Aspects of Thermal Tolerance and Exertional Heat Illness Susceptibility


Clinical symptoms (sepsis, septic shock)


Reports of EHS cases with clinical symptoms


qSOFA:

 

 Respiratory rate ≥22/min


[1, 3, 8, 13]


 Altered mentation


[1, 3, 8, 13, 16]


 Systolic blood pressure ≤100 mm hg


[8, 13, 16]


SOFA score >2 any of:

 

 Glasgow coma scale 10–12


[8, 13, 16]


 Creatinine 2.0–3.4 mg/dL or greater


[8, 13, 16]


 Urine output <500 mL/d


Dehydration [1]


 Bilirubin 2.0–5.9 mg/dL or greater


[8, 13]


Septic shock symptoms:

 

 Hypotension requiring vasopressors to maintain MAP ≥65 mmHG


[13]


 Serum lactate >2 mmol/L(18 mg/dL) despite adequate volume resuscitation


Normally elevated during exercise


[16]


 Disseminated intravascular coagulation


[13]




Endotoxemia is a damaging innate immune response caused by the presence of endotoxins such as LPS in the blood. LPS and other endogenous pyrogens are thought to raise the hypothalamic set point during exercise through the action of prostaglandin E2 [17]. Endotoxemia/sepsis and systemic inflammation are likely major contributors to pathophysiology of EHS [18].


LPS is normally present in the protected environment of the intestine. The intestinal barrier consists of the biological barrier, the physical barrier, and the immune barrier. The biological barrier consists of a normal functional intestinal microbiota (IM), which helps to regulate pathogenic bacteria by competition [19]. The microbiota assists the host in breaking down molecules and providing essential vitamins. The physical barrier consists of the intestinal mucus layer, the epithelial cells, and the tight junctions which prevent translocation of pathogenic bacteria [20] into the circulation. The immune barrier consists of gut-associated lymphoid tissue (GALT) and tissue-specific lymphocytes which interact with the IM to maintain a healthy balance [21].


Intestinal barrier dysfunction during exercise-heat stress can be caused by reduced intestinal blood flow [17] which may result in tissue hypoxia and acidosis [22], oxidative and nitrosative stress [23], and the intestinal inflammatory response [14], all of which may result in increased LPS passage [24]. Nonsteroidal anti-inflammatory drugs (NSAIDS) which are frequently used by athletes have been shown to increase GI permeability [17, 25]. A review by Armstrong discussed the evidence showing that the IM of athletes can be modified by exercise and diet which a following review addressed specific nutritional recommendation [2, 26]. The chronic low-grade inflammation in obesity has been [18] associated in some cases with the presence of low levels of circulating LPS termed “metabolic endotoxemia ” which supports the notion that diet and exercise induce beneficial adaptations in the gut [27]. Illness caused by infection with pathogenic bacteria has deleterious effects on intestinal epithelial barrier function not limited to diarrhea [28]. Chronic diseases such as inflammatory bowel disease are characterized by intestinal epithelial barrier dysfunction [29]. Given that the intestinal barrier is affected by so many factors related to metabolism, diet, and exercise, one could speculate that EHS patients may experience intestinal barrier damage due to diverse, individual factors.


Intestinal ischemia due to exercise and elevated T c cause a breakdown of the gut barrier resulting in a “leaky gut” allowing toxins and bacteria to pass into the bloodstream. Exercise-induced hypoxia and other stress cause the breakdown of tight junctions and an inflammatory immune response [20]. The bulk of pathogens released into circulation are recognized and taken up by Kupffer cells in the healthy liver [2]. If the influx of pathogens overwhelms the filtering capacity of the liver, immune-activating substances such as LPS , lipoteichoic acid, lipopeptide, peptidoglycan, flagella, and bacterial DNA/RNA pass into the bloodstream [30] where they initiate a systemic innate immune response.


