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Cellular Adaptations to High-Intensity and Sprint Interval Training
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Martin J. MacInnis, Lauren E. Skelly
ATP demand is positively related to exercise intensity and can increase as much as 100-fold relative to rest when maximal exercise is performed (91). Various metabolic processes regulate substrate metabolism such that ATP synthesis closely matches ATP hydrolysis. In studies that have compared equal durations of exercise performed at different intensities, muscle biopsy samples revealed that greater exercise intensities elicit markedly higher metabolic stress, due to a greater reliance on substrate-level phosphorylation and anaerobic metabolism as the concentration of skeletal muscle metabolites, such as H+, ADP, AMP, Pi, creatine, and lactate, increase with exercise intensity (57, 89, 90). Although it could be argued that the greater concentration of metabolites in these studies is a result of a greater amount of work being performed—not the rate of work, per se—these variables seem to reach a steady state, at least at lower intensities (57). Thus, exercise intensity appears to be the key factor dictating the skeletal muscle metabolic response to exercise. For example, even short bursts of “all-out” exercise involving low amounts of total work cause large disruptions to metabolic homeostasis (80).
Cellular and Molecular Mechanisms of Ischemic Acute Renal Failure and Repair
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Joseph V. Bonventre, Ralph Witzgall
Many cellular processes are critically dependent upon ATP hydrolysis. These processes cease or become markedly impaired when cellular ATP is markedly depleted. Ion gradients will dissipate without the ATP necessary for the ion transporter ATPases involved in maintenance of the ionic gradients. Sodium and calcium may accumulate in the cell. Deacylation, acylation cycling will be disrupted and fatty acids will accumulate due to the absence of energy required for the reacylation. Acidosis will develop as a consequence of increased glycolytic metabolism.
Striated MusclesSkeletal and Cardiac Muscles
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
ATP hydrolysis provides the energy for each cycle. The ATPase myosin heads are independent force generators and will undergo such cycles when actin is accessible, as regulated by calcium, troponin and tropomyosin. The physical process of cross-bridge activity is unclear; the myosin heads may swivel on the tails and the long chain may flex at the S2 segment.
Pharmacotherapeutic options for cancer cachexia: emerging drugs and recent approvals
Published in Expert Opinion on Pharmacotherapy, 2023
Lorena Garcia-Castillo, Giacomo Rubini, Paola Costelli
Implying the dissipation of energy via thermogenesis, UCP up-regulation in the skeletal muscle and in the adipose tissue is one of the main causes of REE elevation in cachexia. This phenomenon is closely related to inflammation, as the UCPs are induced by pro-inflammatory cytokines, such as TNF-α and IL-6 [7,8]. Furthermore, the sarcoplasmic reticulum Ca2+-ATPase and other ATPases can be involved in energetic inefficiency, producing heat through the uncoupling of ATP hydrolysis. Additionally, in the context of ATP mismanagement, mitochondrial ATP synthesis in the skeletal muscle can be impaired, for example, due to proton leakage from the inner mitochondrial membrane. Finally, abnormalities in carbohydrate, protein, and lipid metabolism can lead to REE elevation through the activation of futile cycles. These latter consist in the cycling of metabolic intermediates using ATP without metabolic gain and generating heat, thus representing a source of energetic inefficiency. Such inefficient metabolic cycles can also be established as a consequence of tumor metabolisms, such as lactate recycling (Cori cycle) between the tumor and the host [7].
Nanocarrier-based co-delivery approaches of chemotherapeutics with natural P-glycoprotein inhibitors in the improvement of multidrug resistance cancer therapy
Published in Journal of Drug Targeting, 2022
Shadab Md, Nabil A. Alhakamy, Priyanka Sharma, Mohammad Shahnawaze Ansari, Bapi Gorain
Delivery of therapeutics that undergo efflux by the P-gp pump can be improved by the application of P-gp inhibitors. Three different mechanisms promote such inhibitory function. The binding of ATP to the transmembrane and hydrolysis to generate energy is essential for the functioning of P-gp. Usually, one molecule of the drug is effluxed in exchange for hydrolysis of two molecules of ATP [51]. Thus, interference in energy generation by preventing ATP hydrolysis can stop the function of the energy-dependent transmembrane efflux pump. Alternatively. competitive or non-competitive blockade of the P-gp protein could prevent its function. The binding of competitive antagonistic substrates to the P-gp protein transport site competes with other substrates and does not allow agonistic agents to bind at the site in a competitive manner. On the other hand, the non-competitive inhibitors could not bind to the transport site, but rather attach to the allosteric binding site to alter the conformation of P-gp transport site (Figure 2) [49,50]. Concurrently, alteration of cell membrane lipid integrity has the consequences of altering the efflux potential of P-gp transporter [52]. The inhibitory role of P-gp transporter reflects an increase in uptake of therapeutics, particularly those that are P-gp substrates, thus increasing the intracellular availability of the drug, which simultaneously improves the efficacy of the drug. Several P-gp inhibitors have been identified, which are structurally diverse [53], whereas, many of them are transported by this transmembrane efflux protein [54].
Coronavirus helicases: attractive and unique targets of antiviral drug-development and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2021
Austin N. Spratt, Fabio Gallazzi, Thomas P. Quinn, Christian L. Lorson, Anders Sönnerborg, Kamal Singh
Due to their essential function(s) during the viral life cycle, helicases are clearly attractive antiviral targets regardless of the pathogen. While some helicase-targeting small molecules inhibitors have entered clinical trials, drug development against helicases remains challenging. One of these challenges is to design specific nsp13 inhibitors that compete with the natural substrate (ATP) and bind at the ATP binding site. As with many viral functional proteins and enzymes, the ATPase function of nsp13 is common to a broad array of cellular enzymes. Therefore, not only is binding essential, but substrate specificity amongst a sea of similar substrates adds an additional layer of complexity. For example, protein phosphatase 2A (PP2A), which is involved in many cellular functions, also conducts ATP hydrolysis by binding ATP through two metal ions [91]. Hence, any inhibitor that chelates metal ions can bind PP2A-like enzymes resulting into adverse toxicity profiles. Additionally, a two metal ions mechanism originally proposed for the 3ʹ – 5ʹ exonuclease function of E. coli DNA polymerase I [92] is used by many cellular polymerases and primases. Therefore, the compounds targeting ATPase function of nsp13 through metal chelating property can potentially bind to these enzymes and interfere normal cellular function. This type of challenge is not unique to drugs targeting viral proteins/enzymes, as similar issues emerged during the discovery of anti-HIV compounds. Several nucleoside reverse transcriptase inhibitors (NRTIs) inhibit polymerase γ, a mitochondrial DNA polymerase and exert mitochondrial toxicity [93–96].