Energetics of muscle contraction: the whole is less than the sum of its parts

2002 ◽  
Vol 30 (2) ◽  
pp. 227-231 ◽  
Author(s):  
M. J. Kushmerick ◽  
K. E. Conley

Understanding muscle energetics is a problem in optimizing supply of ATP to the demands of ATPases. The complexity of reactions and their fluxes to achieve this balance is greatly reduced by recognizing constraints imposed by the integration of common metabolites at fixed stoichiometry among modular units. ATPase is driven externally. Oxidative phosphorylation and glycogenolysis are the suppliers. We focus on their regulation which involves different controls, but reduces to two principles that enable facile experimental analysis of the supply and demand fluxes. The ratio of concentration of phospho-creatine (PCr) to ATP, not their individual values, sets the range of achievable concentrations of ADP in resting and active muscle (at fixed pH) in different cell types. This principle defines the fraction of available flux of oxidative phosphorylation utilized (at fixed enzyme activities). Then the kinetics of PCr recovery defines the kinetics of oxygen supply and substrate utilization. The second principle is the constancy of PCr and H+ (lactate) production by glycogenolysis due to the coupling of ATPase and glycolysis. This principle enables glycogenolytic flux to be measured from intracellular proton loads. Further simplification occurs because the magnitude of the interacting fluxes and metabolite concentrations are specified within narrow limits when both the resting and active fluxes are quantified. Thus there is a small set of rules for assessing and understanding the thermodynamics and kinetics of muscle energetics.

2020 ◽  
Vol 21 (3) ◽  
pp. 998
Author(s):  
Weiye Zhao ◽  
Yufan Wang ◽  
Fu-Sen Liang

The epigenome defines the unique gene expression patterns and resulting cellular behaviors in different cell types. Epigenome dysregulation has been directly linked to various human diseases. Epigenome editing enabling genome locus-specific targeting of epigenome modifiers to directly alter specific local epigenome modifications offers a revolutionary tool for mechanistic studies in epigenome regulation as well as the development of novel epigenome therapies. Inducible and reversible epigenome editing provides unique temporal control critical for understanding the dynamics and kinetics of epigenome regulation. This review summarizes the progress in the development of spatiotemporal-specific tools using small molecules or light as inducers to achieve the conditional control of epigenome editing and their applications in epigenetic research.


1994 ◽  
Vol 5 (7) ◽  
pp. 819-828 ◽  
Author(s):  
Y Wang ◽  
G M Fuller

Recent evidence has shown that members of the Jak kinase family are activated after IL-6 binds to its receptor complex, leading to a tyrosine phosphorylation of gp130, the IL-6 signal-transducing subunit. The different members of the IL-6 cytokine subfamily induce distinct patterns of Jak-Tyk phosphorylation in different cell types. Using monospecific antibodies to gp130, Jak2 kinase, and phosphotyrosine, we investigated the kinetics of IL-6 stimulation of members of this pathway in primary hepatocytes. Our findings show that Jak 2 is maximally activated within 2 min of exposure to IL-6, followed by gp130 phosphorylation that reaches its peak in another 2 min then declines to basal level by 60 min. In vitro phosphorylation experiments show that activated Jak 2 is able to phosphorylate both native gp130 and a fusion peptide containing its cytoplasmic domain, demonstrating gp130 is a direct substrate of Jak 2 kinase. Experiments designed to explore the cell surface expression of gp130 show that > or = 2 h are required to get a second round of phosphorylation after the addition of more cytokines. This finding suggests that activated gp130 is internalized from the cell surface after IL-6 stimulation. Additional experiments using protein synthesis inhibitors reveal that new protein synthesis is required to get a second cycle of gp130 phosphorylation indicating gp130 must be synthesized de novo and inserted into the membrane. These findings provide strong evidence that down regulation of the IL-6 signal in hepatocytes involves the internalization and cytosol degradation of gp130.


2018 ◽  
Vol 91 (2) ◽  
pp. 179-189 ◽  
Author(s):  
Suzane Ramos da Silva ◽  
Fan Cheng ◽  
I‐Chueh Huang ◽  
Jae U. Jung ◽  
Shou‐Jiang Gao

Oncogene ◽  
2021 ◽  
Author(s):  
Sarah L. Gillen ◽  
Joseph A. Waldron ◽  
Martin Bushell

