Altered Glucose Kinetics Occurs With Aging, A New Outlook on Metabolic Flexibility.

Our purpose was to determine how age affects metabolic flexibility and underlying glucose kinetics in healthy young and older adults. Therefore, glucose and lactate tracers, along with pulmonary gas exchange data were used to determine glucose kinetics and respiratory exchange ratios (RER=CO2/O2) during a 2-hour 75-gram oral glucose tolerance test (OGTT). After an 12-hour overnight fast, 28 participants, 15 young (21-35 yr.; 7 men and 8 women) and 13 older (60-80 yr.; 7 men and 6 women) received venous primed-continuous infusions of [6,6-2H]glucose, and [3-13C]lactate with a H13CO3- bolus. Following a 90-minute metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. Arterialized glucose concentrations ([glucose]) started to rise 15 minutes post-glucose consumption, peaked at 60 minutes, and remained elevated. As assessed by rates of appearance (Ra), disposal (Rd) and metabolic clearance (MCR) glucose kinetics were suppressed in older compared to young individuals. As well, unlike in young individuals, fractional gluconeogenesis (fGNG) remained elevated in the older population following the oral glucose challenge. Lastly, there were no differences in 12-hr fasting baseline or peak RER values following an oral glucose challenge in older compared to young men and women, making RER an incomplete measure of metabolic flexibility in the volunteers we evaluated. Our study revealed that glucose kinetics are significantly altered in a healthy aged population following a glucose challenge. Further, those physiological deficits are not detected from changes in RER during an OGTT.

Enteric and systemic postprandial lactate shuttle phases and dietary carbohydrate carbon flow in humans.

Dietary glucose in excess is stored in the liver in the form of glycogen. As opposed to direct conversion of glucose into glycogen, the hypothesis of the postprandial lactate shuttle (PLS) proposes that dietary glucose uptake is metabolized to lactate in the gut, thereby being transferred to the liver for glycogen storage. In the present study, we provide evidence of a PLS in young healthy men and women. Overnight fasted participants underwent an oral glucose tolerance test, and arterialized lactate concentration and rate of appearance were determined. The concentration of lactate in the blood rose before the concentration of glucose, thus providing evidence of an enteric PLS. Secondary increments in the concentration of lactate in the blood and its rate of appearance coincided with those of glucose, which indicates the presence of a larger, secondary, systemic PLS phase driven by hepatic glucose release. The present study challenges the notion that lactate production is the result of hypoxia in skeletal muscles, because our work indicates that glycolysis proceeds to lactate in fully aerobic tissues and dietary carbohydrate is processed via lactate shuttling. Our study proposes that, in humans, lactate is a major vehicle for carbohydrate carbon distribution and metabolism.

Underfeeding Alters Brain Tissue Synthesis Rate in a Rat Brain Injury Model.

Brain injuries (BI) are highly disruptive, often having long lasting effects. Inadequate standard of care (SOC) energy support in the hospital leads to dietary energy deficiencies in BI patients. However, it is unclear how underfeeding (UF) affects protein synthesis post-BI. Therefore, in a rat model, we addressed the issue of UF on the protein fractional synthesis rate (fSR) post-BI. Compared to ad libitum (AL)-fed animals, we found that UF decreased protein synthesis in hind-limb skeletal muscle and cortical mitochondrial and structural proteins (p ≤ 0.05). BI significantly increased protein synthesis in the left and right cortices (p ≤ 0.05), but suppressed protein synthesis in the cerebellum (p ≤ 0.05) as compared to non-injured sham animals. Compared to underfeeding alone, UF in conjunction with BI (UF+BI) caused increased protein synthesis rates in mitochondrial, cytosolic, and whole-tissue proteins of the cortical brain regions. The increased rates of protein synthesis found in the UF+BI group were mitigated by AL feeding, demonstrating that caloric adequacy alleviates the effects of BI on protein dynamics in cortical and cerebellar brain regions. This research provides evidence that underfeeding has a negative impact on brain healing post-BI and that protein reserves in uninjured tissues are mobilized to support cortical tissue repair following BI.

Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism.

