Living Under Extreme Conditions

Physiology 29:386-387, 2014. doi:10.1152/physiol.00044.2014 You might find this additional info useful... This article cites 7 articles, 7 of which can be accessed free at: /content/29/6/386.full.html#ref-list-1

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Physiology (formerly published as News in Physiological Science) publishes brief review articles on major physiological developments. It is published bimonthly in January, March, May, July, September, and November by the American Physiological Society, 9650 Rockville Pike, Bethesda, MD 20814-3991. Copyright © 2014 by the American Physiological Society. ISSN: 1548-9213, ESSN: 1548-9221. Visit our website at

PHYSIOLOGY IN PERSPECTIVE Gary Sieck, Editor-in-Chief Mayo Clinic, Rochester, Minnesota

PHYSIOLOGY 29: 386 –387, 2014; doi:10.1152/physiol.00044.2014

Living Under Extreme Conditions


suffering from hypoxic insult secondary to numerous pathologies. Chronic mountain sickness (CMS) is a disease that affects many high-altitude dwellers, particularly in the Andean Mountains in South America. In contrast, other high-altitude populations (e.g., Tibetans and Ethiopians) are seemingly well adapted to hypoxia, and the prevalence of CMS is very low. The hallmark symptom of CMS is polycythemia, which causes increased risk of pulmonary hypertension and stroke. A prevailing hypothesis in highaltitude medicine is that CMS results from a population-specific “maladaptation” to the hypoxic conditions at high altitude. In recent years, concurrent with the advent of genomic technologies, several studies have investigated the genetic basis of adaptation to altitude. These studies have identified several candidate genes that may underlie the adaptation, or maladaptation. In their review (6), Ronen and colleagues discuss recent discoveries, alongside the methodologies used to obtain them, and outline some of the challenges remaining in the field. The fact that known drugs are already being used to target some candidate genes makes it likely that new treatments for CMS, heart attack, stroke, sickle cell disease, and other ischemic diseases can be identified through this research. Does it matter that rodents used as preclinical models of human biology are routinely housed below their thermoneutral zone? Although typical animalhouse temperature (21–22°C) is comfortable for humans working there, it is cold for laboratory rodents. In their review (4), Maloney et al. compile evidence showing that such rodents are cold stressed, hypermetabolic, hypertensive, sleep deprived, obesity resistant, fever resistant, aging resistant, and tumor prone compared with mice housed at thermoneutrality. The same genotype of mouse has a very different phenotype and response to physiological or pharmacological intervention when raised below or at thermoneutrality. Therefore, experiments done on cold rodents may lead to false predictions

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When asked why he endangered his life in repeated attempts to climb Mount Everest, George Mallory replied, “For the stone from the top for geologists, the knowledge of the limits of endurance for the doctors, but above all for the spirit of adventure to keep alive the soul of man.” Despite suffering mountain sickness, barely surviving avalanches, and finally before disappearing on the mountain in 1924, Mallory succinctly responded to the question why he continued his goal to climb Mount Everest: “Because it’s there.” Whether climbing the tallest mountains, diving the deepest oceans, trekking the hottest, driest desserts, or suffering the frigid cold of the Arctic or Antarctic, humans have always explored and met the challenges of extreme conditions. This adventure drives physiology, and it appears that there is nowhere on earth, and now beyond, where humans cannot live by adapting to their environment. In this issue of Physiology, we continue to explore physiological adaptations that allow us to live in and explore these extreme environments. Anecdotal evidence surrounding Tibetans’ and Sherpas’ exceptional tolerance to the low oxygen levels (hypoxia) associated with high altitude have been recorded since the beginning of highaltitude exploration. For hundreds of generations, indigenous high-altitude populations have successfully lived and reproduced with hypoxia as a constant evolutionary pressure. To tolerate sustained hypoxia, they are likely to have undergone natural selection to alter their DNA and physiology. In their review (2), Gilbert-Kawai and colleagues provide a comprehensive summary of the scientific literature encompassing Tibetan and Sherpa physiological adaptations to a high-altitude residence. A greater understanding of the mechanisms by which evolutionary pressure has refined the physiology of this high-altitude population could lead to new therapies with the potential to improve the care of thousands of hospitalized patients worldwide

