Lactate as a fulcrum of metabolism.

Mistakenly thought to be the consequence of oxygen lack in contracting skeletal muscle we now know that the L-enantiomer of the lactate anion is formed under fully aerobic conditions and is utilized continuously in diverse cells, tissues, organs and at the whole-body level. By shuttling between producer (driver) and consumer (recipient) cells lactate fulfills at least three purposes: 1] a major energy source for mitochondrial respiration; 2] the major gluconeogenic precursor; and 3] a signaling molecule. Working by mass action, cell redox regulation, allosteric binding, and reprogramming of chromatin by lactylation of lysine residues on histones, lactate has major influences in energy substrate partitioning. The physiological range of tissue [lactate] is 0.5-20 mM and the cellular Lactate/Pyruvate ratio (L/P) can range from 10 to >500; these changes during exercise and other stress-strain responses dwarf other metabolic signals in magnitude and span. Hence, lactate dynamics have rapid and major short- and long-term effects on cell redox and other control systems. By inhibiting lipolysis in adipose via HCAR-1, and muscle mitochondrial fatty acid uptake via malonyl-CoA and CPT1, lactate controls energy substrate partitioning. Repeated lactate exposure from regular exercise results in major effects on the expression of regulatory enzymes of glycolysis and mitochondrial respiration. Lactate is the fulcrum of metabolic regulation in vivo

Energy Flux, Lactate Shuttling, Mitochondrial Dynamics, and Hypoxia.

Our understanding of what happens in working muscle and at the whole-body level at sea level and at high altitude is different from that a few years ago. If dietary CHO and nutrition are adequate, at sea level metabolism shifts from a mix of lipid and CHO-derived fuels toward carbohydrate (glycogen, glucose, and lactate) oxidation at moderate and greater exercise intensities. As given by the Crossover Concept, a percentage to total energy expenditure, lipid oxidation is greatest at exercise power outputs eliciting 45-50 % of VO2max with greater intensities requiring relatively more CHO and lesser lipid oxidation. At altitude, a given exercise power output is achieved at a greater relative intensity expressed as % VO2max. Hence, exercise under conditions of hypoxia requires greater glycolytic flux, and lactate production than does the same effort at sea level, normoxic conditions. Glycolytic flux is further augmented at altitude by the effect of hypoxemia on sympathetic nervous system activity. Hence, augmented lactate production during exercise is adaptive. Over the short term, accelerated lactate flux provides ATP supporting muscle contraction and balances cytosolic redox. As well, lactate provides and energy substrate and gluconeogenic precursor. Over a longer term, via redox and ROS-generating mechanisms, lactate may affect adaptations in mitochondrial biogenesis and solute (glucose and lactate) transport. While important, the energy substrate, gluconeogenic, and signaling qualities of lactate production and disposal at altitude need to be considered within the context of overall dietary energy intake and expenditure during exercise at sea level and high altitude

The Science and Translation of Lactate Shuttle Theory.

Once thought to be a waste product of anaerobic metabolism, lactate is now known to form continuously under aerobic conditions. Shuttling between producer and consumer cells fulfills at least three purposes for lactate: (1) a major energy source, (2) the major gluconeogenic precursor, and (3) a signaling molecule. "Lactate shuttle" (LS) concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signaling. In medicine, it has long been recognized that the elevation of blood lactate correlates with illness or injury severity. However, with lactate shuttle theory in mind, some clinicians are now appreciating lactatemia as a "strain" and not a "stress" biomarker. In fact, clinical studies are utilizing lactate to treat pro-inflammatory conditions and to deliver optimal fuel for working muscles in sports medicine. The above, as well as historic and recent studies of lactate metabolism and shuttling, are discussed in the following review

The tortuous path of lactate shuttle discovery: From cinders and boards to the lab and ICU.

Once thought to be a waste product of oxygen limited (anaerobic) metabolism, lactate is now known to form continuously under fully oxygenated (aerobic) conditions. Lactate shuttling between producer (driver) and consumer cells fulfills at least 3 purposes; lactate is: (1) a major energy source, (2) the major gluconeogenic precursor, and (3) a signaling molecule. The Lactate Shuttle theory is applicable to diverse fields such as sports nutrition and hydration, resuscitation from acidosis and Dengue, treatment of traumatic brain injury, maintenance of glycemia, reduction of inflammation, cardiac support in heart failure and following a myocardial infarction, and to improve cognition. Yet, dysregulated lactate shuttling disrupts metabolic flexibility, and worse, supports oncogenesis. Lactate production in cancer (the Warburg effect) is involved in all main sequela for carcinogenesis: angiogenesis, immune escape, cell migration, metastasis, and self-sufficient metabolism. The history of the tortuous path of discovery in lactate metabolism and shuttling was discussed in the 2019 American College of Sports Medicine Joseph B. Wolffe Lecture in Orlando, FL

Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells.