No longer viewed as a metabolic waste product and cause of muscle fatigue, a contemporary view incorporates the roles of lactate in metabolism, sensing and signaling in normal as well as pathophysiological conditions. Lactate exists in millimolar concentrations in muscle, blood, and other tissues and can rise more than an order of magnitude as the result of increased production and clearance limitations. Lactate exerts its powerful driver-like influence by mass action, redox change, allosteric binding, and other mechanisms described in this article. Depending on the condition, such as during rest and exercise, following carbohydrate nutrition, injury, or pathology, lactate can serve as a myokine or exerkine with autocrine-, paracrine-, and endocrine-like functions that have important basic and translational implications. For instance, lactate signaling is: involved in reproductive biology, fueling the heart, muscle adaptation, and brain executive function, growth and development, and a treatment for inflammatory conditions. Lactate also works with many other mechanisms and factors in controlling cardiac output and pulmonary ventilation during exercise. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic ß-cell membranes is not suppressed, and in carcinogenesis when factors that suppress carcinogenesis are inhibited, whereas factors that promote carcinogenesis are upregulated. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, neurobiology, gut physiology, appetite regulation, nutrition, and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.NEW & NOTEWORTHY Lactate sensing and signaling is a relatively new and rapidly changing field. As a physiological signal lactate works both independently and in concert with other signals. Lactate operates via covalent binding and canonical signaling, redox change, and lactylation of DNA. Lactate can also serve as an element of feedback loops in cardiopulmonary regulation. From conception through aging lactate is not the only a myokine or exerkine, but it certainly deserves consideration as a physiological signal.

Fractional Gluconeogenesis: A Biomarker of Dietary Energy Adequacy in a Rat Brain Injury Model.

Patients treated for traumatic brain injury (TBI) are in metabolic crises because of the trauma and underfeeding. We utilized fractional gluconeogenesis (fGNG) to assess nutritional adequacy in ad libitum-fed and calorically-restricted rats following TBI. Male Sprague-Dawley individually housed rats 49 days of age were randomly assigned into four groups: ad libitum (AL) fed control (AL-Con, sham), AL plus TBI (AL+TBI), caloric restriction (CR) control (CR-Con, sham), and CR plus TBI (CR+TBI). From days 1-7 animals were given AL access to food and water containing 6% deuterium oxide (D2O). On day 8, a pre-intervention blood sample was drawn from each animal, and TBI, sham injury, and CR protocols were initiated. On day 22, the animals were euthanized, and blood was collected to measure fGNG. Pre-intervention, there was no significant difference in fGNG among groups (p ≥ 0.05). There was a significant increase in fGNG due to caloric restriction, independent of TBI (p ≤ 0.05). In addition, fGNG may provide a real-time, personalized biomarker for assessing patient dietary caloric needs.

Tracing the lactate shuttle to the mitochondrial reticulum.

Isotope tracer infusion studies employing lactate, glucose, glycerol, and fatty acid isotope tracers were central to the deduction and demonstration of the Lactate Shuttle at the whole-body level. In concert with the ability to perform tissue metabolite concentration measurements, as well as determinations of unidirectional and net metabolite exchanges by means of arterial-venous difference (a-v) and blood flow measurements across tissue beds including skeletal muscle, the heart and the brain, lactate shuttling within organs and tissues was made evident. From an extensive body of work on men and women, resting or exercising, before or after endurance training, at sea level or high altitude, we now know that Organ-Organ, Cell-Cell, and Intracellular Lactate Shuttles operate continuously. By means of lactate shuttling, fuel-energy substrates can be exchanged between producer (driver) cells, such as those in skeletal muscle, and consumer (recipient) cells, such as those in the brain, heart, muscle, liver and kidneys. Within tissues, lactate can be exchanged between white and red fibers within a muscle bed and between astrocytes and neurons in the brain. Within cells, lactate can be exchanged between the cytosol and mitochondria and between the cytosol and peroxisomes. Lactate shuttling between driver and recipient cells depends on concentration gradients created by the mitochondrial respiratory apparatus in recipient cells for oxidative disposal of lactate.

Lactate in contemporary biology: a phoenix risen.

After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology.

The blood lactate/pyruvate equilibrium affair.

The Lactate Shuttle hypothesis is supported by a variety of techniques including mass spectrometry analytics following infusion of carbon-labeled isotopic tracers. However, there has been controversy over whether lactate tracers measure lactate (L) or pyruvate (P) turnover. Here, we review the analytical errors, use of inappropriate tissue and animal models, failure to consider L and P pool sizes in modeling results, inappropriate tracer and blood sampling sites, and failure to anticipate roles of heart and lung parenchyma on L⇔P interactions. With support from magnetic resonance spectroscopy (MRS) and immunocytochemistry, we conclude that carbon-labeled lactate tracers can be used to quantitate lactate fluxes.

Post-Exercise Recovery Following 30-Day Supplementation of Trans-Resveratrol and Polyphenol-Enriched Extracts.

