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While diving, seals are exposed to apnea-induced hypoxemia and repetitive cycles of ischemia/reperfusion. While on land, seals experience sleep apnea, as well as prolonged periods of food and water deprivation. Prolonged fasting, sleep apnea, hypoxemia and ischemia/reperfusion increase oxidant production and oxidative stress in terrestrial mammals. In seals, however, neither prolonged fasting nor apnea-induced hypoxemia or ischemia/reperfusion increase systemic or local oxidative damage. The strategies seals evolved to cope with increased oxidant production are reviewed in the present manuscript. Among these strategies, high antioxidant capacity and the oxidant-mediated activation of hormetic responses against hypoxia and oxidative stress are discussed. In addition to expanding our knowledge of the evolution of antioxidant defenses and adaptive responses to oxidative stress, understanding the mechanisms that allow adapted mammals to avoid oxidative damage has the potential to advance our knowledge of oxidative stress-induced pathologies and to enhance the translative value of biomedical therapies in the long term.

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SUMMARYNorthern elephant seals experience prolonged periods of absolute food and water deprivation (fasting) while breeding, molting or weaning. The postweaning fast in elephant seals is characterized by increases in the renin-angiotensin system, expression of the oxidant-producing protein Nox4, and NADPH oxidase activity; however, these increases are not correlated with increased oxidative damage or inflammation. Glutathione (GSH) is a potent reductant and a cofactor for glutathione peroxidases (GPx), glutathione-S transferases (GST) and 1-cys peroxiredoxin (PrxVI) and thus contributes to the removal of hydroperoxides, preventing oxidative damage. The effects of prolonged food deprivation on the GSH system are not well described in mammals. To test our hypothesis that GSH biosynthesis increases with fasting in postweaned elephant seals, we measured circulating and muscle GSH content at the early and late phases of the postweaning fast in elephant seals along with the activity/protein content of glutamate-cysteine ligase [GCL; catalytic (GCLc) and modulatory (GCLm) subunits], -glutamyl transpeptidase (GGT), glutathione disulphide reductase (GR), glucose-6-phosphate dehydrogenase (G6PDH), GST and PrxVI, as well as plasma changes in -glutamyl amino acids, glutamate and glutamine. GSH increased two-to four-fold with fasting along with a 40-50% increase in the content of GCLm and GCLc, a 75% increase in GGT activity, a two-to 2.5-fold increase in GR, G6PDH and GST activities and a 30% increase in PrxVI content. Plasma -glutamyl glutamine, -glutamyl isoleucine and -glutamyl methionine also increased with fasting whereas glutamate and glutamine decreased. Results indicate that GSH biosynthesis increases with fasting and that GSH contributes to counteracting hydroperoxide production, preventing oxidative damage in fasting seals.

The development of heart rate and respiratory patterns related to sleep-associated apnea were studied in northern elephant seal (Mirounga angustirostris) pups and adult males. Heart rate patterns became more refined in conjunction with an age-related increase in apnea duration in pups. That is, older pups showed significant sinus arrhythmia, while breathing and apneic heart rate were both stable and similar in magnitude to the sinus arrhythmia minimum. By contrast, younger pups showed poor or nonexistent sinus arrhythmia and shorter apnea durations with a variable and/or high heart rate during apnea. Apnea duration was positively correlated with the development of sinus arrhythmia and negatively correlated with both eupneic and apneic heart rate. Adult males showed extremely well-developed patterns of sinus arrhythmia and, in all cases, the minimum heart rate during the sinus arrhythmia was lower than the average heart rate recorded during apnea. These results suggest that seal pups are not born with the cardiac control associated with voluntary long duration apnea, but that apnea tolerance increases with refined cardiorespiratory control.