scholarly journals Magnitude and control of mitochondrial sensitivity to ADP

2009 ◽  
Vol 297 (3) ◽  
pp. E774-E784 ◽  
Author(s):  
Jeroen A. L. Jeneson ◽  
Joep P. J. Schmitz ◽  
Nicole M. A. van den Broek ◽  
Natal A. W. van Riel ◽  
Peter A. J. Hilbers ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
In Silico ◽  
Adenine Nucleotide ◽  
Atp Synthesis ◽  
Model Parameters ◽  
Kinetic Properties ◽  
Mitochondrial Enzymes ◽  
Concentration Changes ◽  
Multiparametric Sensitivity Analysis

The transduction function for ADP stimulation of mitochondrial ATP synthesis in skeletal muscle was reconstructed in vivo and in silico to investigate the magnitude and origin of mitochondrial sensitivity to cytoplasmic ADP concentration changes. Dynamic in vivo measurements of human leg muscle phosphocreatine (PCr) content during metabolic recovery from contractions were performed by 31P-NMR spectroscopy. The cytoplasmic ADP concentration ([ADP]) and rate of oxidative ATP synthesis (Jp) at each time point were calculated from creatine kinase equilibrium and the derivative of a monoexponential fit to the PCr recovery data, respectively. Reconstructed [ADP]-Jp relations for individual muscles containing more than 100 data points were kinetically characterized by nonlinear curve fitting yielding an apparent kinetic order and ADP affinity of 1.9 ± 0.2 and 0.022 ± 0.003 mM, respectively (means ± SD; n = 6). Next, in silico [ADP]-Jp relations for skeletal muscle were generated using a computational model of muscle oxidative ATP metabolism whereby model parameters corresponding to mitochondrial enzymes were randomly changed by 50–150% to determine control of mitochondrial ADP sensitivity. The multiparametric sensitivity analysis showed that mitochondrial ADP ultrasensitivity is an emergent property of the integrated mitochondrial enzyme network controlled primarily by kinetic properties of the adenine nucleotide translocator.

scholarly journals Dietary Flaxseed Mitigates Impaired Skeletal Muscle Regeneration: in Vivo, in Vitro and in Silico Studies

2016 ◽  
Vol 13 (3) ◽  
pp. 206-219 ◽  
Author(s):  
Felicia Carotenuto ◽  
Alessandra Costa ◽  
Maria Cristina Albertini ◽  
Marco Bruno Luigi Rocchi ◽  
Alexander Rudov ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
In Silico ◽  
Skeletal Muscle Regeneration ◽  
In Silico Studies

In Vivo Skeletal Muscle Oxidative and Glycolytic ATP Synthesis in Young and Older Adults

2006 ◽  
Vol 38 (Supplement) ◽  
pp. S521
Author(s):  
Ian R. Lanza ◽  
Douglas E. Befroy ◽  
Danielle M. Wigmore ◽  
Jane A. Kent-Braun
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Atp Synthesis ◽  
Glycolytic Atp

scholarly journals Efficiency of human skeletal muscle in vivo: comparison of isometric, concentric, and eccentric muscle action

1997 ◽  
Vol 83 (3) ◽  
pp. 867-874 ◽  
Author(s):  
T. W. Ryschon ◽  
M. D. Fowler ◽  
R. E. Wysong ◽  
A.-R. Anthony ◽  
R. S. Balaban
Keyword(s):  
Skeletal Muscle ◽  
Steady State ◽  
Production Rate ◽  
Human Skeletal Muscle ◽  
Atp Synthesis ◽  
High Energy ◽  
High Energy Phosphates ◽  
Muscle Action ◽  
Atp Production

Ryschon, T. W., Fowler, R. E. Wysong, A.-R. Anthony, and R. S. Balaban. Efficiency of human skeletal muscle in vivo: comparison of isometric, concentric, and eccentric muscle action. J. Appl. Physiol. 83(3): 867–874, 1997.—The purpose of this study was to estimate the efficiency of ATP utilization for concentric, eccentric, and isometric muscle action in the human tibialis anterior and extensor digitorum longus in vivo. A dynamometer was used to quantitate muscle work, or tension, while simultaneous 31P-nuclear magnetic resonance data were collected to monitor ATP, phosphocreatine, inorganic phosphate, and pH. The relative efficiency of the actions was estimated in two ways: steady-state effects on high-energy phosphates and a direct comparison of ATP synthesis rates with work. In the steady state, the cytosolic free energy dropped to the lowest value with concentric activity, followed by eccentric and isometric action for comparative muscle tensions. Estimates of ATP synthesis rates revealed a mechanochemical efficiency [i.e., ATP production rate/work (both in J/s)] of 15.0 ± 1.3% in concentric and 34.7 ± 6.1% in eccentric activity. The estimated maximum ATP production rate was highest in concentric action, suggesting an activation of energy metabolism under these conditions. By using direct measures of metabolic strain and ATP turnover, these data demonstrate a decreasing metabolic efficiency in human muscle action from isometric, to eccentric, to concentric action.