Once in systemic circulation, LPS, other pathogen-associated molecular patterns (PAMPs) , or danger-associated molecular patterns (DAMPs) that may be increased by exercise [31, 32] are recognized by toll-like receptor 4 (TLR4) found on the surface of white blood cell membranes, specifically macrophages and monocytes [2, 33]. TLR4 binds LPS with the cooperation of LPS-binding protein (LBP), CD14, and myeloid differentiation protein-2 (MD-2) [30, 33]. After LPS binding, the TLR4/MD-2 complex stimulates two canonical pathways through TRIF and MyD88 that result in activation of transcription factors IRF3, NF-κB, and AP-1, which all increase production of inflammatory molecules including TNFα, IL-1β, and IL-18 [30]. The TRIF pathway specifically results in the release of type 1 interferons (IFN) which have a role in activating the cellular caspase recognition system and further redundant, inflammatory pathways [33].


In animal and cell culture models, administering agonists for multiple TLRs (enhancing TLR activity, including TLR2, −3, −4) during hyperthermia/fever (39.5 °C) increased pathogenesis of sepsis [34, 35]. More detailed mechanistic studies demonstrate that exposure to febrile-range temperatures of ~40 °C physically affects recruitment of LPS-induced transcription factors to different cytokines that are critical to inflammation (TNF-α and IL-1β) [36, 37]. Increasing TLR4 activity or LPS concentrations and inducing endotoxemia/sepsis appear to magnify the pathophysiological effects of exposure to febrile temperatures. This may be by modulation of inflammatory gene expression during hyperthermia/fever. The direct mechanistic links between endotoxemia and sepsis speak to the molecular and cellular impact that these pathways likely have in EHS if circulating LPS is increased during exercise in the heat and extremely so in some patients who develop EHS.


However, endotoxemia and sepsis do not entirely explain EHS susceptibility and pathophysiology; LPS-induced TLR4 signaling is only one partial aspect of the molecular mechanisms. This is demonstrated by experiments showing that a TLR4 blocker, eritoran, was not effective in clinical trials for sepsis treatment. These experiments resulted in the discovery of a noncanonical inflammasome pathway which may also be involved in LPS-induced inflammatory pathophysiology. In this pathway, cytosolic LPS recognition is mediated by direct binding to caspase-11 in mice and − 4/5 in humans [38, 39]. What immunologists understand and contribute to our understanding of immune system physiology in EHS is multifold (Fig. 8.1):


  1. 1.

    LPS is one of many ligands that directly bind to TLR4 to promote inflammation and sepsis inducing inflammatory pathways.


     

  2. 2.

    Other ligands that can stimulate TLR4 that are unstudied in EHS pathophysiology research include endogenous molecules that are important to exercise-heat stress responses.


     

  3. 3.

    Other bacterial components leaked from the gut during exercise-heat stress may stimulate TLR signaling.


     

  4. 4.

    TLR2 also contributes, by MyD88 signaling, to the production of inflammatory cytokines and is capable of binding ligands associated with cellular exercise-heat stress responses.


     

  5. 5.

    TLR4 signals by at least one noncanonical pro-inflammatory pathway that is yet unstudied in EHS animal models and patients.


     

  6. 6.

    Febrile temperatures.


     

  7. 7.

    Likely other context-dependent situations (e.g., sleep deprivation, endocrine dysfunction) affect the TLR4-dependent gene expression of specific cytokines. The signaling that links LPS in systemic circulation to pathophysiology associated with sepsis and perhaps heat stroke is likely complicated, involving multiple positive feedback mechanisms of inflammation and innate immune response that have yet been unstudied in EHS, specifically.


     

../images/471692_1_En_8_Chapter/471692_1_En_8_Fig1_HTML.png

Fig. 8.1

Sepsis and inflammation resulting from endotoxemia and exercise-heat stress-induced signaling are likely highly complex. LPS (lipopolysaccharide ) and specific LPS structural variants, pathogen-associated molecular patterns (PAMPs) from other bacterial components, danger-associated molecular patterns (DAMPs) that include endogenous heat shock proteins and lipoproteins, and other ligands directly bind TLR4 (toll-like receptor 4) during exercise, heat exposure, oxidative stress, and tissue damage to promote gene expression of multiple pro-inflammatory proteins. Other receptors such as TLR2, enzymes that can directly bind LPS, like caspase, and other potential noncanonical mechanisms funnel into multiple transcription factors to increase pro-inflammatory gene expression. The pro-inflammatory mediators themselves, including cytokines and heat shock proteins, may feedback positively to augment the entire signaling. Under normal, healthy conditions, an individual is able to recover from this acute systemic inflammation, but with a combination of other exacerbating factors, inflammation goes unchecked and resulting tissue damage and sepsis may contribute to EHS pathophysiology. Damage to specific organs like the brain and kidneys results in clinical manifestations associated with EHS above and beyond increases in core temperature


