Fasting promotes acute hypoxic adaptation by suppressing mTOR-mediated pathways

Rapid adaptation to a hypoxic environment is an unanswered question that we are committed to exploring. At present, there is no suitable strategy to achieve rapid hypoxic adaptation. Here, we demonstrate that fasting preconditioning for 72 h reduces tissue injuries and maintains cardiac function, consequently significantly improving the survival rates of rats under extreme hypoxia, and this strategy can be used for rapid hypoxic adaptation. Mechanistically, fasting reduces blood glucose and further suppresses tissue mTOR activity. On the one hand, fasting-induced mTOR inhibition reduces unnecessary ATP consumption and increases ATP reserves under acute hypoxia as a result of decreased protein synthesis and lipogenesis; on the other hand, fasting-induced mTOR inhibition improves mitochondrial oxygen utilization efficiency to ensure ATP production under acute hypoxia, which is due to the significant decrease in ROS generation induced by enhanced mitophagy. Our findings highlight the important role of mTOR in acute hypoxic adaptation, and targeted regulation of mTOR could be a new strategy to improve acute hypoxic tolerance in the body.

Exogenous ketosis increases blood and muscle oxygenation but not performance during exercise in hypoxia

Available evidence indicates that elevated blood ketones are associated with improved hypoxic tolerance in rodents. From this perspective, we hypothesized that exogenous ketosis by oral intake of the ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) may induce beneficial physiological effects during prolonged exercise in acute hypoxia. As we recently demonstrated KE to deplete blood bicarbonate, which per se may alter the physiological response to hypoxia, we evaluated the effect of KE both in the presence and absence of bicarbonate intake (BIC). Fourteen highly trained male cyclists performed a simulated cycling race (RACE) consisting of 3h intermittent cycling (IMT180') followed by a 15-min time-trial (TT15') and an all-out sprint at 175% of lactate threshold (SPRINT). During RACE, fraction of inspired oxygen (FiO2) was gradually decreased from 18.6 to 14.5%. Before and during RACE, participants received either i) 75g ketone ester (KE), ii) 300 mg/kg body mass bicarbonate (BIC), iii) KE+BIC or iv) a control drink in addition to 60g carbohydrates per h in a randomized, crossover design. KE counteracted the hypoxia-induced drop in blood (SpO2) and muscle oxygenation by ~3%. In contrast, BIC decreased SpO2 by ~2% without impacting muscle oxygenation. Performance during TT15' and SPRINT were similar between all conditions. In conclusion, KE slightly elevated the degree of blood and muscle oxygenation during prolonged exercise in moderate hypoxia without impacting exercise performance. Our data warrant to further investigate the potential of exogenous ketosis to improve muscular and cerebral oxygenation status, and exercise tolerance in extreme hypoxia.

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.

850 REM Sleep and ST Deviation in Acute Myocardial Infarction

Introduction Sleep stage architecture and amount of REM sleep have been associated with mortality and clinical recovery, without clear etiology. Patients recovering from critical illness frequently experience sleep disturbances, episodic arrhythmogenesis, EKG changes. This case aims to add to current field of study and describes an unusual pattern of sleep stage dependent, hypoxia independent, ST segment variation, which may benefit from further exploration and utilization of polysmongoraphy (PSG) in the immediate post acute MI period. Report of case(s) 46 year old female with history of smoking, obesity, and diabetes presented for a sleep medicine evaluation, four days following a hospitalization for non ST elevation myocardial infarction (NSTEMI) and percutaneous coronary intervention. Her split night PSG data revealed severe obstructive sleep apnea (OSA) with apnea hypopnia index (AHI) of 131. Patient did not report acute cardiac symptoms during overnight sleep evaluation. On close observation of PSG data, the patient had grossly evident baseline ST segment depression during wake period. The ST depression persisted through stages 1 and 2 with unchanged morphology. During Stage 3, the ST segment showed progressive elevation to near the isoelectric line. During REM sleep without positive airway pressure (PAP), ST segment was noted at or near isoelectric line, even in the setting of hypoxia with saturation (Sao2) of 75%. During REM Sleep with PAP, the ST segment remained at the isoelectric line, and returning to baseline depression during wake phase while on BiPAP. Conclusion Residual ST segment deviation, and its resolution, are strong predictors of prognosis in patients with MI. Prior studies focused on hypoxic tolerance and sleep disordered breathing, with limited attention on specific sleep stage evaluation. REM sleep has been described as potentially having restorative effect on ischemic myocardium. Additionally, the transition period from non REM to REM sleep was reported to provide potential for myocardial restoration. PSG with cardiac monitoring remains a unique tool in further assessment of a possible association. This case aims to bring attention to the potential association of EKG ST segment variation with sleep stages, especially REM and S3, independent of hypoxia. Support (if any):

