia from the villous tips at 30 min of exposure. At 45 min, there is significant lifting of villi epithelial linings at the top and sides, which is completed denuded by 60 min of exposure. Bars represent 100 μM. N = 2 to 4 rats per time point.

Reprinted (with permission) from Lambert et al.
Figure 24. Figure 24.

Computer tomography (CT) scans of a 45‐year‐old man that collapsed from exertional heat stroke on a hot summer day. He was unconscious and hyperthermic (42°C) with convulsion at the time of hospital admission. The patient remained unconscious for 5 days. (A) Normal CT scan of the cerebellum 2 weeks following collapse (B) and (C). Progression of cerebellar atrophy from 10 weeks (B) to 11 months (C). Note that hypothalamic damage was not reported in this patient.

Reprinted (with permission) from Albukrek et al.
Figure 25. Figure 25.

Time course of core temperature (A; °C; radiotelemetry), metabolic rate (B; oxygen consumption, ), and respiratory exchange ratio (C; RER) of control and mild heat stroke mice during heat stroke and recovery in an indirect calorimeter. Time 0 represents the start of recovery following heat stroke collapse. Note that mice developed hypothermia immediately following collapse that was preceded by ∼35% reduction in . Despite reliance on fatty acid oxidation (RER∼0.7) during hypothermia, mice developed fever (∼1°C), which was associated with ∼20% increase in from 20 to 32 h of recovery. Note that hypothermia and fever were observed in heat‐stroked mice in the absence of histological damage (hematoxylin and eosin) to the preoptic area of the hypothalamus. Data are 1‐h averages. Black horizontal bars indicate lights‐off periods. *represents significant difference between heat stroke and control animals at P < 0.05.

Reprinted (with permission) from Leon et al.
Figure 26. Figure 26.

Mechanisms of disseminated intravascular coagulation (DIC). Heat injury to the vascular endothelium initiates the coagulation and fibrinolysis pathways. Excess fibrin deposition may lead to vascular thrombosis in the arterioles and capillaries and lead to occlusion of the blood supply to the organ bed. As coagulation proceeds, platelets and coagulation proteins are consumed at a faster rate than they are produced resulting in blood loss from multiple tissue sites (e.g., venipuncture wounds and gums). The combined effects of vessel occlusion and excess blood loss result in coagulopathies leading to multiorgan dysfunction.

Reprinted (with permission) from Leon and Helwig
Figure 27. Figure 27.

IL‐6 receptor signaling pathways. Classic signaling involves IL‐6 binding to the membrane‐bound IL‐6 receptor (IL‐6R), which stimulates an interaction between the IL‐6:IL‐6R complex and the membrane‐bound gp130 to initiate intracellular signaling. Transignaling occurs when the extracellular domain of the membrane‐bound IL‐6R is proteolytically cleaved to generate the soluble IL‐6R (sIL‐6R) that binds IL‐6. The IL‐6:sIL‐6R complex can stimulate cells that only express gp130 (i.e., do not normally possess the transmembrane IL‐6R) to transmit an intracellular signal. Cells that express gp130 only would not be able to respond to IL‐6 in the absence of the sIL‐6R.

Reprinted (with permission) from Leon and Kenefick
Figure 28. Figure 28.

Representative photomicrographs of histological damage (hematoxylin and eosin; 200×) to the kidney of a normothermic (A) and passively heat‐stroked mouse (core temperature = 42.7°C). (B) Arrows indicate identified tissue lesions which included renal tubular necrosis in the straight tubules of the kidney lower cortex. This was observed as shrunken, acidophilic, and fragmented epithelial cells with pyknotic nuclei. Renal damage was first detected at the time of heat stroke collapse with progressively greater damage from hypothermia to 24 h of recovery (time of fever).

Reprinted (with permission) from Leon et al.
Figure 29. Figure 29.

Fatty liver change observed in a heat‐stroked mice (right) ∼72 h following heat stroke collapse (core temperature = 42.7°C). Liver from a nonheated control (left) and heat stroke nonsurvivor (right) are shown.