Cellular Heat Shock Response


In addition to inflammatory cytokine gene expression resulting from immune responses during heat stress and EHS, heat-inducible heat shock protein (Hsp72) of the 70 kilodalton (kD) family (Hsp70) is expressed. Hsp72 is critical to the cellular heat shock response [40] but has different roles intracellularly versus extracellularly [41], though much remains unknown about the diverse functions of Hsp70 family members. Hsp72 is regulated by many factors, including TLR4 signaling, and this is powerfully demonstrated by the increases in expression of Hsp70 (estimate of Hsp72) in mice challenged with both hyperthermia and LPS (vs. either treatment alone) [34, 35]. The presence of Hsp72, through transcription factor known as NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), positively feeds back and increases inflammatory cytokine gene expression through TLR4 as shown in clinical inflammatory conditions (not EHS) [42, 43]. In TLR4 null mutants, the effects of Hsp72 on cytokine expression, such as that of interleukin 8 (IL-8), are reduced [42], supporting the notion that the cellular Hsp response and TLR4 signaling are directly linked to promote inflammation during clinical conditions and perhaps during EHS.


Hsp treatment [44], transgenic expression of porcine Hsp70 [45] (i.e., Hsp72), overexpression of Hsp72 [46], and exercise preconditioning to induce Hsp72 [47] have all been shown to reduce symptoms and severity of EHS. Well-controlled animal work has demonstrated that genotypes associated with Hsp70/72 may be linked to thermal tolerance [4850], but very little has demonstrated that Hsp72 genotypes are linked to Malignant Hyperthermia (MH) or EHS susceptibility. We speculate that although Hsp72 has such a critical role in the molecular mechanisms of heat stress response and EHS, it is difficult to associate genotypically with the condition because of its fundamental, diverse, and pleiotropic roles in physiology.


Pharmacological Treatments Reveal Pathophysiological Molecular Mechanisms


Much remains unknown about non-sepsis-related molecular/cellular contributors to EHS susceptibility and pathophysiology. Studies of pharmacological agents used to treat symptoms or severity of heat stroke are revealing. For example, despite evidence that glucocorticoid (dexamethasone ) treatment in baboons does not protect and may exacerbate heat stroke [51], promising evidence suggests that glucocorticoid administration helps reduce symptom heat stroke lethality, symptom severity, and recovery time [5254]. It is not clear whether the anti-inflammatory effects of glucocorticoids or another mechanism is involved in this endocrine factor in heat stroke pathophysiology. Additionally, whether these treatments are translatable to pre- or posttreatment of EHS is not clear from the current literature base.


Similarly, melatonin , a multifunctional, potential antioxidant treatment, appears to reduce lung damage [55] and brain damage [56] in animal models of heat stroke. Two key reviews have determined that multiple pharmacological agents with antioxidant, stem cell, anti-inflammatory, endocrine, and antihypertensive functions were effective in reducing hypothalamic damage during heat stroke [5, 57].


These studies indicate possible pathways to explore for molecular mechanisms of EHS development. Genotypes associated with variants in proteins associated with these pathways are not associated clearly with susceptibility to EHS or thermal intolerance. In many cases, identifying genotypes in these pathways may be difficult to relate to heat stroke susceptibility because of the fundamental and pleiotropic roles of many of these molecular factors. At the protein/molecular level, these can be targeted with pharmacological treatments, and additional research on genotypes clearly associated with EHS risk may be complimentary to such therapy options.