AbstractA key characteristic of cancer cells is their increased proliferative capacity, which requires elevated levels of protein synthesis. The process of protein synthesis involves the translation of codons within the mRNA coding sequence into a string of amino acids to form a polypeptide chain. As most amino acids are encoded by multiple codons, the nucleotide sequence of a coding region can vary dramatically without altering the polypeptide sequence of the encoded protein. Although mutations that do not alter the final amino acid sequence are often thought of as silent/synonymous, these can still have dramatic effects on protein output. Because each codon has a distinct translation elongation rate and can differentially impact mRNA stability, each codon has a different degree of ‘optimality’ for protein synthesis. Recent data demonstrates that the codon preference of a transcriptome matches the abundance of tRNAs within the cell and that this supply and demand between tRNAs and mRNAs varies between different cell types. The largest observed distinction is between mRNAs encoding proteins associated with proliferation or differentiation. Nevertheless, precisely how codon optimality and tRNA expression levels regulate cell fate decisions and their role in malignancy is not fully understood. This review describes the current mechanistic understanding on codon optimality, its role in malignancy and discusses the potential to target codon optimality therapeutically in the context of cancer.


2005 ◽  
Vol 37 (6) ◽  
pp. 379-385 ◽  
Author(s):  
Xiao-Qi Wang ◽  
Xiu-Mei Duan ◽  
Li-Hua Liu ◽  
Yan-Qiu Fang ◽  
Yan Tan

Abstract Our objective was to study the properties of the carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) and the methodology of cell labeling using CFDA-SE fluorescent dye. First, we analyzed the kinetics of CFDA-SE fluorescent dye intensity over time. Second, we determined the optimal concentration of CFDA-SE fluorescent dye for cell labeling. Third, we tested the toxicity of CFDA-SE fluorescent dye on labeled cells. Finally, we determined the optimal staining time of CFDA-SE fluorescent dye for cell labeling. The results show that the optimal concentration of CFDA-SE fluorescent dye for cell labeling varies according to different cell types. CFDA-SE fluorescent dye is non-toxic to cells as the cell death rate caused by CFDASE labeling is below 5%. The optimal cell labeling time was determined to be 8 min of incubation with CFDA-SE fluorescent dye. We concluded that the advantages of using CFDA-SE fluorescent dye for cell labeling are as follows: (1) the binding of CFDA-SE fluorescent dye to cells is stable; (2) CFDA-SE fluorescent dye is not toxic and does not modify the viability of labeled cells; and (3) CFDA-SE fluorescent dye is a suitable fluorochrome for cell labeling.


2018 ◽  
Author(s):  
Shengbao Suo ◽  
Qian Zhu ◽  
Assieh Saadatpour ◽  
Lijiang Fei ◽  
Guoji Guo ◽  
...  

AbstractRecent progress in single-cell technologies has enabled the identification of all major cell types in mouse. However, for most cell types, the regulatory mechanism underlying their identity remains poorly understood. By computational analysis of the recently published mouse cell atlas data, we have identified 202 gene regulatory networks whose activities are highly variable across different cell types, and more importantly, predicted a small set of essential regulators for each of over 800 cell types in mouse for the first time. Systematic validation by automated literature- and data-mining provides strong additional support for our predictions. Thus, these predictions serve as a valuable resource that would be useful for the broad biological community. Finally, we have built a user-friendly, interactive, web-portal to enable users to navigate this mouse cell network atlas.


1999 ◽  
Vol 80 (3) ◽  
pp. 543-547 ◽  
Author(s):  
D Zipeto ◽  
B Bodaghi ◽  
L Laurent ◽  
J L Virelizier ◽  
S Michelson

1963 ◽  
Vol 19 (1) ◽  
pp. 33-44 ◽  
Author(s):  
Maureen Owen ◽  
Sheila MacPherson

A study of the cell kinetics on the actively growing periosteal surface of the femur of rabbits aged 2 weeks has been continued. A single injection of tritiated thymidine was given and the rabbits killed from 1 hour to 4 days after injection. The grain count spectra of the different cell types, pre-osteoblast, osteoblast, and osteocyte, have been compared at different times after injection. The results showed evidence for the uptake of thymidine in nuclei which is not associated with cell division. A small percentage of osteoblasts was initially labeled at 1 hour and there was evidence that the majority of these had not divided by 3 or 4 days after injection. Some thymidine-labeled cells had also become osteocytes without division. Furthermore, it appeared that a considerable fraction of the initially labeled pre-osteoblasts did not divide. The S period for the pre-osteoblasts and osteoblasts was measured using a double-labeled thymidine technique.


Author(s):  
U. Aebi ◽  
P. Rew ◽  
T.-T. Sun

Various types of intermediate-sized (10-nm) filaments have been found and described in many different cell types during the past few years. Despite the differences in the chemical composition among the different types of filaments, they all yield common structural features: they are usually up to several microns long and have a diameter of 7 to 10 nm; there is evidence that they are made of several 2 to 3.5 nm wide protofilaments which are helically wound around each other; the secondary structure of the polypeptides constituting the filaments is rich in ∞-helix. However a detailed description of their structural organization is lacking to date.


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