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.
Though originally thought of as a metabolic waste product and fatigue agent, lactate can now be regarded as the link between glycolytic and aerobic pathways. From its discovery to more recent clinical applications, Brooks provides a comprehensive look at lactate metabolism and shuttling in both basic physiology and medicine.
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.
New directions in thermoresponsive polymers Roy, Debashish; Brooks, William L A; Sumerlin, Brent S
Chemical Society reviews,
01/2013, Letnik:
42, Številka:
17
Journal Article
Recenzirano
Interest in thermoresponsive polymers has steadily grown over many decades, and a great deal of work has been dedicated to developing temperature sensitive macromolecules that can be crafted into new ...smart materials. However, the overwhelming majority of previously reported temperature-responsive polymers are based on poly(N-isopropylacrylamide) (PNIPAM), despite the fact that a wide range of other thermoresponsive polymers have demonstrated similar promise for the preparation of adaptive materials. Herein, we aim to highlight recent results that involve thermoresponsive systems that have not yet been as fully considered. Many of these (co)polymers represent clear opportunities for advancements in emerging biomedical and materials fields due to their increased biocompatibility and tuneable response. By highlighting recent examples of newly developed thermoresponsive polymer systems, we hope to promote the development of new generations of smart materials.
Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product lactate is formed and utilized continuously in diverse cells under fully aerobic conditions. ...‘Cell–cell’ and ‘intracellular lactate shuttle’ concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signalling. Examples of the cell–cell shuttles include lactate exchanges between between white‐glycolytic and red‐oxidative fibres within a working muscle bed, and between working skeletal muscle and heart, brain, liver and kidneys. Examples of intracellular lactate shuttles include lactate uptake by mitochondria and pyruvate for lactate exchange in peroxisomes. Lactate for pyruvate exchanges affect cell redox state, and by itself lactate is a ROS generator. In vivo, lactate is a preferred substrate and high blood lactate levels down‐regulate the use of glucose and free fatty acids (FFA). As well, lactate binding may affect metabolic regulation, for instance binding to G‐protein receptors in adipocytes inhibiting lipolysis, and thus decreasing plasma FFA availability. In vitro lactate accumulation upregulates expression of MCT1 and genes coding for other components of the mitochondrial reticulum in skeletal muscle. The mitochondrial reticulum in muscle and mitochondrial networks in other aerobic tissues function to establish concentration and proton gradients necessary for cells with high mitochondrial densities to oxidize lactate. The presence of lactate shuttles gives rise to the realization that glycolytic and oxidative pathways should be viewed as linked, as opposed to alternative, processes, because lactate, the product of one pathway, is the substrate for the other.
Loot boxes are virtual goods in video games that produce randomly-generated in-game rewards, and have attracted scrutiny because of a resemblance to gambling. This study tests relationships between ...gaming involvement, engagement with loot boxes, and their associations with disordered gambling and gambling-related cognitions. Online questionnaires were completed by 144 adults via MTurk (Study 1) and 113 undergraduates (Study 2). Gaming and loot box-related variables included estimated time spent gaming and monthly expenditure, the Internet Gaming Disorder Scale (IGDS), and questions that assessed perceptions and behaviours related to loot boxes. Most participants thought loot boxes were a form of gambling (68.1% & 86.2%). A subset of items were condensed into a unidimensional “Risky Loot-box Index” (RLI) via exploratory factor analysis. In Study 1, the RLI showed significant associations with the Problem Gambling Severity Index (r = .491, p < .001) and the Gambling Related Cognitions Scale (r = .518, p < .001). Overall, gambling-related variables predicted 37.1% (p < .001) of the variance in RLI scores. Findings were replicated, though attenuated, in Study 2. These results demonstrate that besides the surface similarity of loot boxes to gambling, loot box engagement is correlated with gambling beliefs and problematic gambling behaviour in adult gamers.
•The majority of video game players are familiar with, and have used, Loot Boxes.•Most gamers agreed with the statement that Loot Box are a form of gambling.•Risky Loot Box use correlated moderately with gambling-related measures.•Gambling-related variables predicted 37.1% of the variance for risky Loot Box use.
As exercise intensity exceeds 65% of maximal oxygen uptake carbohydrate energy sources predominate. However, relative to the meager 4-5 g blood glucose pool size in a postabsorptive individual ...(0.9-1.0 g·L
× 5 L blood = 18-20 kcal), carbohydrate (CHO) oxidation rates of 20 kcal·min
can be sustained in a healthy and fit person for one hour, if not longer, all the while euglycemia is maintained. While glucose rate of appearance (i.e., production, Ra) from splanchnic sources in a postabsorptive person can rise 2-3 fold during exercise, working muscle and adipose tissue glucose uptake must be restricted while other energy substrates such as glycogen, lactate, and fatty acids are mobilized and utilized. If not for the use of alternative energy substrates hypoglycemia would occur in less than a minute during hard exercise because blood glucose disposal rate (Rd) could easily exceed glucose production (Ra) from hepatic glycogenolysis and gluconeogenesis. The goal of this paper is to present and discuss the integration of physiological, neuroendocrine, circulatory, and biochemical mechanisms necessary for maintenance of euglycemia during sustained hard physical exercise.