Genotypes Associated with Risk for EHI and EHS


Malignant Hyperthermia (MH) and EHS Share Genotype-Associated Susceptibility


A remarkable case study presented identical twins who experienced exertional heat stroke during the same race in which there were ~14 EHS cases among 38,000 competitors [58]; that there is a genetic link to thermal tolerance and EHS susceptibility is clear, although the nature of that link remains undefined. Heritable genetic variants associated with anesthetic-triggered hyperthermia, metabolic disturbances, and altered hematology are among those considered to be related to increased risk for exertional heat stroke (EHS) (Table 8.2). Among these genetic variants include those relevant to malignant hyperthermia (MH), a skeletal muscle disorder [59]. Malignant hyperthermia is associated with most commonly (>70% of cases) [60] a heterozygous mutation in the gene coding for the ryanodine receptor RYR1, a calcium channel in the membrane of the sarcoplasmic reticulum, which is responsible for the release of calcium during muscle contractions [61]. Inappropriately timed releases of calcium from intermuscular calcium stores can occur in susceptible individuals as a result of exposure to anesthetic agents or muscle relaxants such as succinylcholine [62]. MH susceptibility is tested functionally by an in vitro contracture test (IVCT) , a highly invasive procedure that exposes muscle fibers to halothane and caffeine to measure a response [62, 63]. The subsequent contraction of the muscle results in muscle rigidity, large increases in the production of metabolic heat leading to hyperthermia, metabolic and respiratory acidosis, and rhabdomyolysis. The test is 97–99% sensitive and 78–94% specific [64, 65].


Table 8.2

Genes associated with variants that reduce exercise and thermal tolerance and likely increase exertional heat stroke (EHS) susceptibility





























































































Disease


Affected gene


Gene location


Effect


Malignant hyperthermia


RYR1


Ryanodine receptor 1, skeletal muscle sarcoplasmic metabolism


19q13.2


Increase in intramuscular calcium in response to anesthetic agents


CACNA1S


Alpha-1 subunit, L-type voltage-gated calcium channel


1q32.1


Increase in intramuscular calcium in response to a depolarizing stimulus

 

SCN4A


Alpha subunit, type 4 voltage-gated sodium channel


17q


Typically associated with hyperkalemic paralysis, MH susceptibility

 

CACNA2D1, non-coding region


Alpha-2 subunit, L-type voltage-gated calcium channel


7q21-q22


Affects RYR1 function at triadic junctions, increases intramuscular calcium

 

CASQ1


Calsequestrin 1, Ca2+ binding protein


1q23.2


Main Ca2+ buffer of the sarcoplasmic reticulum of cardiac and skeletal muscle

 

TRPV1


Transient receptor potential cation channel subfamily V, member 1


17p13.2


Nonselective cation channel activated by noxious stimuli to central nervous system (pain, temperature)


Catecholaminergic ventricular tachycardia


RYR2


Ryanodine receptor 2, cardiac muscle sarcoplasmic reticulum

 

Increase in intramuscular calcium, resulting in tachycardia and cardiac dysfunction


Sickle cell trait


HBB


Hemoglobin beta-chain


11p15.4


Polymerization of hemoglobin β-chains


Carnitine palmitoyltransferase II deficiency


CPTII


Carnitine palmitoyltransferase II, inner membrane of mitochondria


1p32.3


Inability to bring fatty acids into mitochondria for beta-oxidation


Very long-chain acetyl-CoA dehydrogenase deficiency


VLCAD


Very long-chain acetyl-CoA dehydrogenase, helps catalyze beta-oxidation


17p13.1


Very long-chain fatty acid beta-oxidation is decreased


McArdle disease


PYGM


Muscle glycogen phosphorylase


11q13.1


Inability to breakdown muscle glycogen


Glycogen storage disease VII


PFKM


Muscle phosphofructokinase, a regulatory enzyme required for glycolysis


12q13.11


Impaired glycolysis, resulting in exertional myopathy, muscle cramping, myoglobinuria


Glycogen storage disease XI


LDHA


Lactate dehydrogenase A


11p15.1


Decreased interconversion of lactate and pyruvate. Results in low exercise tolerance and myoglobinuria