Reprinted (with permission) from Leon
Figure 30. Figure 30.

Representative data showing that common clinical measures do not always accurately reflect the presence of peripheral organ damage. Core temperature (radiotelemetry; ±0.1°C) of male Fischer 344 rats was recorded at 1‐min intervals during 10 days of heat stroke recovery. On day 10, circulating levels of blood urea nitrogen (BUN), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were compared with gross morphology and histological damage (hematoxylin and eosin) to the kidney and liver. Representative core temperature tracings (top row), kidney pathology and BUN levels (middle row), and liver pathology, AST and ALT levels (bottom row) from one control (left panel) and two heat stroke rats (middle and right panel; core temperature = 42.0°C) are shown. Left panel: Nonheated control rat displayed a normal circadian core temperature profile through 10 days with low daytime (∼37°C) and high nighttime (∼38°C) values. The kidney and liver showed normal gross and histological appearance, and circulating levels of BUN, AST, and ALT were within the normal range. Middle panel: Following heat stroke collapse, profound hypothermia (∼34‐35°C) was observed through 5 days of recovery and then the animal re‐warmed to ∼37°C by day 10 of recovery, but failed to re‐establish a normal circadian rhythm. Gross appearance of the kidney and liver indicated damage, which was confirmed by histological analysis. The kidney showed bilateral renal tubular degeneration with protenuria and multifocal necrosis of hepatocytes was evident in the liver (indicated by black arrows in representative photomicrographs). High circulating BUN, AST, and ALT levels accurately reflected the extensive histological damage to these organs. Right panel: Following heat stroke collapse, hyperthermia (∼39°C) was observed through day 3 and then the animal re‐established a normal circadian core temperature profile through 10 days of recovery. Gross appearance of the kidney and liver suggested residual damage in these organs, which was confirmed histologically as bilateral mineralization and protenuria in the kidney and extramedullary hematopoiesis with mineralization of hepatocytes (indicated by black arrows in representative photomicrographs). Circulating levels of BUN, AST, and ALT levels were virtually identical to controls and did not accurately reflect the presence of organ damage in this animal. These data demonstrate that traditional clinical biomarkers of organ function lack specificity and sensitivity to detect damage in all animals following heat stroke collapse. Gray shading in core temperature graphs represents 12‐h lights‐off, active period. *Indicates values elevated above control.

Adapted (with permission) from Leon and Helwig
Figure 31. Figure 31.

Interpretation of Venn diagram for gene expression experiments.

Figure 32. Figure 32.

Gene expression responses to physical exercise, heat injury, and heat shock.



Figure 1.

Active (vastus medialis) and inactive (triceps brachii) muscle temperatures relative to core and mean skin temperature changes during exercise.

Reprinted (with permission) from Jay et al.


Figure 2.

Core (rectal and esophageal) temperature during rest and aerobic exercise in the heat.

Reprinted (with permission) from Sawka and Wenger


Figure 3.

Possible core temperatures steady‐state during aerobic exercise at metabolic rates of 200, 350, 500, and 1000 W at different environmental conditions.

Reprinted (with permission) from Sawka et al.


Figure 4.

Schematic diagram of the thermoregulatory control system. Tsk represents skin temperature and Tc represents core temperature.

Reprinted (with permission) from Sawka et al.


Figure 5.

Schematic diagram of thermoregulatory effector (e.g., sweating rate and skin blood flow) responses (forcing function analysis with linear plots) to: (A) increased load error (LE), (B) parallel shift in threshold temperature suggesting change in “set point,” and (C) slope or sensitivity changes suggesting peripheral modifications. LE, load error; D, decrease; and I, increase.

Reprinted (with permission) from Gisolfi and Wenger


Figure 6.

Differences between the elevation of core temperature in fever and during exercise.

Reprinted (with permission) from Sawka and Wenger ; redrawn (with permission) from Stitt and Gisolfi and Wenger


Figure 7.

Schematic description of the thermoregulatory control of skin blood flow as modified by moderately intense exercise.