An in Silico, Biomarker-Based Method for the Evaluation of Virtual Neuropsychiatric Drug Effects

2017 ◽  
Vol 29 (4) ◽  
pp. 1021-1052 ◽  
Author(s):  
Peter J. Siekmeier
Keyword(s):  
In Silico ◽  
Fragile X ◽  
Drug Effects ◽  
Cellular Level ◽  
Model Parameters ◽  
Virtual Agents ◽  
In Vitro Test ◽  
Pharmacologic Treatments

The recent explosion in neuroscience research has markedly increased our understanding of the neurobiological correlates of many psychiatric illnesses, but this has unfortunately not translated into more effective pharmacologic treatments for these conditions. At the same time, researchers have increasingly sought out biological markers, or biomarkers, as a way to categorize psychiatric illness, as these are felt to be closer to underlying genetic and neurobiological vulnerabilities. While biomarker-based drug discovery approaches have tended to employ in vivo (e.g., rodent) or in vitro test systems, relatively little attention has been paid to the potential of computational, or in silico, methodologies. Here we describe such a methodology, using as an example a biophysically detailed computational model of hippocampus that is made to generate putative schizophrenia biomarkers by the inclusion of a number of neuropathological changes that have been associated with the illness (NMDA system deficit, decreased neural connectivity, hyperdopaminergia). We use the specific inability to attune to gamma band (40 Hz) auditory stimulus as our illness biomarker. We expose this system to a large number of virtual medications, defined by systematic variation of model parameters corresponding to five cellular-level effects. The potential efficacy of virtual medications is determined by a wellness metric (WM) that we have developed. We identify a number of virtual agents that consist of combinations of mechanisms, which are not simply reversals of the causative lesions. The manner in which this methodology could be extended to other neuropsychiatric conditions, such as Alzheimer’s disease, autism, and fragile X syndrome, is discussed.

scholarly journals Modeling Skeletal Muscle Stress and Intramuscular Pressure: A Whole Muscle Active–Passive Approach

2018 ◽  
Vol 140 (8) ◽  
Author(s):  
Benjamin B. Wheatley ◽  
Gregory M. Odegard ◽  
Kenton R. Kaufman ◽  
Tammy L. Haut Donahue
Keyword(s):  
Skeletal Muscle ◽  
Muscle Weakness ◽  
Muscle Force ◽  
Fluid Pressure ◽  
Model Parameters ◽  
Intramuscular Pressure ◽  
Geometry Model ◽  
Model Fluid ◽  
Fluid Pressurization

Clinical treatments of skeletal muscle weakness are hindered by a lack of an approach to evaluate individual muscle force. Intramuscular pressure (IMP) has shown a correlation to muscle force in vivo, but patient to patient and muscle to muscle variability results in difficulty of utilizing IMP to estimate muscle force. The goal of this work was to develop a finite element model of whole skeletal muscle that can predict IMP under passive and active conditions to further investigate the mechanisms of IMP variability. A previously validated hypervisco-poroelastic constitutive approach was modified to incorporate muscle activation through an inhomogeneous geometry. Model parameters were optimized to fit model stress to experimental data, and the resulting model fluid pressurization data were utilized for validation. Model fitting was excellent (root-mean-square error or RMSE <1.5 kPa for passive and active conditions), and IMP predictive capability was strong for both passive (RMSE 3.5 mmHg) and active (RMSE 10 mmHg at in vivo lengths) conditions. Additionally, model fluid pressure was affected by length under isometric conditions, as increases in stretch yielded decreases in fluid pressurization following a contraction, resulting from counteracting Poisson effects. Model pressure also varied spatially, with the highest gradients located near aponeuroses. These findings may explain variability of in vivo IMP measurements in the clinic, and thus help reduce this variability in future studies. Further development of this model to include isotonic contractions and muscle weakness would greatly benefit this work.

Prolonged adenine nucleotide resynthesis and reperfusion injury in postischemic skeletal muscle

1992 ◽  
Vol 262 (5) ◽  
pp. H1538-H1547 ◽  
Author(s):  
B. B. Rubin ◽  
S. Liauw ◽  
J. Tittley ◽  
A. D. Romaschin ◽  
P. M. Walker
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Time Course ◽  
Adenine Nucleotide ◽  
Adenine Nucleotides ◽  
Prolonged Release ◽  
Intracellular Acidosis ◽  
Edema Formation ◽  
Muscle Necrosis