Among individuals with genetic susceptibility to MH, there are those who appear to be at risk also for what is termed “awake” or nonanesthetic malignant hyperthermia that was defined early on as porcine stress syndrome in the 1960s and linked to human conditions [66, 67]. More than 50 years later, EHS links to MH have been more specifically defined with terminology such as “MH-like syndrome” to address possible variations of the syndromes [59]. Novel variants or presence of two mutations on different alleles [68] may decrease the thermal tolerance of an individual to environmental conditions, exercise, infection, and any drugs that affect heat balance. Data confirm the likelihood of relationships between MH-related genotypes and exertional heat stroke or sensitivity to exercise-heat stress. Strenuous treadmill running induces hyperthermia and rhabdomyolysis in mice with altered RYR1 genes [65]. Researchers have performed diagnostic contracture tests on individuals who have collapsed with EHS [69], observing that up to 45.6% of EHS survivors were positive for an in vitro contracture test, indicating MH susceptibility [63]. Multiple case reports have described cases in which individuals who suffer from an exertional heat stroke respond positively to an IVCT [10, 11]. Wappler et al. identified 10 out of 12 patients presenting with EHS symptoms to also be MH-susceptible. Three of these ten had candidate ryr1 variants [70]]. Bendahan et al. diagnosed 26 with EHS and all of them were positive for an IVCT test [71].


A dysfunctional RYR1 variant confirms a diagnosis of MH in conjunction to an IVCT, but MHS (malignant hyperthermia susceptibility) is genetically heterogeneous [69]. Genetic variants other than those associated with RYR1 are associated with different forms of MH and thus perhaps with EHI/EHS susceptibility. Among MH cases not associated with RYR1 variants, ~1% [60] (MH5) are associated with defects in the CACNA1S gene. CACNA1S encodes the alpha-1 subunit of an L-type voltage-gated calcium channel in skeletal muscle that responds to a depolarizing stimulus [61, 72]. Another calcium channel gene associated with MH, CACNA2D1 [73, 74], encodes the subunit of a calcium channel in the skeletal muscle that is associated with RYR1 at triadic junctions. These and other genetic variants associated with less common types of malignant hyperthermia (MH2–6) exhibit clinical manifestations that may be related to thermal intolerance and risk for exertional heat complications, but no consistent and direct link has been found between many of these variants and risk for EHS or thermal intolerance in exercise-heat stress settings. Studies of MH and EHI/EHS patients have revealed isolated cases of individuals positive for mutations in CACNA1S and CACNA2D1 [75, 76].


Other proteins such as calsequestrin-1 (CASQ1) have also been explored as candidate genes for MH and EHS susceptibility [77, 78]. CASQ1 encodes a protein that regulates RYR1-mediated calcium release. In 2009, researchers [77] created a CASQ1 knockout model in mice and observed that these mice had increased susceptibility to and spontaneous mortality during halothane anesthetic administration and heat stress. CASQ1 null mice experienced hyperthermia and rhabdomyolysis during heat stress and were successfully treated if administered with dantrolene, a drug that is known to reduce RyR1 calcium release and is used to treat malignant hyperthermia. In a study of 75 MH-susceptible (MHS) individuals diagnosed by positive IVCT, clinicians and researchers determined that a CASQ1 variant (c.260 T > C) was present in 6 heterozygous individuals also carrying an MH-causative mutation in RYR1; further analysis of 130 additional patients with MH susceptibility (positive IVCT and causative RYR1 mutation) revealed 9 additional heterozygous individuals for the CASQ1 variant. However, based on analysis of additional MHS and MHS-negative samples, researchers determined that the CASQ1 variant they observed was not likely to be a major MHS locus in the North American population [79]. Other investigators [78] have identified additional CASQ1 variants that appear to be linked to heat stroke patients in populations outside North America and further identified other possible genetic links to heat intolerance and heat stroke susceptibility and pathophysiology.