Reprinted (with permission) from Gonzalez‐Alonso et al.


Figure 8.

Cardiovascular responses during sustained moderate intensity (70% ) exercise in temperate and hot conditions. BF, blood flow; PV, plasma volume; SV, stroke volume; CO, cardiac output; Tsk, skin temperature; Tes, esophageal temperature; and Ta, ambient temperature. Drawn (with permission) from data presented by Nadel et al. .



Figure 9.

The impact of high skin temperature on elevating heart rate during light‐intensity exercise.

Reprinted (with permission) from Cheuvront et al.


Figure 10.

The impact of graded exercise intensity on cardiovascular responses during hot (triangle) and temperate (circle) conditions.

Reprinted (with permission) from Rowell


Figure 11.

Nomogram examining the potential performance decrement (y‐axis) based on projected marathon finishing time (x‐axis) with increasing Wet Bulb Globe Temperature.

Reprinted (with permission) from Ely et al.


Figure 12.

Maximum aerobic power values for the pre‐ and postacclimation tests in both environments.

Reprinted (with permission) from Sawka et al.


Figure 13.

The percent decrement in time trial performance from euhydration at each skin temperature.

Reprinted (with permission) from Kenefick et al.


Figure 14.

A comparison of the benefits from an aerobic training program with a heat acclimation program on reducing physiological strain and improving performance during exercise‐heat stress.

Reprinted (with permission) from Sawka and Young . Original data adapted (with permission) from Cohen and Gisolfi


Figure 15.

Cardiorespiratory and performance changes as a percent change from the preacclimation trials in both environmental conditions.

Reprinted (with permission) from Lorenzo et al. . *P < .05 vs. the preacclimation trials in both environments


Figure 16.

(A) Comparison of baseline heat shock protein (HSP) values between day 1 and day 10 of heat acclimation (HA). (B) Quantification of Western blot analysis in densitometry units representing ratio of HSP:β‐tubulin. Values are means and standard deviation with correlation between post‐HA (day 10 vs. day 1) increase in HSP72 and HSP90 expression.

Reprinted (with permission) from McClung et al.


Figure 17.

Predictions of daily water requirements as function of daily energy expenditure and air temperature. Figure adapted (with permission) from Institute of Medicine .



Figure 18.

Predictions of daily sodium requirements as function of daily energy expenditure and air temperature. Figure adapted (with permission) from Institute of Medicine .



Figure 19.

Predicted body mass loss (due to water deficit; left panel) for two 70‐kg people of different body composition, running at 8.5 km·h−1 in temperate weather (18°C), and drinking water at three rates [400 ml·h−1 (solid line), 600 ml·h−1 (broken line), 800 ml·h−1 (broken dotted line)]. The yellow‐shaded areas indicate when water loss would be sufficient to modestly degrade performance, and when water loss would substantially degrade performance (red). Also predicted are plasma sodium concentrations for three rates sweat sodium loss. Two lines sharing the same line style are the predicted outcomes for people of two different body compositions; with total body water accounting for 50% and 63% (leaner) of body mass. The hatched shaded areas denote the presence of hyponatremia (plasma sodium concentration <130 mEq·liter−1) into the range where symptoms develop.



Figure 20.

Distribution of relative risk among male Marine Corps recruits and distribution of exertional heat stroke at Parris Island, SC, for years 1988 to 1992. High risk = body mass index (BMI) ≥22 kg·m−2, 1.5 mi run time ≥12 min; medium risk = BMI ≥26 kg·m−2, 1.5 mi run time <12 min or BMI <22 kg·m−2, 1.5 mi run time ≥12 min; low risk = BMI <26 kg·m−2, 1.5 mi run time <12 min. Adapted (with permission) from Gardner et al. .



Figure 21.

Core temperature of a male Marine Corp recruit during normal physical training and when incurring exertional heat stroke, conducted on two different days. Note the rapid development of hyperthermia on the day of heat stroke despite performing the same activity as the day that heat stroke was not observed. Wenger et al. (unpublished data).



