Model of skeletal muscle cramp and its reversal

In an accompanying paper [2], we developed the Shorten [3] model of skeletal muscle by incorporating equations such as surface calcium fluxes. In further research in this paper, we succeeded in reproducing muscle cramp, as well as its prevention and reversal, by investigating muscle contraction and cramp, in which calcium regulatory networks are involved, using the extended model in comparison with the original model. Incorporation of data from a traditional medicine from root extracts of paeony and licorice and one of its pure chemicals was modeled. The sensitivity analysis of the extended model shows the robustness of the calcium regulatory networks. Muscle cramp, in the extended model, requires calcium influx via the L-type calcium channel and it will not occur without calcium influx. Reduced calcium influx can delay or prevent cramp. Increased interstitial potassium is implicated in developing and maintaining cramp. Mechanism of reversal of cramp requires wash-out of extracellular potassium via increased blood flow, followed by calcium efflux via sodium-calcium exchange. This paper shows the first successful quantitative electrophysiological and mechanical model of cramp and of its reversal.

Hepatic endoplasmic reticulum calcium fluxes: effect of free fatty acids and KATP channel involvement

As a common sequel to obesity, plasma and intracellular free fatty acid (FFA) concentrations are elevated and, as a consequence, manifold disturbances in metabolism may ensue. Biochemical processes in the cytosol and organelles, such as mitochondria and endoplasmic reticulum (ER), can be disturbed. In the ER, the maintenance of a high calcium gradient is indispensable for viability. In sarcoplasmic reticulum, selective FFA can induce ER stress by disrupting luminal calcium homeostasis; however, there are limited studies in hepatic microsomes. Our studies found that FFA has a noxious effect on rat hepatic microsomal calcium flux, and the extent of which depended on the number of double bonds and charge. Furthermore, insofar as the FFA had no effect on microsomal calcium efflux, their inhibitory action primarily involves calcium influx. Finally, other cationic channels have been found in hepatic ER, and evidence is presented of their interaction with the Ca2+ ATPase pump.

Theoretical Study of the Function of the IP3 Receptor / BK Channel Complex in a Single Neuron

Large conductance calcium-activated potassium (BK) channels carry out many functions in the central nervous system. The opening of BK channels requires a rise in the cytosolic calcium ([Ca2+]cyt) concentration, which can occur in two ways: calcium influx from voltage-gated calcium channels (VGCCs) located on the plasma membrane and calcium efflux through the endoplasmic reticulum (ER) membrane to the cytosol triggered by inositol 1,4,5-trisphosphate (IP3) receptors (IP3-Rs) and ryanodine receptors (RyRs). The BK channel/IP3-R/RyR interaction has been widely reported in smooth muscle but scarce information exist on neurons, where its presence is uncertain. The aim of this study was to develop a computational model of a neuron to replicate the interaction between the release of Ca2+ from the ER (through IP3-Rs and RyRs) and the opening of BK channels on the plasma membrane to regulate the level of [Ca2+]cyt, based on the Hodgkin-Huxley formalism and the Goldbeter model. The mathematical models were implemented on Visual Basic® and differential equations were solved numerically. Various conditions of BK conductance and the efflux of endoplasmic Ca2+ were explored. The results show that an abrupt increase in [Ca2+]cyt (≥ 5 mM) activates the BK channels and either pauses or stops the action potential train.

PINK1 Contained in huMSCs-Exosomes Prevents Cardiomyocyte Mitochondrial Calcium Overload in Sepsis by Recovering Mitochondrial Ca2+ Efflux

Background: Sepsis is a systemic inflammatory response to a local severe infection that can lead to multiple organ failure and ultimately death. Studies have shown that 40%-50% of septic patients have diverse myocardial injuries, with mortality ranging from 70% to 90% in contrast to 20% in septic patients without myocardial injury. Therefore, uncovering the mechanism of myocardial injury induced by sepsis and finding a treatment for the corresponding target are immensely important.Methods: We employed cecal ligation and puncture (CLP) for inducing sepsis in mice, and detect the situation of myocardial injury and cardiac function through serological markers and echocardiography. The cardiomyocytes apoptosis and the ultrastructural of heart tissue detected by TUNEL and transmission electron microscope (TEM) respectively. The Fura-2 AM was used to monitored Ca2+ uptake and efflux of mitochondria. FQ-PCR and Western blot detected the expression of mitochondria Ca2+ distribution regulators and PINK1. JC-1 was used to detected the mitochondrial membrane potential (Δψm) of cardiomyocytes. Results: We found that the expression of PINK1 decreased in mouse hearts during sepsis, which caused cardiomyocyte mitochondrial calcium efflux disorder, mitochondrial calcium overload and cardiomyocyte injury. In contrast, we found that exosomes isolated from huMSCs (huMSCs-exo) carried Pink1 mRNA that could be transferred to recipient cardiomyocytes, increasing PINK1 expression. Then, the reduction in cardiomyocyte mitochondrial calcium efflux was reversed, and cardiomyocytes recovered from their injury. Furthermore, we confirmed the effect of the PINK1-PKA-NCLX axis on mitochondrial calcium homeostasis in cardiomyocytes during sepsis.Conclusion: The PINK1-PKA-NCLX axis play an important role in cardiomyocytes mitochondrial calcium efflux, therefore PINK1 could be a therapeutic target to protect cardiomyocyte mitochondria, and the application of huMSCs-exo is a promising strategy against heart dysfunction induced by sepsis.