Gene variants associated with additional MHS classifications have not been as well-studied with respect to EHS susceptibility, but they are considered candidate genes to explore in the future. MHS2 is a form of malignant hyperthermia that stems from a mutation on the gene coding for the voltage-gated sodium channel SCNA4 on chromosome 17q [80, 81]. Problems with this channel typically result in hyperkalemic periodic paralysis, but Olckers et al. [81] felt there was enough evidence to link mutations in the SCNA4 gene to malignant hyperthermia susceptibility. MHS4 was determined to exist in a single German family by Sudbrak et al. (1995). They linked markers defining a 1-cM interval on chromosome 3q13.1. They confirmed the MH phenotype via an in vitro contracture test [82]. MHS6 was discovered in 1997 by Robinson et al. A genome-wide search of a Belgian family with MH revealed linkage to a region on chromosome 5p. Robinson et al. concluded their study by suggesting that there is at least one more MHS locus [72].


Novel genes not yet associated with specific MH subtypes also are interesting candidates to consider in EHS susceptibility. One recent target is the TRPV1 (transient receptor potential vanilloid 1) nonselective cation channel which is responsible for sensing noxious stimuli in the nervous system. This receptor which is capable of detecting temperature, pain, and other stimuli can vary among individuals and appears to be affected by the hypermetabolic state in MH. One comprehensive study in 2018 [83] identified that TRPV1 is activated by anesthetics in cell culture models of MH. More compelling are their findings that of 28 MH patients, 2 unrelated patients possessed rare genetic TRPV1 variants; transfection of these variants into cell culture affected calcium signaling and response to anesthetic-induced events in vitro/in situ. Treatment of animal models of heat stroke with GSK2193874, a TRPV4 channel, was not prophylactically effective but was effective in reducing heat stroke-related injury when administered at the onset of heat stroke [84]. Physiological, tissue-level, biomarker, and lethality outcomes were improved with the administration of this drug [84], contributing to the evidence that this may also be a novel MHS genotype that can be further explored in future EHS research. There are likely other heritable factors that contribute to different classifications of MH and may be associated with EHS but much remains unknown in this area.


Non-MH Related Heritability Is Associated with Exercise-Heat Intolerance


Data linking MH and EHI/EHS are compelling. Less understood is how genotypes associated with other clinical conditions are related to high incidence of intolerance to exercise-heat stress. For example, mutations in gene coding for RYR2, a ryanodine receptor found in cardiac muscle, can lead to sudden, exercise-induced death (catecholaminergic ventricular tachycardia). There are two proposed mechanisms. The first is that a decreased concentration of channel stabilizing protein calstabin-2, which binds and stabilizes the “closed” state of RYR2, causes a calcium leak into the cardiac tissue, triggering cardiac arrhythmias. The second mechanism purports that during exercise, RYR2 is phosphorylated by PKA, causing dissociation of the binding protein FKBP12.6. In patients with stress-induced polymorphic ventricular tachycardia, mutations in the genes coding for RYR2 resulted in a decrease in affinity for FKBP12.6. Similar to the first mechanism, this dissociation causes an increase in intercellular calcium, resulting in cardiac dysfunction [85].


Another example of a heritable condition increasing susceptibility to exercise-heat stress is sickle cell trait/disease. Individuals with sickle cell trait (SCT) are already at a greater risk of exercise-induced death illness given the nature of the disease. Exertional sickling can be compounded by high heat, humidity, and dehydration, coupled with intense bouts of exercise in which blood oxygen is reduced [85].


SCT is no longer considered a result of one genetic mutation but rather a combination of multiple genotypes that determine the severity of an individual’s disease [86, 87]. Hemoglobin, the oxygen-carrying protein in red blood cells, comprises two α and two β-subunits. Fetal hemoglobin contains γ-subunits instead of β-subunits. Sickle cell hemoglobin (HbS) is monogenetically inherited and is common across all phenotypes. A single nucleotide substitution occurs on chromosome 11p15.5 and results in hydrophobic valine replacing hydrophilic glutamic acid in the β-subunit of hemoglobin (Hb), denoted as βS [88]. This mutation can interact with other β-subunit mutations to produce varying severities of sickle cell disease. Other genotypes can influence sickle cell aggregation to the endothelial cells, the degree of sickling, and the concentration of fetal hemoglobin. Homozygotes for βS, which lead to a condition known as sickle cell anemia (HbSS) , demonstrate the most severe phenotype, which manifests almost identically to another genotype, heterozygous HbS/β0 thalassemia. β0 thalassemia is a condition in which no β-subunits are produced. HbS/β+ thalassemia is a heterozygotic disease in which β-subunits are produced, but in lower amounts, and phenotypically is much less severe [89]. Individuals with HbS combined with a hereditary persistence of fetal Hb demonstrate a mild phenotype or are symptom-free [87, 88].