BACKGROUND: The purpose of this study was to investigate the effects of 30-day consumption of trans-resveratrol and polyphenol-enriched extracts on indices of exercise-induced muscle damage (EIMD) and performance following eccentric-loaded resistance exercise (ECRE). METHODS: Following 30 days of resveratrol-polyphenol (RES) (n = 10) or placebo control (CTL) (n = 12) supplementation, subjects performed a bout of ECRE to induce EIMD. EIMD biomarkers, perceived soreness, pain threshold and tolerance, range of motion, and performance were measured before and 24 and 48 h after ECRE. RESULTS: CTL subjects demonstrated increased soreness at 24 (p = 0.02) and 48 h (p = 0.03) post-ECRE, while RES subjects reported increased soreness at 24 h post-ECRE (p = 0.0003). CTL subjects exhibited decreased pain threshold in the vastus lateralis at 24 h post-ECRE (p = 0.03). CTL subjects also displayed decreased pain tolerance in the vastus intermedius at 24 h post-ECRE (p = 0.03) and the vastus lateralis at 24 (p = 0.003) and 48 h (p = 0.003). RES participants showed no change in pain threshold or tolerance from baseline. CTL subjects showed a decrease in mean (p = 0.04) and peak power (p = 0.04) at 24 h post-ECRE, while RES participants demonstrated no changes from baseline. No between-group differences were observed for the changes in serum creatine kinase. Serum C-reactive protein increased similarly in both groups at 24 h post-ECRE (p < 0.002), remaining elevated in CTL subjects while RES participants demonstrated a decline from 24 to 48 h (p = 0.04). Serum interleukin 6 increased at 24 h post-ECRE in both groups (p < 0.003) followed by a decrease from 24 to 48 h, returning to baseline levels only for RES subjects. CONCLUSION: Trans-resveratrol and polyphenol-enriched extract supplementation may support the attenuation of soreness and inflammation and improve performance recovery following ECRE without modulation of indirect biomarkers of EIMD.

The Effects of a Multi-Ingredient Performance Supplement Combined with Resistance Training on Exercise Volume, Muscular Strength, and Body Composition.

The effects of a multi-ingredient performance supplement (MIPS) incorporating a mixture of branched chain amino acids, beta-alanine, glutamine, creatine, and piperine on resistance training (RT)-induced adaptations remains unclear. Therefore, the purpose of this study was to investigate the effects of this investigational MIPS during six weeks of RT on performance and body composition. Thirty recreationally trained males and females were recruited for this pair-matched, double-blind, placebo-controlled investigation. Subjects were assigned to consume either an experimental MIPS (MIPS) (n = 15) or a placebo (PLA) (n = 15) concurrently with a six-week periodized RT program. Body composition, one-repetition maximum (1RM), and muscular power were assessed at pre- and post-training. Weekly relative volume load was compared between groups. The MIPS and PLA groups demonstrated a significant increase in total body mass (MIPS = +2.9 ± 1.3%; PLA = +2.5 ± 1.7%) and lean mass (MIPS = +5.0 ± 2.1%; PLA = +3.1 ± 1.9%) (p < 0.001) with no changes in fat mass. There were no group × time interactions for any of the body composition measures. Both groups demonstrated similar improvements in maximum strength for the back squat, bench press, and deadlift as well as lower body power from pre- to post-training (p < 0.001). Within the limitations of the current investigation, results failed to demonstrate the benefits of the experimental MIPS for muscular strength and body composition across six weeks of RT compared to PLA.

The Effects of Leucine-Enriched Branched-Chain Amino Acid Supplementation on Recovery After High-Intensity Resistance Exercise.

CONTEXT: Of the 3 branched-chain amino acids (BCAA), leucine has arguably received the most attribution for the role of BCAA supplementation in alleviating symptoms of exercise-induced muscle damage and facilitation of acute performance recovery. PURPOSE: To examine whether enrichment of a standard BCAA supplement with additional leucine or a standalone leucine (LEU) supplement differentially affects exercise-induced muscle damage and performance recovery compared with a standard BCAA supplement. METHODS: A total of 22 recreationally active male and female subjects were recruited and assigned to consume a BCAA, leucine-enriched BCAA (LBCAA), or LEU supplement for 11 d. On the eighth day, subjects performed eccentric-based resistance exercise (ECRE). Lower-body mean average and peak power, plasma creatine kinase, soreness, and pain threshold were measured before and 24, 48, and 72 h after ECRE. RESULTS: LEU showed decreased mean average power (P = .02) and mean peak power (P = .01) from baseline to 48 h post-ECRE, whereas LBCAA and BCAA only trended toward a reduction at 24 hours post-ECRE. At 48 h post-ECRE, BCAA showed greater recovery of mean peak power than LEU (P = .04). At 24 h post-ECRE, LEU demonstrated a greater increase in plasma creatine kinase from baseline than BCAA (P = .04). Area under the curve for creatine kinase was greater in LEU than BCAA (P = .02), whereas BCAA and LBCAA did not differ. Only LEU demonstrated increased soreness during rest and under muscular tension at 24 and 48 h post-ECRE (P < .05). CONCLUSIONS: LBCAA failed to afford any advantages over a standard BCAA supplement for postexercise muscle recovery, whereas a LEU supplement was comparatively ineffective.