Skeletal muscle ischemia results in energy depletion and intracellular acidosis. Reperfusion is associated with impaired adenine nucleotide resynthesis, edema formation, and myocyte necrosis. The purpose of these studies was to define the time course of cellular injury and adenine nucleotide depletion and resynthesis in postischemic skeletal muscle during prolonged reperfusion in vivo. The isolated canine gracilis muscle model was used. After 5 h of ischemia, muscles were reperfused for either 1 or 48 h. Lactate and creatine phosphokinase (CPK) release during reperfusion was calculated from arteriovenous differences and blood flow. Adenine nucleotides, nucleosides, bases, and creatine phosphate were quantified by high-performance liquid chromatography, and muscle necrosis was assessed by nitroblue tetrazolium staining. Reperfusion resulted in a rapid release of lactate, which paralleled the increase in blood flow, and a delayed but prolonged release of CPK. Edema formation and muscle necrosis increased between 1 and 48 h of reperfusion (P less than 0.05). Recovery of energy stores during reperfusion was related to the extent of postischemic necrosis, which correlated with the extent of nucleotide dephosphorylation during ischemia (r = 0.88, P less than 0.001). These results suggest that both adenine nucleotide resynthesis and myocyte necrosis, which are protracted processes in reperfusing skeletal muscle, are related to the extent of nucleotide dephosphorylation during ischemia.

Regulation of oxidative phosphorylation during work transitions results from its kinetic properties

2014 ◽  
Vol 116 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Bernard Korzeniewski
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Metabolic Control ◽  
Experimental Studies ◽  
Complex Iii ◽  
Activation Mechanism ◽  
Kinetic Properties ◽  
Group Model ◽  
Work Transitions

The regulation of oxidative phosphorylation (OXPHOS) during work transitions in skeletal muscle and heart is still not well understood. Different computer models of this process have been developed that are characterized by various kinetic properties. In the present research-polemic theoretical study it is argued that models belonging to one group (Model A), which predict that among OXPHOS complexes complex III keeps almost all of the metabolic control over oxygen consumption (Vo2) and involve a strong complex III activation by inorganic phosphate (Pi), lead to the conclusion that an increase in Pi is the main mechanism responsible for OXPHOS activation (feedback-activation mechanism). Models belonging to another group (Model B), which were developed to take into account an approximately uniform distribution of metabolic control over Vo2 among particular OXPHOS complexes (complex I, complex III, complex IV, ATP synthase, ATP/ADP carrier, phosphate carrier) encountered in experimental studies in isolated mitochondria, predict that all OXPHOS complexes are directly activated in parallel with ATP usage and NADH supply by some external cytosolic factor/mechanism during rest-to-work or low-to-high work transitions in skeletal muscle and heart (“each-step-activation” mechanism). Model B demonstrates that different intensities of each-step activation can account for the very different (slopes of) phenomenological Vo2-ADP relationships observed in various skeletal muscles and heart. Thus they are able to explain the differences in the regulation of OXPHOS during work transitions between skeletal muscle (where moderate changes in ADP take place) and intact heart in vivo (where ADP is essentially constant).

scholarly journals Signaling Role of Mitochondrial Enzymes and Ultrastructure in the Formation of Molecular Mechanisms of Adaptation to Hypoxia

2021 ◽  
Vol 22 (16) ◽  
pp. 8636
Author(s):  
Ludmila Lukyanova ◽  
Elita Germanova ◽  
Natalya Khmil ◽  
Lybov Pavlik ◽  
Irina Mikheeva ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Oxygen Sensor ◽  
Ultrastructural Changes ◽  
Hypoxic Exposure ◽  
Adaptation To Hypoxia ◽  
Kinetic Properties ◽  
Mitochondrial Enzymes ◽  
Resistance To Hypoxia

This study was the first comprehensive investigation of the dependence of mitochondrial enzyme response (catalytic subunits of mitochondrial complexes (MC) I-V, including NDUFV2, SDHA, Cyt b, COX1 and ATP5A) and mitochondrial ultrastructure in the rat cerebral cortex (CC) on the severity and duration of in vivo hypoxic exposures. The role of individual animal’s resistance to hypoxia was also studied. The respiratory chain (RC) was shown to respond to changes in environmental [O2] as follows: (a) differential reaction of mitochondrial enzymes, which depends on the severity of the hypoxic exposure and which indicates changes in the content and catalytic properties of mitochondrial enzymes, both during acute and multiple exposures; and (b) ultrastructural changes in mitochondria, which reflect various degrees of mitochondrial energization. Within a specific range of reduced О2 concentrations, activation of the МС II is a compensatory response supporting the RC electron transport function. In this process, MC I develops new kinetic properties, and its function recovers in hypoxia by reprograming the RC substrate site. Therefore, the mitochondrial RC performs as an in vivo molecular oxygen sensor. Substantial differences between responses of rats with high and low resistance to hypoxia were determined.