Healthy erythrocytes have a high degree of deformability, allowing them to traverse small arterioles and capillaries. In individuals with sickle cell trait, stress (e.g., low oxygen, dehydrated, high temperature, low pH) induces HbS polymerization and erythrocyte sickling [87]. Sickled red blood cells [26, 27] become trapped resulting in vaso-occlusion and reduced blood flow to tissues including skeletal muscle. Other events compounding this include adhesion of erythrocytes to the epithelium and the binding of leukocytes to the sickled cells [27]. The presence of epinephrine can also exacerbate the adhesion of sickled cells [88]. Local inflammatory responses continue to aggravate the adhesion and the binding of immune cells, and the local hypoxic environment caused by the vaso-occlusion contributes to further sickling of cells. This causes a positive feedback loop that ultimately results in the “metabolic failure” of exercising muscle [87].


The risk of death from exertional sickling is greatly elevated in both athletes and military personnel [90, 91]. Most reported cases of exertional collapse associated with sickle cell trait (ECAST) occur during preseason training, or after return from injury. Other musculoskeletal stresses, especially those which have been shown to lead to exertional rhabdomyolysis (ER) , can decrease the “threshold” required for a severe ECAST [92].


Of note, while many case studies examine exertional sickling, rhabdomyolysis, and exertional heat stroke during the football preseason when athletes are exposed to hot and humid environmental conditions in an unacclimatized state, high temperatures are not a prerequisite for exertional sickling. Individuals will often have an ECAST episode early enough during the exercise without core body temperature reaching pathologically high levels. Thus, patients lack the elevated core temperature found in EHS patients and do not have impaired CNS function [92, 93]. It is thought that leading cause of exertional sickling is exercise intensity [93]. The link between SCT and EHS genetic susceptibilities is thus not entirely clear, though data linking SCT and EHI/EHS is suggestive, both in military and athlete populations [9496].


Metabolic Disturbances Likely Reduce Tolerance to Exercise-Heat Stress


Rhabdomyolysis is a condition during which striated muscle, typically skeletal muscle, breaks down due to high mechanical and metabolic stress. The consequent release of the muscle contents can lead to myoglobinuria, acute kidney injuries, acute compartment syndrome, and, in extreme cases, arrhythmias and death [97]. Exertional rhabdomyolysis (ER) is a pathological condition where muscle breakdown occurs after a bout of exercise. In most cases, ER occurs as a result of excessive, prolonged, or repeated eccentric exercises [97, 98]. Individuals with a low baseline fitness level or low heat tolerance are also at risk for ER [29]. There are several inherited skeletal muscle metabolic disorders that increase the risk of developing ER as a result of intense exercise.


Carnitine palmitoyltransferase (CPT) II is an enzyme located on the inner mitochondrial membrane that catalyzes the formation of fatty acyl co-A. The CPT system facilitates long-chain fatty acid transport into the mitochondria. Mutations in the gene coding for CPT II can cause deficiency of the enzyme, though the degree of disease caused by CPT II deficiency is variable [32]. Nonfatal forms of the disease are characterized by exercise-induced muscle pain, rhabdomyolysis, and myoglobinuria [99]. A Japanese study [100] of 24 heat stroke (non-exertional) patients revealed a common CPTII variant (F352C) in 11 patients that was associated with greater JAAM DIC diagnostic criteria score and SOFA indicating greater coagulopathy and organ dysfunction that was associated with double mean hospital stays (21.5 ± 23.0 vs. 9.5 ± 13.2 days). All other aspects of acute illness including body temperature, albumin, and creatine kinase, were similar between those with F352C variant and control patients.