Lactate is a ubiquitous molecule in cancer. In this exploratory study, our aim was to test the hypothesis that lactate could function as an oncometabolite by evaluating whether lactate exposure modifies the expression of oncogenes, or genes encoding transcription factors, cell division, and cell proliferation in MCF7 cells, a human breast cancer cell line. Gene transcription was compared between MCF7 cells incubated in (a) glucose/glutamine-free media (control), (b) glucose-containing media to stimulate endogenous lactate production (replicating some of the original Warburg studies), and (c) glucose-containing media supplemented with L-lactate (10 and 20 mM). We found that both endogenous, glucose-derived lactate and exogenous, lactate supplementation significantly affected the transcription of key oncogenes (MYC, RAS, and PI3KCA), transcription factors (HIF1A and E2F1), tumor suppressors (BRCA1, BRCA2) as well as cell cycle and proliferation genes involved in breast cancer (AKT1, ATM, CCND1, CDK4, CDKN1A, CDK2B) (0.001 < p < 0.05 for all genes). Our findings support the hypothesis that lactate acts as an oncometabolite in MCF7 cells. Further research is necessary on other cell lines and biopsy cultures to show generality of the findings and reveal the mechanisms by which dysregulated lactate metabolism could act as an oncometabolite in carcinogenesis

Sample Size Considerations for Multiple Comparison Procedures in ANOVA

Adequate sample sizes for omnibus ANOVA tests do not necessarily provide sufficient statistical power for post hoc multiple comparisons typically performed following a significant omnibus F test. Results reported support a comparison-of-most-interest approach for sample size determination in ANOVA based on effect sizes for multiple comparisons

Assessment of alternative strategies for sludge disposal into deep ocean basins off Southern California

The general framework of engineering alternatives for regional ocean sludge disposal is well described in a report by Raksit, and will not be repeated here. The various ocean disposal alternatives are less costly than all land-disposal and incineration/pyrolysis systems studied. Even though ocean sludge disposal is currently contrary to both state and federal regulations, it is hoped that this study will advance our scientific and engineering knowledge of the behavior and effects of sludge discharge in deep water, in case the regulatory policy is reexamined in the future. With this report we hope we have demonstrated the potential and difficulties of some new modeling techniques for predicting the effects of sludge discharge in the ocean. In the future. we believe it will be possible to formulate policy of ocean sludge discharges with much better case-by-case predictions of impacts for comparison with other alternatives (such as land disposal). not only for the Los Angeles/Orange County areas, but for all coastal urban areas

Direct and indirect lactate oxidation in trained and untrained men.

Lactate has been shown to be an important oxidative fuel. We aimed to quantify the total lactate oxidation rate (Rox) and its direct vs. indirect (glucose that is gluconeogenically derived from lactate and subsequently oxidized) components (mg·kg(-1)·min(-1)) during rest and exercise in humans. We also investigated the effects of endurance training, exercise intensity, and blood lactate concentration ([lactate]b) on direct and indirect lactate oxidation. Six untrained (UT) and six trained (T) men completed 60 min of constant load exercise at power outputs corresponding to their lactate threshold (LT). T subjects completed two additional 60-min sessions of constant load exercise at 10% below the LT workload (LT-10%), one of which included a lactate clamp (LC; LT-10%+LC). Rox was higher at LT in T [22.7 ± 2.9, 75% peak oxygen consumption (Vo2peak)] compared with UT (13.4 ± 2.5, 68% Vo2peak, P < 0.05). Increasing [lactate]b (LT-10%+LC, 67% Vo2peak) significantly increased lactate Rox (27.9 ± 3.0) compared with its corresponding LT-10% control (15.9 ± 2.2, P < 0.05). Direct and indirect Rox increased significantly from rest to exercise, and their relative partitioning remained constant in all trials but differed between T and UT: direct oxidation comprised 75% of total lactate oxidation in UT and 90% in T, suggesting the presence of training-induced adaptations. Partitioning of total carbohydrate (CHO) use showed that subjects derived one-third of CHO energy from blood lactate, and exogenous lactate infusion increased lactate oxidation significantly, causing a glycogen-sparing effect in exercising muscle

Roles of estrogen receptor-alpha in mediating life span: the hypothalamic deregulation hypothesis.

In several species caloric restriction (CR) extends life span. In this paper we integrate data from studies on CR and other sources to articulate the hypothalamic deregulation hypothesis by which estrogen receptor-alpha (ER-α) signaling in the hypothalamus and limbic system affects life span under the stress of CR in mammals. ER-α is one of two principal estrogen-binding receptors differentially expressed in the amygdala, hippocampus, and several key hypothalamic nuclei: the arcuate nucleus (ARN), preoptic area (POA), ventromedial nucleus (VMN), antero ventral periventricular nucleus (AVPV), paraventricular nucleus (PVN), supraoptic nucleus (SON), and suprachiasmatic nucleus (SCN). Estradiol signaling via ER-α is essential in basal level functioning of reproductive cycle, sexually receptive behaviors, physiological stress responses, as well as sleep cycle, and other nonsexual behaviors. When an organism is placed under long-term CR, which introduces an external stress to this ER-α signaling, the reduction of ER-α expression is attenuated over time in the hypothalamus. This review paper seeks to characterize the downstream effects of ER-α in the hypothalamus and limbic system that affect normal endocrine functioning