The Effects of Multi-Day vs. Single Pre-exercise Nitrate Supplement Dosing on Simulated Cycling Time Trial Performance and Skeletal Muscle Oxygenation.

Jo, E, Fischer, M, Auslander, AT, Beigarten, A, Daggy, B, Hansen, K, Kessler, L, Osmond, A, Wang, H, and Wes, R. The effects of multiday vs. single pre-exercise nitrate supplement dosing on simulated cycling time trial performance and skeletal muscle oxygenation. J Strength Cond Res 33(1): 217-224, 2019-A transient augmentation in the metabolic efficiency of skeletal muscle is the purported basis for dietary nitrate supplementation amongst competitive and recreational athletes alike. Previous studies support the ergogenic effects of nitrate supplementation, as findings indicated improved microvascular blood flow, exercise economy, and performance with relatively short-term supplementation. As with most ergogenic aids, the optimum duration of supplementation before performance or competition, i.e., loading phase, is a critical determinant for efficacy. Therefore, the purpose of this study was to investigate the effects of long-term vs. single dosing nitrate supplementation on skeletal muscle oxygenation and cycling performance. In a randomized, placebo controlled, double blind, parallel design study, healthy, recreationally active men (n = 15) and women (n = 14) subjects (age = 18-29 years) completed an 8 km (5 mi) simulated cycling time trial before and after a 14-day supplementation period with either a nitrate supplement (Multi-Day Dosing Group) (n = 14) or placebo (Single Pre-Exercise Dosing Group; SD) (n = 15). Both groups consumed a single dose of the nitrate supplement 2 hours before the post-treatment time trial. In addition, skeletal muscle oxygenation was measured via near-infrared spectroscopy during each time trial. Multiday nitrate supplementation significantly decreased time to completion (p = 0.01) and increased average power (p = 0.04) and speed (p = 0.02) from pre-to post-treatment, while a single dosing produced no significant changes to these measures. There were no significant differences over time and across treatments for any other measures including muscle oxygenation variables. Overall, long-term nitrate supplementation appears to have an advantage over a single pre-exercise dosing on cycling performance and metabolic efficiency as indicated by an increase in power output with no change in oxygenation.

Dietary Caffeine and Polyphenol Supplementation Enhances Overall Metabolic Rate and Lipid Oxidation at Rest and After a Bout of Sprint Interval Exercise.

Jo, E, Lewis, KL, Higuera, D, Hernandez, J, Osmond, AD, Directo, DJ, and Wong, M. Dietary caffeine and polyphenol supplementation enhances overall metabolic rate and lipid oxidation at rest and after a bout of sprint interval exercise. J Strength Cond Res 30(7): 1871-1879, 2016-The purpose of this study was to investigate the effects of a caffeine-polyphenolic supplement on (a) metabolic rate and fat oxidation at rest and after a bout of sprint interval exercise (SIE) and (b) SIE performance. In a double-blind, randomized, placebo-controlled, crossover study and after an initial familiarization visit, 12 subjects (male: n = 11; female: n = 1) (body mass = 76.1 ± 2.2 kg; height = 169.8 ± 1.6 cm; body mass index = 22.7 ± 3.0 kg·m; body fat % = 21.6 ± 2.0%) underwent 2 testing sessions during which time they consumed either a caffeine-polyphenol supplement or placebo. After supplementation, resting energy expenditure, heart rate (HR), and blood pressure (BP) were assessed. Subsequently, subjects performed 30 minutes of SIE while researchers collected performance data. Subjects were then tested for post-SIE energy expenditure, HR, and BP. The caffeine-polyphenol treatment resulted in significantly (p ≤ 0.05) greater energy expenditure (+7.99% rest; +10.16% post-SIE), V[Combining Dot Above]O2 (+9.64% rest; +12.10% post-SIE), and fat oxidation rate (+10.60% rest; +9.76% post-SIE) vs. placebo at rest and post-SIE. No significant differences were detected for peak and average power at all sprint intervals between treatments. Post-SIE HR was significantly (p ≤ 0.05) greater with caffeine-polyphenol supplementation vs. placebo (90.8 ± 3.5 vs. 85.1 ± 3.6 b·min). There were no significant between-treatment differences for BP. It may be concluded that the observed thermogenic response after SIE was directly attributable to caffeine-polyphenol supplementation as opposed to an indirect manifestation of enhanced performance and work output. Collectively, these results corroborate the use of dietary caffeine and polyphenols to support efforts to reduce adiposity and improve overall body composition especially in conjunction with SIE.