Very long-chain acetyl-CoA dehydrogenase deficiency (VLCAD) is an inherited metabolic disease of fatty acid beta-oxidation. Clinically, VLCAD deficiency manifests in one of three ways: (1) early onset, which is very severe and has a high mortality rate, (2) childhood onset with intermediate severity and a more favorable outcome, and (3) adult onset, which is usually characterized by rhabdomyolysis and myoglobinuria after exercise [101]. The disease is the result of a homozygous mutation in the gene coding for very long-chain acyl-CoA dehydrogenase on chromosome 17p13 [101]. Other common inherited fatty acid metabolic disorders leading to rhabdomyolysis are medium-chain acyl-CoA dehydrogenase (MCAD) and trifunctional enzyme deficiency [102, 103].


McArdle disease , or glycogen storage deficiency V is another heritable metabolic disease that increases susceptibility to rhabdomyolysis. GSD5 is caused by a homozygous mutation in the genes coding for muscle glycogen phosphorylase, at chromosome 11q13 [104]. Affected individuals are unable to mobilize muscle glycogen stores [105]. During exercise, patients experience muscle cramps, weakness, and myalgia [35]. Transient episodes of myoglobinuria can occur as a result of rhabdomyolysis, and severe myoglobinuria can lead to kidney failure [104, 106].


Other forms of glycogen storage deficiencies can lead to an increased risk of exertional myopathies. GSD7 is an autosomal recessive disorder and comes from a mutation on chromosome 12q13, the gene coding for muscle phosphofructokinase (PFK) [106]. Symptoms include muscle cramping, exercise intolerance, and exertional myopathies such as a rhabdomyolysis. In severe cases, myoglobinuria occurs as a result of muscle damage. Unique to GSD7 are a partial loss of muscle PFK and partial loss of red cell PFK activity [107]. GSD11 is caused by a mutation in the gene coding for muscle lactate dehydrogenase (LDHM), on chromosome 11p15. As with other glycogen storage deficiencies, patients complain of exercise intolerance and myoglobinuria. GSD11 has been documented only in the Japanese populations, thus far, and is relatively rare [108]. In many cases, glycogen storage deficiencies are mild, and many patients do not seek medical attention [107].


The link between rhabdomyolysis and exertional heat stroke is complex though the conditions often occur concurrently due to MOD and specifically muscle tissue damage often seen in EHS. However, individuals with genetic predisposition to rhabdomyolysis and other muscle disorders often present exercise intolerance as a symptom, due to factors like ineffective fatty acid metabolism and issues related to glycogen storage and use. This could limit the ability of an athlete to exercise effectively in the hot conditions.


Summary and Conclusions


Current understanding is limited regarding genetic predispositions for EHI/EHS. Known mechanisms of cellular/molecular mechanisms of thermal tolerance have given scientists and clinicians an indication of where to look for potential factors in EHS susceptibility, but thermoregulation, cellular/molecular thermal tolerance, and EHS pathophysiology are all independently complex with some, and to what degree, unknown overlap. For example, Hsp72 is known to be critical for cellular recovery from heat stress and cytoprotection from subsequent heat insults. However, on a whole-body level, although Hsp72 is elevated in response to exercise-heat stress, there is little evidence that Hsp72 treatment clinically would prevent or treat EHS. Researchers and clinicians should acknowledge that it is improbable that manipulating a single cytoprotective molecule will prevent a systemic EHS event in every individual. In considering the biological importance of Hsp72, much additional research should be done to explore either genetic knockout/knockdown models, individual Hsp72 variants, pharmacological treatments with Hsp72, and expression of Hsp72, in human studies and ideally in EHS patients. To truly pursue discovery of molecular and cellular mechanisms that might have practical application in EHS treatment and prevention, scientists and clinicians must collaborate in a multidisciplinary fashion. Clearly defining mechanisms that contribute to thermal tolerance while concurrently exploring ways to manipulate those mechanisms in a practically meaningful way for clinicians will support forward progress in the field.


  1. 1.

    Cellular and whole-body thermal tolerance should be considered separately and differently when seeking markers for EHS susceptibility. Not all cellular stress responses are detectable systemically, and often, as in the case of Hsp72, intracellular and extracellular forms of the protein have different physiological roles and consequences.

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Nov 7, 2020 | Posted by in SPORT MEDICINE | Comments Off on Aspects of Thermal Tolerance and Exertional Heat Illness Susceptibility
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