Can L‐glutamine augmented heat shock protein 70 expression prevent exercise‐induced exertional heat stroke and sudden cardiac death?

Dear Editor‐in‐Chief, Glutamine has been shown to protect cells, tissues, and whole organ‐ isms from stress and injury.1 This protection has largely been thought to be related to augmented expression of 70‐kDa heat shock protein (Hsp70). Hsp70 is expressed in normal cells and can be enhanced by environmental stresses (eg, heat, and hypoxia) and pathophysiologi‐ cal states (eg, inflammation, ischemia). Hsp70 acts in chaperoning the folding, aggregation, or degradation of other proteins and functions in maintaining the metabolic and structural integrity of the cell, as a protective response to external stresses. Much work has been done in recent years to explore the therapeutic role of Hsp70 expression in several types of diseases, including Alzheimer's disease, heart dis‐ ease, stroke, and cancer. Briefly, Hsp70 exerts the cytoprotective properties through its capacity of tissue protection, preservation of tissue metabolic function in stress states, and anti‐inflammatory and antioxidant regulation.2 Despite well‐studied mechanisms related to the stress response in clinical settings, the investigation of Hsp70 applications in health and disease remains limited because the ex‐ pression is usually subject to external stimuli. Recent advances using pharmacologic supplementation of glutamine3 shed new light in this regard and may offer a viable option for potentiating Hsp70 response prior to, and following, stressors (eg, hyperthermia, and cardiac strain) in humans in a controlled and efficient manner.

properties through its capacity of tissue protection, preservation of tissue metabolic function in stress states, and anti-inflammatory and antioxidant regulation. 2 Despite well-studied mechanisms related to the stress response in clinical settings, the investigation of Hsp70 applications in health and disease remains limited because the expression is usually subject to external stimuli. Recent advances using pharmacologic supplementation of glutamine 3 shed new light in this regard and may offer a viable option for potentiating Hsp70 response prior to, and following, stressors (eg, hyperthermia, and cardiac strain) in humans in a controlled and efficient manner.

| MODE OF AC TI ON
Of great interests regarding the protective effects of the Hsp70 is its role in the development of heatstroke and myocardial ischemia.
First, Hsp70 expression functions as cryoprotectants during hyperthermia and heatstroke. 4 Hsp70 is well known to provide cells with elevated thermal resistance, which is critical for the survival of most living organisms that are exposed to extreme temperatures. During heat stress, Hsp70 provides cells with time to repair damage and prevents necrosis. It has been suggested that the relative resistance to heatstroke in the canine heatstroke model is related to the upregulation of Hsp70. 4 Its protective role in the pathophysiology of hyperthermia and heatstroke is unequivocal.
Second, Hsp70 overexpression protects against lethal injuries such as myocardial infarction. Data have shown that an infarcted heart has a lower production capacity of Hsp70 and consequently, this reduction in the expression of Hsp70 leads to the further decrease in contractile function during subsequent development of myocardial infarction. 2 Conversely, Hsp70 overexpression modulates the process of intracellular repair by reducing heart necrosis in coronary heart disease and thereby provides a significant reduction in the infarcted area as well as improved postischemic contractile recovery. Current evidences suggest that Hsp70 exhibits a protective effect in heart and brain tissue against repeated ischemic injury.
Third, glutamine, in part dependent on Hsp70 expression, is a powerful anti-oxidant, antiinflammatory, and pharmacologic agent that regulates immune response at a number of different levels. 1 Hsp70-mediated anti-inflammation action has been noted to attenuate nuclear factor NF-κB and inhibitor factor IκBα signaling pathways. Hsp70 also interacts with the activation of the stress kinase pathway. This inhibitory effect could attenuate tumor necrosis factor-α, interleukin-6, and interleukin-18 expression after sepsis, thereby fulfilling various cellular-level anti-inflammatory and stressinduced functions. Remarkably, inflammation plays a pivotal role in the development of cardiovascular disease. In this regard, the mechanisms of Hsp70 expression in antioxidation and anti-inflammation underscore an important implication for a therapeutic role of L-glutamine in cardiovascular disease.
Given the importance of Hsp70 in a range of cytoprotective and immunomodulatory cascade reactions, insightful examination of the physiological and immunological role of Hsp70 is warranted, as this will facilitate the development of optimal approaches for reducing morbidity and mortality in heat susceptible soldiers, firefighters, and athletes. In this regard, the therapeutic potential of modulating Hsp70 expression via L-glutamine supplementation is of particular interest.

| TARG E TED PRE VENTI ON
Extreme high temperature is one of the most important environmental stresses experienced by soldiers, firefighters, and athletes.  Not surprisingly, it is well known that firefighting is associated with acute myocardial ischemia and sudden cardiac death, which is the leading cause of duty-related fatalities among US firefighters. 6 In general, soldiers, firefighters, and athletes are at increased risks of exertional heatstroke and sudden cardiac death due to obligations of strenuous exercise under high ambient temperatures.
Novel strategies supplementing the current methods should be explored as potential preventive measures and post-incident medical care against these lethal injuries. Additionally, there are other unanswered questions about the practical utility of L-glutamine. An important consideration that must be addressed is drug safety. Short-term supplementation of glutamine appears to be safe; however, there are no clear data regarding the long-term safety. Prior work has revealed that critically ill patients with multiorgan failure had paradoxically higher mortality rates when treated with a combination of IV and enteral glutamine (0.35 g/kg/day and 30 g/day, respectively). 12 Notably, low glutamine levels have been detected in critically ill patients, which in turn completely inhibit Hsp70 expression thereby damaging monocytes during hyperthermia. 13 Nevertheless, the overall efficacy of L-glutamine supplementation in occupational and athletic settings most certainly warrants exploration. L-glutamine augmented Hsp70 expression is established science.

| FUTURE OF L-G LUTAMINE AUG MENTED H S P70 E XPRE SS I ON
Indeed, more than a decade ago it was reported that glutamine supplementation enhanced Hsp70 expression and improved survival following hyperthermia. 14 The clinical benefit of L-glutamine revealed by Luo and colleagues 3 appears to be promising and opens up translationally unexamined research possibilities. Practically speaking, L-glutamine can be prescribed in IV administration, and more conveniently, it can be taken orally and available in over-thecounter formulation. The functional role of L-glutamine in exercise physiology and exercise immunology is currently in its infancy, thus, published primary data regarding the drug efficacy and safety will first be needed for L-glutamine to gain common acceptance by the clinical community and practitioners. Taken collectively, we envision L-glutamine may constitute the first pharmacological candidate to mitigate specific risks of medical complications for soldiers, firefighters, and athletes undergoing heat exposure.