Increased muscle mitochondrial mass is characteristic of elite professional endurance athletes (PAs), whereas increased blood lactate levels (lactatemia) at the same absolute submaximal exercise ...intensities and decreased mitochondrial oxidative capacity are characteristics of individuals with low aerobic power. In contrast to PAs, patients with metabolic syndrome (MtS) are characterized by a decreased capacity to oxidize lipids and by early transition from fat to carbohydrate oxidation (FATox/CHOox), as well as elevated blood lactate concentration La
as exercise power output (PO) increases, a condition termed 'metabolic inflexibility'.
The aim of this study was to assess metabolic flexibility across populations with different metabolic characteristics.
We used indirect calorimetry and La
measurements to study the metabolic responses to exercise in PAs, moderately active individuals (MAs), and MtS individuals.
FATox was significantly higher in PAs than MAs and patients with MtS (p < 0.01), while La
was significantly lower in PAs compared with MAs and patients with MtS. FATox and La
were inversely correlated in all three groups (PA: r = -0.97, p < 0.01; MA: r = -0.98, p < 0.01; MtS: r = -0.92, p < 0.01). The correlation between FATox and La
for all data points corresponding to all populations studied was r = -0.76 (p < 0.01).
Blood lactate accumulation is negatively correlated with FATox and positively correlated with CHOox during exercise across populations with widely ranging metabolic capabilities. Because both lactate and fatty acids are mitochondrial substrates, we believe that measurements of La
and FATox rate during exercise provide an indirect method to assess metabolic flexibility and oxidative capacity across individuals of widely different metabolic capabilities.
The anaerobic threshold (AT) remains a widely recognized, and contentious, concept in exercise physiology and medicine. As conceived by Karlman Wasserman, the AT coalesced the increase of blood ...lactate concentration (La−), during a progressive exercise test, with an excess pulmonary carbon dioxide output (V̇CO2). Its principal tenets were: limiting oxygen (O2) delivery to exercising muscle→increased glycolysis, La− and H+ production→decreased muscle and blood pH→with increased H+ buffered by blood HCO3−→increased CO2 release from blood→increased V̇CO2 and pulmonary ventilation. This schema stimulated scientific scrutiny which challenged the fundamental premise that muscle anoxia was requisite for increased muscle and blood La−. It is now recognized that insufficient O2 is not the primary basis for lactataemia. Increased production and utilization of La− represent the response to increased glycolytic flux elicited by increasing work rate, and determine the oxygen uptake (V̇O2) at which La− accumulates in the arterial blood (the lactate threshold; LT). However, the threshold for a sustained non‐oxidative contribution to exercise energetics is the critical power, which occurs at a metabolic rate often far above the LT and separates heavy from very heavy/severe‐intensity exercise. Lactate is now appreciated as a crucial energy source, major gluconeogenic precursor and signalling molecule but there is no ipso facto evidence for muscle dysoxia or anoxia. Non‐invasive estimation of LT using the gas exchange threshold (non‐linear increase of V̇CO2 versus V̇O2) remains important in exercise training and in the clinic, but its conceptual basis should now be understood in light of lactate shuttle biology.
figure legend As originally posited and defended most ardently by Karlman Wasserman and Brian J. Whipp, the anaerobic threshold (AT) concept represents the epitome of integrative physiological control. The graph at the upper right portrays blood La−, arterial CO2 partial pressure (PCO2) and ventilation (V̇E) as a function of V̇O2 increasing from rest to maximum (V̇O2max). The AT is identified (black arrow) by the departure of V̇E from linearity without PCO2 decreasing. As shown rightwards from the ‘Original theory’ box, the AT held that lack of (or very low) muscle O2, via the Pasteur effect, increased muscle and blood lactic acid, then H+ dissociated from the lactic acid and was buffered by bicarbonate thus increasing CO2 evolution from the blood; this stimulated the ‘extra’ V̇E at AT simultaneous with the increase in La−. Currently we understand that neither anoxia nor dysoxia underpins increased muscle La− production and efflux, but rather its increase in the blood is attributed to the rate of La− appearance being greater than disappearance. Also, as long appreciated, the variability in, and complexities of, the control of breathing dictate that the V̇CO2 versus V̇O2 relation (gas exchange threshold) more reliably approximates the lactate threshold than does the ventilatory profile. At the bottom, the modern understanding of metabolism is that La− is a central element linking glycolysis (Gly) and oxidative phosphorylation (OxPhos) energetics. Via cell signalling, La− also plays roles in short‐ and long‐term adaptations in both health and disease.
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