Figure 22.

Summary of exertional heat stroke pathophysiological responses that culminate in multiorgan system failure. During exercise heat stress, there is an increase in cutaneous blood flow and decrease in splanchnic blood flow. Gut epithelial membrane ischemia induces oxidative and nitrosative stress that increases tight junction permeability and allows endotoxin to leak into the systemic and portal circulation. Toll‐like receptors (e.g., TLR4) detect pattern‐associated molecular patterns (PAMPs) on the cell membrane of endotoxin and stimulate pro‐ and anti‐inflammatory cytokine production. Heat is toxic to several organs and stimulates the secretion of heat shock proteins (HSPs) that interact with cytokines and other proteins to mediate the systemic inflammatory response syndrome of the host. A shift of the cytokine milieu from anti‐inflammatory (Th2) to a pro‐inflammatory (Th1) balance (a process known as anergy) is thought to mediate many of the adverse consequences of the heat stroke syndrome that lead to multiorgan system failure and death.



Figure 23.

Representative light micrographs of histological damage (hematoxylin and eosin stain) to inverted rat small‐intestinal sac tissue exposed to 41.5 to 42°C over a 60‐min time course. Villi appear normal at 15 min compared with the initial sloughing of epithelia from the villous tips at 30 min of exposure. At 45 min, there is significant lifting of villi epithelial linings at the top and sides, which is completed denuded by 60 min of exposure. Bars represent 100 μM. N = 2 to 4 rats per time point.

Reprinted (with permission) from Lambert et al.


Figure 24.

Computer tomography (CT) scans of a 45‐year‐old man that collapsed from exertional heat stroke on a hot summer day. He was unconscious and hyperthermic (42°C) with convulsion at the time of hospital admission. The patient remained unconscious for 5 days. (A) Normal CT scan of the cerebellum 2 weeks following collapse (B) and (C). Progression of cerebellar atrophy from 10 weeks (B) to 11 months (C). Note that hypothalamic damage was not reported in this patient.

Reprinted (with permission) from Albukrek et al.


Figure 25.

Time course of core temperature (A; °C; radiotelemetry), metabolic rate (B; oxygen consumption, ), and respiratory exchange ratio (C; RER) of control and mild heat stroke mice during heat stroke and recovery in an indirect calorimeter. Time 0 represents the start of recovery following heat stroke collapse. Note that mice developed hypothermia immediately following collapse that was preceded by ∼35% reduction in . Despite reliance on fatty acid oxidation (RER∼0.7) during hypothermia, mice developed fever (∼1°C), which was associated with ∼20% increase in from 20 to 32 h of recovery. Note that hypothermia and fever were observed in heat‐stroked mice in the absence of histological damage (hematoxylin and eosin) to the preoptic area of the hypothalamus. Data are 1‐h averages. Black horizontal bars indicate lights‐off periods. *represents significant difference between heat stroke and control animals at P < 0.05.

Reprinted (with permission) from Leon et al.


Figure 26.

Mechanisms of disseminated intravascular coagulation (DIC). Heat injury to the vascular endothelium initiates the coagulation and fibrinolysis pathways. Excess fibrin deposition may lead to vascular thrombosis in the arterioles and capillaries and lead to occlusion of the blood supply to the organ bed. As coagulation proceeds, platelets and coagulation proteins are consumed at a faster rate than they are produced resulting in blood loss from multiple tissue sites (e.g., venipuncture wounds and gums). The combined effects of vessel occlusion and excess blood loss result in coagulopathies leading to multiorgan dysfunction.

Reprinted (with permission) from Leon and Helwig


Figure 27.

IL‐6 receptor signaling pathways. Classic signaling involves IL‐6 binding to the membrane‐bound IL‐6 receptor (IL‐6R), which stimulates an interaction between the IL‐6:IL‐6R complex and the membrane‐bound gp130 to initiate intracellular signaling. Transignaling occurs when the extracellular domain of the membrane‐bound IL‐6R is proteolytically cleaved to generate the soluble IL‐6R (sIL‐6R) that binds IL‐6. The IL‐6:sIL‐6R complex can stimulate cells that only express gp130 (i.e., do not normally possess the transmembrane IL‐6R) to transmit an intracellular signal. Cells that express gp130 only would not be able to respond to IL‐6 in the absence of the sIL‐6R.