about human physiology. By increasing awareness of the thermal neutral zone and the effects of housing temperature on rodent physiology, we hope to improve the translation of experimental results from rodents to humans. The marked increase in blood flow in contracting skeletal muscles and myocardium due to acute exercise is well documented. However, many important issues pertaining to perfusion and metabolism in brain, liver, pancreas, gut, bone, and adipose tissue remain to be elucidated. Although the state of general metabolism does not change substantially in nonmuscular tissues during acute exercise, it is nonetheless conceivable that the alterations in central (blood pressure that is transmitted to the periphery) and local (shear stress) hemodynamics, as well as changes in energy substrate and hormonal milieu, produce adaptations in these tissues. In their review (3), Heinonen and colleagues integrate current information on physiological responses to acute exercise and to long-term physical training in major metabolically active human organs, mostly based on state-ofthe-art, non-invasive human imaging studies. Further research in this area should enhance our understanding of the health benefits of exercise such as improved cognitive performance, anxiety relief, appetite control, and prevention of depression. Hundreds of thousands of persons are victims of traumatic peripheral nerve injuries in the U.S. each year. Despite the fact that axons in injured peripheral nerves can regenerate and reconnect with their targets, functional recovery in these people is poor. Fewer than 10% will ever regain full functionality. The slow and inefficient process of axon regeneration has been blamed for this poor functional outcome so that treatment approaches that promote better regeneration have been sought. One such treatment is exercise. Whether in the form of treadmill walking, swimming, or cycling, exercise after nerve injury results in striking improvements in axon regeneration. In their review (1), English et al. explore the fundamental cellular and molecular mechanisms underlying the effectiveness of exercise as a treatment for peripheral nerve injuries. Exercise prescriptions are complicated since they must be unique to the injured nerve, the desired regeneration of

tics are generated, thereby making networks that “work.” They discuss the necessity of a structure that provides short diffusion distances from capillaries to tissue and efficient distribution of convective blood flow in addition to angiogenesis to generate well organized functional networks. All vertebrates regulate the strength and rate of cardiac contraction by altering cellular Ca2⫹ flux in their myocytes. However, the source of Ca2⫹ and the mechanisms used to cycle it vary with species, developmental stage, and cardiac tissue. The sarcoplasmic reticulum (SR) is a specialized form of endoplasmic reticulum found in muscle cells that provides an intracellular reservoir of Ca2⫹. Most vertebrates including fish, amphibians, and reptiles do not rely on the SR for cycling Ca2⫹, but in those species that do rely on the SR, their cardiac function is elevated. Routine use of the SR allows birds and mammals to develop the cardiac pressures and cardiac frequencies necessary for life as an adult endotherm. In their review (7), Shiels and Galli discuss how SR recruitment relates to the structural organization of the cardiomyocyte to provide new insight into the evolution of cardiac design and function in vertebrates. Medical studies provide considerable evi-

dence that disruptions in SR function occur in the failing human heart. Understanding the structure and function of this membranous organelle, and its associated ion pumps and proteins, is crucial for understanding the evolution of the vertebrate heart and holds potential for new therapies in the management of numerous cardiac pathologies. 䡲

References 1.

English AW, Wilhelm JC, Ward PJ. Exercise, neurotrophins, and axon regeneration in the PNS. Physiology 29: 437– 445, 2014.


Gilbert-Kawai ET, Milledge JS, Grocott MPW, Martin DS. King of the mountains: Tibetan and Sherpa physiological adaptations for life at high altitude. Physiology 29: 388 – 402, 2014.


Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J. Organ-specific physiological responses to acute physical exercise and long-term training in humans. Physiology 29: 421– 436, 2014.


Maloney SK, Fuller A, Mitchell D, Gordon C, Overton JM. Translating animal model research: does it matter that our rodents are cold? Physiology 29: 413– 420, 2014.


Pries AR, Secomb TW. Making microvascular networks work: angiogenesis, remodeling, and pruning. Physiology 29: 446 – 455, 2014.


Ronen R, Zhou D, Bafna V, Haddad GG. The genetic basis of chronic mountain sickness. Physiology 29: 403– 412, 2014.


Shiels H, Galli G. The role of the sarcoplasmic reticulum in the evolution of the vertebrate heart. Physiology 29: 456 – 469, 2014.

PHYSIOLOGY • Volume 29 • November 2014 •


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different types of axons, and the developmental stage and genetic background of the patient. A greater understanding of the cellular mechanisms underlying these exercise therapies may lead to guidelines for translation to human patients. The circulatory system transports substances throughout the body by convection in flowing blood and diffusive exchange between blood and surrounding tissues. The basic physics of these processes imply stringent constraints on the structure of the blood vessel network so that it functions effectively and efficiently. The delivery of oxygen and other substrates by diffusion to tissues depends on the spatial arrangement of vessels, whereas the distribution of flow depends on the structure of the network. Abnormalities in the structure and function of the vessels play major roles in many diseases, including cancer, heart attacks, and strokes. In recent decades, efforts to understand the biological basis for the structure of the vessels have focused on angiogenesis, i.e., the formation of new blood vessels. In their review (5), Pries and Secomb draw on results from theoretical models for vessel adaptation and angiogenesis to address the question of how microvascular networks with adequate transport characteris-

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