Regulation of HIF-1α and p53 in stress responses in the subterranean rodents Lasiopodomys mandarinus and Lasiopodomys brandtii (Rodentia: Cricetidae)

The response mechanism and interaction patterns of HIF-1α and p53 in animals in an hypoxic environment are crucial for their hypoxic tolerance and adaptation. Many studies have shown that underground rodents have better hypoxic adaptation characteristics. However, the mechanism by which HIF-1α and p53 in underground rodents respond to hypoxic environments compared with in ground rodents remains unclear. Further, whether a synergy between HIF-1α and p53 enables animals tolerate extremely hypoxic environments is unclear. We studied HIF-1α and p53 expression in the brain tissue and cell apoptosis in the hippocampal CA1 region during 6 hours of acute hypoxia (5% oxygen) in Lasiopodomys mandarinus (Milne-Edwards, 1871) and Lasiopodomys brandtii (Radde, 1861), two closely related small rodents with different life characteristics (underground and aboveground, respectively), using a comparative biology method to determine the mechanisms underlying their adaptation to this environment. Our results indicate that HIF-1α and p53 expression is more rapid in L. mandarinus than in L. brandtii under acute hypoxic environments, resulting in a significant synergistic effect in L. mandarinus. Correlation analysis revealed that HIF-1α expression and the apoptotic index of the hippocampal CA1 regions of the brain tissues of L. mandarinus and L. brandtii, both under hypoxia, were significantly negatively and positively correlated, respectively. Long-term existence in underground burrow systems could enable better adaptation to hypoxia in L. mandarinus than in L. brandtii. We speculate that L. mandarinus can quickly eliminate resulting damage via the synergistic effect of p53 and HIF-1α in response to acute hypoxic environments, helping the organism quickly return to a normal state after the stress.

Quantitative Visualization of Hypoxia and Proliferation Gradients Within Histological Tissue Sections

The formation of hypoxic microenvironments within solid tumors is known to contribute to radiation resistance, chemotherapy resistance, immune suppression, increased metastasis, and an overall poor prognosis. It is therefore crucial to understand the spatial and molecular mechanisms that contribute to tumor hypoxia formation to improve the efficacy of radiation treatment, develop hypoxia-directed therapies, and increase patient survival. The objective of this study is to present a number of complementary novel methods for quantifying tumor hypoxia and proliferation, especially in relation to the location of perfused blood vessels.Multiplexed immunofluorescence staining can produce whole slide scanned image datasets that are amenable for computational pathology analysis. A standard marker analysis strategy is to take a positive pixel count approach, in which a threshold for positive stain is used to compute a positive area fraction for hypoxia. This work is a reassessment of that approach, utilizing not only cell segmentation but also distance to nearest blood vessel in order to incorporate spatial information into the analysis. We describe a reproducible pipeline for the visualization and quantitative analysis of hypoxia using a vessel distance analysis approach. This methodological pipeline can serve to further elucidate the relationship between vessel distance and microenvironment-linked markers such as hypoxia and proliferation, can help to quantify parameters relating to oxygen consumption and hypoxic tolerance in tissues, as well as potentially serve as a hypothesis generating tool for future studies testing hypoxia-linked markers.