Reprinted (with permission) from Leon and Kenefick


Figure 28.

Representative photomicrographs of histological damage (hematoxylin and eosin; 200×) to the kidney of a normothermic (A) and passively heat‐stroked mouse (core temperature = 42.7°C). (B) Arrows indicate identified tissue lesions which included renal tubular necrosis in the straight tubules of the kidney lower cortex. This was observed as shrunken, acidophilic, and fragmented epithelial cells with pyknotic nuclei. Renal damage was first detected at the time of heat stroke collapse with progressively greater damage from hypothermia to 24 h of recovery (time of fever).

Reprinted (with permission) from Leon et al.


Figure 29.

Fatty liver change observed in a heat‐stroked mice (right) ∼72 h following heat stroke collapse (core temperature = 42.7°C). Liver from a nonheated control (left) and heat stroke nonsurvivor (right) are shown.

Reprinted (with permission) from Leon


Figure 30.

Representative data showing that common clinical measures do not always accurately reflect the presence of peripheral organ damage. Core temperature (radiotelemetry; ±0.1°C) of male Fischer 344 rats was recorded at 1‐min intervals during 10 days of heat stroke recovery. On day 10, circulating levels of blood urea nitrogen (BUN), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were compared with gross morphology and histological damage (hematoxylin and eosin) to the kidney and liver. Representative core temperature tracings (top row), kidney pathology and BUN levels (middle row), and liver pathology, AST and ALT levels (bottom row) from one control (left panel) and two heat stroke rats (middle and right panel; core temperature = 42.0°C) are shown. Left panel: Nonheated control rat displayed a normal circadian core temperature profile through 10 days with low daytime (∼37°C) and high nighttime (∼38°C) values. The kidney and liver showed normal gross and histological appearance, and circulating levels of BUN, AST, and ALT were within the normal range. Middle panel: Following heat stroke collapse, profound hypothermia (∼34‐35°C) was observed through 5 days of recovery and then the animal re‐warmed to ∼37°C by day 10 of recovery, but failed to re‐establish a normal circadian rhythm. Gross appearance of the kidney and liver indicated damage, which was confirmed by histological analysis. The kidney showed bilateral renal tubular degeneration with protenuria and multifocal necrosis of hepatocytes was evident in the liver (indicated by black arrows in representative photomicrographs). High circulating BUN, AST, and ALT levels accurately reflected the extensive histological damage to these organs. Right panel: Following heat stroke collapse, hyperthermia (∼39°C) was observed through day 3 and then the animal re‐established a normal circadian core temperature profile through 10 days of recovery. Gross appearance of the kidney and liver suggested residual damage in these organs, which was confirmed histologically as bilateral mineralization and protenuria in the kidney and extramedullary hematopoiesis with mineralization of hepatocytes (indicated by black arrows in representative photomicrographs). Circulating levels of BUN, AST, and ALT levels were virtually identical to controls and did not accurately reflect the presence of organ damage in this animal. These data demonstrate that traditional clinical biomarkers of organ function lack specificity and sensitivity to detect damage in all animals following heat stroke collapse. Gray shading in core temperature graphs represents 12‐h lights‐off, active period. *Indicates values elevated above control.

Adapted (with permission) from Leon and Helwig


Figure 31.

Interpretation of Venn diagram for gene expression experiments.



Figure 32.

Gene expression responses to physical exercise, heat injury, and heat shock.

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Michael N. Sawka, Lisa R. Leon, Scott J. Montain, Larry A. Sonna. Integrated Physiological Mechanisms of Exercise Performance, Adaptation, and Maladaptation to Heat Stress. Compr Physiol 2011, 1: 1883-1928. doi: 10.1002/cphy.c100082