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Cell Physiology
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
Four reactions in glycolysis play key roles in regulating its flux: hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), and 6-phosphofructo 2-kinase/fructose 2,6-bisphosphate (PFKFB) (Panel 3.12). These four enzymes along with pyruvate dehydrogenase kinase (PDK) regulate the flux of glucose carbon and its distribution at the pyruvate node. We will take a simplified view to largely divide glycolysis into two types of metabolism: one high flux in proliferating cells and the other low flux in quiescent cells (Figure 3.9). These two types of metabolism are influenced by the isoforms involved, the composition of the medium, and the growth rate, among other factors. With some isoform combinations, a number of reaction steps are activated by the accumulation of F2,6P and F1,6P (Figure 3.9a). Upon full activation, one may see a 5-fold or higher increase in glucose consumption, whereas with the isoform combination depicted in Figure 3.9b, the degree of activation is much lower. Below, we will describe the allosteric regulation of a few major enzymes that play key roles in determining the flux. Table 3.1 lists the compositions of the isozymes of glycolysis in a few human tissues.
In silico design of PDHK inhibitors: From small molecules to large fluorinated compounds
Published in Tanmoy Chakraborty, Prabhat Ranjan, Anand Pandey, Computational Chemistry Methodology in Structural Biology and Materials Sciences, 2017
This reaction depletes the carbohydrate reserves in mammals, and hence, to conserve these resources under conditions offasting or pathological conditions associated with insulin resistance, such as obesity and diabetes, the PDC activity is reduced [6,16,20,28]. This happens by the action of another enzyme, the pyruvate dehydrogenase kinase (PDHK), which phosphorylates PDC, rendering it inactive. In humans and other mammals, there are at least four PDHK enzymes (PDHKI, PDHK2, PDHK3 and PDHK4), all of which are similar in their amino acid sequence, but very different in their activities, tissue distribution and regulation [3,8,24]. Of these, PDHK2 is the most widely distributed amongst tissues [3,32] and we focus on it in this work.
Substrate metabolism during exercise: Sexual dimorphism and women’s specificities
Published in European Journal of Sport Science, 2022
Nathalie Boisseau, Laurie Isacco
In menopausal women, oestrogen circulating levels are significantly reduced. Associated with this decline, women may show lower whole-body fat oxidation rates at rest (Lovejoy, Champagne, De Jonge, Xie, & Smith, 2008), and lower fat oxidation rates (g.min−1.kgFFM−1) and energy expenditure (kcal.min−1) during exercise (45 min cycling at 50% of VO2max) compared with premenopausal women (Abildgaard, Pedersen, Green, Harder-Lauridsen, & Solomon, 2013). The close correlation between reduction in lean body mass and lower fat oxidation rates and energy expenditure in postmenopausal women suggests that the loss of lean mass could be a critical factor. Therefore, it should be important to develop strategies, such as physical activity training, to counteract or slowdown this decrease. Interestingly, despite the differences in whole-body fat oxidation rates, the basal mRNA levels of factors involved in fat oxidation and energy expenditure regulation, such as CPT-I, citrate synthase (CS), PPARα, β-HAD, PGC-1, and pyruvate dehydrogenase kinase isozyme 4, do not appear different in pre- and postmenopausal women (Abildgaard et al., 2013). Similarly, the activity of key oxidative enzymes (β-HAD and CS) does not seem to be affected by the menopausal status. Conversely, exercise-induced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle might be lower in postmenopausal than in premenopausal women. In agreement, previous studies showed that AMPK is activated by oestrogen (D'Eon, Rogers, Stancheva, & Greenberg, 2008)
Metabolic adaptations to endurance training and nutrition strategies influencing performance
Published in Research in Sports Medicine, 2019
Conrad P. Earnest, Jeff Rothschild, Christopher R. Harnish, Alireza Naderi
For example, ingestion of CHO during exercise decreased the gene expression involved in lipid metabolism (e.g., GLUT-4, PDK4, AMPK, CD36, CPT-1, and UCP3) rather than increasing genes involved in carbohydrate metabolism, with the exception of decreasing the expression of pyruvate dehydrogenase kinase-4 (Civitarese et al., 2005). Intra-workout CHO ingestion may also blunt the interleukin-6 response to exercise (Akerstrom, Krogh-Madsen, Petersen, & Pedersen, 2009). Future studies are needed to determine the impact of these changes, acute exercise responses are not predictive of longer-term adaptations (Cochran et al., 2014), which may be influenced to the contraction-induced signaling in mitochondrial adaptations and redundancies in the adaptive process (Raney & Turcotte, 2006).
p-Synephrine, the main protoalkaloid of Citrus aurantium, raises fat oxidation during exercise in elite cyclists
Published in European Journal of Sport Science, 2021
Jorge Gutiérrez-Hellín, Gabriel Baltazar-Martins, Iván Rodríguez, Beatriz Lara, Carlos Ruiz-Moreno, Millán Aguilar-Navarro, Juan Del Coso
p-Synephrine has been included in the Monitoring Program of the World Anti-Doping Agency (WADA) since 2005 due to is purported effect on increasing physical performance (World Anti-Doping Agency, 2018). It tracks the use of ergogenic substances that are not prohibited in- or out-of-competition but are still under anti-doping control until sufficient scientific or medical evidence indicates that they are safe/unsafe. However, the evidence to support p-synephrine’s ergogenicity is scarce and contradictory. It has been found that acute p-synephrine intake might increase muscle endurance performance (Ratamess et al., 2015) and reduce perceived exertion during endurance exercise (Haller et al., 2008). Conversely, p-synephrine did not increase running velocity or jump performance in experienced sprinters during simulated competition (Gutierrez-Hellin et al., 2016). Although this was not the purpose of the current investigation, we indirectly assessed cyclists’ physical performance because the end-point of the ramps tests was voluntary fatigue. The ingestion of p-synephrine did not modify the maximal wattage obtained in the test (458;441–475 vs 457;439–474 W) nor the VO2max values (78.0 ± 3.53 vs 78.0 ± 2.79 mL/kg/min). Although these outcomes preclude the categorization of p-synephrine as an ergogenic aid, the higher fat oxidation rates at moderate exercise intensities – at the expense of lower carbohydrate use – might help elite cyclists to spare muscle and liver glycogen in competition. The reasons for the reduction in carbohydrate oxidation in several exercise loads might be related to the downregulation of the enzyme pyruvate dehydrogenase kinase (Maldonado et al., 2018). However, the current data indicate that increase in fat oxidation rate was not always accompanied of a concomitant reduction in the rate of carbohydrate oxidation because a non-significant change in energy expenditure has been detected in several workloads. While muscle and liver glycogen sparing through carbohydrate feeding during exercise (Stellingwerff et al., 2007) or training with low carbohydrate availability (Hearris, Hammond, Fell, & Morton, 2018) has been found effective to increase cycling performance, the usefulness of the reduction on carbohydrate oxidation p-synephrine ingestion is still speculative and requires further investigation.