Selective PPARδ agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study

2007 ◽  
Vol 293 (5) ◽  
pp. E1256-E1264 ◽  
Author(s):  
Beat M. Jucker ◽  
Dewen Yang ◽  
Warren M. Casey ◽  
Alan R. Olzinski ◽  
Carolyn Williams ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Uncoupling Protein ◽  
Coupling Efficiency ◽  
Atp Synthesis ◽  
Energy Coupling ◽  
Resonance Spectroscopy ◽  
High Dose ◽  
Muscle Lipid

Peroxisome proliferator-activated receptor-δ (PPARδ) activation results in upregulation of genes associated with skeletal muscle fatty acid oxidation and mitochondrial uncoupling. However, direct, noninvasive assessment of lipid metabolism and mitochondrial energy coupling in skeletal muscle following PPARδ stimulation has not been examined. Therefore, in this study we examined the response of a selective PPARδ agonist (GW610742X at 5 or 100 mg·kg−1·day−1 for 8 days) on skeletal-muscle lipid metabolism and mitochondrial coupling efficiency in rats by using in vivo magnetic resonance spectroscopy (MRS). There was a decrease in the intramyocellular lipid-to-total creatine ratio as assessed by in vivo 1H-MRS in soleus and tibialis anterior muscles by day 7 (reduced by 49 and 46%, respectively; P < 0.01) at the high dose. Following the 1H-MRS experiment ( day 8), [1-13C]glucose was administered to conscious rats to assess metabolism in the soleus muscle. The relative fat-vs.-carbohydrate oxidation rate increased in a dose-dependent manner (increased by 52 and 93% in the 5 and 100 mg·kg−1·day−1 groups, respectively; P < 0.05). In separate experiments where mitochondrial coupling was assessed in vivo ( day 7), 31P-MRS was used to measure hindlimb ATP synthesis and 13C-MRS was used to measure the hindlimb tricarboxylic acid cycle flux (Vtca). There was no alteration, at either dose, in mitochondrial coupling efficiency measured as the ratio of unidirectional ATP synthesis flux to Vtca. Soleus muscle GLUT4 expression was decreased by twofold, whereas pyruvate dehydrogenase kinase 4, carnitine palmitoyl transferase 1a, and uncoupling protein 2 and 3 expression was increased by two- to threefold at the high dose ( P < 0.05). In summary, these are the first noninvasive measurements illustrating a selective PPARδ-mediated decrease in muscle lipid content that was consistent with a shift in metabolic substrate utilization from carbohydrate to lipid. However, the mitochondrial-energy coupling efficiency was not altered in the presence of increased uncoupling protein expression.

Harnessing tumor immunity with chemotherapy: Mathematical modeling for decision-making in combinatorial regimen with immune-oncology drugs.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14095-e14095
Author(s):  
Vesna Cuplov ◽  
Guillaume Sicard ◽  
Dominique Barbolosi ◽  
Joseph Ciccolini ◽  
Fabrice Barlesi
Keyword(s):  
Mathematical Modeling ◽  
T Cells ◽  
In Silico ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Model Parameters ◽  
In Vivo Experiments ◽  
The Impact

e14095 Background: Combining chemotherapy and immune checkpoint inhibitors (ICI) is challenging due to the near-infinite choice of dosing, scheduling and sequencing between drugs. The aim of this work is to develop a phenomenological model that describes the synergistic effect between cytotoxics and immune check point inhibitors in patients with cancer. Methods: Inspired from literature, we have developed an integrative mathematical model that includes tumor cells, cytotoxic T cells (CTLs) and regulatory T cells (TREGs) plus pharmacokinetics (PK) inputs. Loss in tumor mass is due to combined effect of direct chemotherapy-induced cytotoxicity and CTLs immune response, which is in turn inhibited by the tumor and mitigated by TREGs in the tumor micro-environment. The model describes as well the impact of chemotherapy-induced lymphodepletion on immune tolerance, whereas ICIs protect CTLs against tumor inhibition. Identification of model’s parameters and simulations of various scheduling were performed using Mlxplore software and a Python standalone code. In vitro and in vivo experiments using lung cancer models generate experimental data to adjust model parameters. Results: Complex interplays between cytotoxics and immune cells were best described by a 10-parameters model so as to ensure better identifiability. PK/PD relationships were integrated using compartmental modeling. In silico simulations show how changes in dosing and scheduling impact efficacy endpoints, an observation in line with data from the literature. Ongoing in vitro and in vivo experiments with pemetrexed-cisplatin doublet and anti-PD1 pembrolizumab help optimizing the model’s parameters in a self-learning loop. Conclusions: This work is at the frontier between mathematical modeling and experimental therapeutics with ICIs. In silico modeling and simulations could help narrow down the treatment choices and define optimal combinations prior to running clinical trials. Such model will help identify optimal dosing and scheduling, so as to achieve better synergism and efficacy.

Sign in / Sign up

Export Citation Format

Share Document