Model of skeletal muscle cramp and its reversal

In an accompanying paper [2], we developed the Shorten [3] model of skeletal muscle by incorporating equations such as surface calcium fluxes. In further research in this paper, we succeeded in reproducing muscle cramp, as well as its prevention and reversal, by investigating muscle contraction and cramp, in which calcium regulatory networks are involved, using the extended model in comparison with the original model. Incorporation of data from a traditional medicine from root extracts of paeony and licorice and one of its pure chemicals was modeled. The sensitivity analysis of the extended model shows the robustness of the calcium regulatory networks. Muscle cramp, in the extended model, requires calcium influx via the L-type calcium channel and it will not occur without calcium influx. Reduced calcium influx can delay or prevent cramp. Increased interstitial potassium is implicated in developing and maintaining cramp. Mechanism of reversal of cramp requires wash-out of extracellular potassium via increased blood flow, followed by calcium efflux via sodium-calcium exchange. This paper shows the first successful quantitative electrophysiological and mechanical model of cramp and of its reversal.

Model of skeletal muscle cramp and its reversal

In an accompanying paper [2], we developed the Shorten [3] model of skeletal muscle by incorporating equations such as surface calcium fluxes. In further research in this paper, we succeeded in reproducing muscle cramp, as well as its prevention and reversal, by investigating muscle contraction and cramp, in which calcium regulatory networks are involved, using the extended model in comparison with the original model. Incorporation of data from a traditional medicine from root extracts of paeony and licorice and one of its pure chemicals was modeled. The sensitivity analysis of the extended model shows the robustness of the calcium regulatory networks. Muscle cramp, in the extended model, requires calcium influx via the L-type calcium channel and it will not occur without calcium influx. Reduced calcium influx can delay or prevent cramp. Increased interstitial potassium is implicated in developing and maintaining cramp. Mechanism of reversal of cramp requires wash-out of extracellular potassium via increased blood flow, followed by calcium efflux via sodium-calcium exchange. This paper shows the first successful quantitative electrophysiological and mechanical model of cramp and of its reversal.

Model of skeletal muscle cramp and its reversal

In an accompanying paper [2], we developed the Shorten [3] model of skeletal muscle by incorporating equations such as surface calcium fluxes. In further research in this paper, we succeeded in reproducing muscle cramp, as well as its prevention and reversal, by investigating muscle contraction and cramp, in which calcium regulatory networks are involved, using the extended model in comparison with the original model. Incorporation of data from a traditional medicine from root extracts of paeony and licorice and one of its pure chemicals was modeled. The sensitivity analysis of the extended model shows the robustness of the calcium regulatory networks. Muscle cramp, in the extended model, requires calcium influx via the L-type calcium channel and it will not occur without calcium influx. Reduced calcium influx can delay or prevent cramp. Increased interstitial potassium is implicated in developing and maintaining cramp. Mechanism of reversal of cramp requires wash-out of extracellular potassium via increased blood flow, followed by calcium efflux via sodium-calcium exchange. This paper shows the first successful quantitative electrophysiological and mechanical model of cramp and of its reversal.

Model of skeletal muscle cramp and its reversal

In an accompanying paper [2], we developed the Shorten [3] model of skeletal muscle by incorporating equations such as surface calcium fluxes. In further research in this paper, we succeeded in reproducing muscle cramp, as well as its prevention and reversal, by investigating muscle contraction and cramp, in which calcium regulatory networks are involved, using the extended model in comparison with the original model. Incorporation of data from a traditional medicine from root extracts of paeony and licorice and one of its pure chemicals was modeled. The sensitivity analysis of the extended model shows the robustness of the calcium regulatory networks. Muscle cramp, in the extended model, requires calcium influx via the L-type calcium channel and it will not occur without calcium influx. Reduced calcium influx can delay or prevent cramp. Increased interstitial potassium is implicated in developing and maintaining cramp. Mechanism of reversal of cramp requires wash-out of extracellular potassium via increased blood flow, followed by calcium efflux via sodium-calcium exchange. This paper shows the first successful quantitative electrophysiological and mechanical model of cramp and of its reversal.

Model of skeletal muscle cramp and its reversal

In an accompanying paper [2], we developed the Shorten [3] model of skeletal muscle by incorporating equations such as surface calcium fluxes. In further research in this paper, we succeeded in reproducing muscle cramp, as well as its prevention and reversal, by investigating muscle contraction and cramp, in which calcium regulatory networks are involved, using the extended model in comparison with the original model. Incorporation of data from a traditional medicine from root extracts of paeony and licorice and one of its pure chemicals was modeled. The sensitivity analysis of the extended model shows the robustness of the calcium regulatory networks. Muscle cramp, in the extended model, requires calcium influx via the L-type calcium channel and it will not occur without calcium influx. Reduced calcium influx can delay or prevent cramp. Increased interstitial potassium is implicated in developing and maintaining cramp. Mechanism of reversal of cramp requires wash-out of extracellular potassium via increased blood flow, followed by calcium efflux via sodium-calcium exchange. This paper shows the first successful quantitative electrophysiological and mechanical model of cramp and of its reversal.