Acute recovery from disuse atrophy: the role of stretch-activated ion channels in the activation of anabolic signaling in skeletal muscle

2019 ◽  
Vol 316 (1) ◽  
pp. E86-E95 ◽  
Author(s):  
Timur M. Mirzoev ◽  
Sergey A. Tyganov ◽  
Irina O. Petrova ◽  
Boris S. Shenkman
Keyword(s):  
Ion Channels ◽  
Time Course ◽  
Glycogen Synthase ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Hindlimb Suspension ◽  
Disuse Atrophy ◽  
Mtorc1 Signaling ◽  
Stretch Activated Ion Channels

The aim of the study was to 1) measure time-course alternations in the rate of protein synthesis (PS) and phosphorylation status of the key anabolic markers, and 2) find out the role of stretch-activated ion channels (SACs) in the activation of anabolic signaling in the rat soleus during an acute reloading following disuse atrophy. Wistar rats were subjected to 14-day hindlimb suspension (HS) followed by 6, 12, and 24 h of reloading. To examine the role of SAC in the reloading-induced activation of anabolic signaling, the rats were treated with gadolinium (Gd3+), a SAC blocker. The content of signaling proteins was determined by Western blot. c-Myc mRNA expression was assessed by RT-PCR. After 24-h reloading, the PS rate was elevated by 44% versus control. After 6-h reloading, the p-70-kDa ribosomal protein S6 kinase (p70S6k) and translation initiation factor 4E-binding protein 1 (4E-BP1) did not differ from control; however, 12-h reloading resulted in an upregulation of both p70s6k and 4E-BP1 phosphorylation versus control. The phosphorylation of AKT (Ser473) and glycogen synthase kinase-3β (Ser9) was reduced after HS and then completely restored by 12-h reloading. c-Myc was significantly upregulated during the entire reloading. Gd3+ treatment during reloading (12 h) prevented a full phosphorylation of p70S6k, rpS6, 4E-BP1, as well as PS activation. The results of the study suggest that 1) enhanced PS during the acute recovery from HS may be associated with the activation of ribosome biogenesis as well as mammalian target of rapamycin complex 1 (mTORC1)-dependent signaling pathways, and 2) functional SACs are necessary for complete activation of mTORC1 signaling in rat soleus during acute recovery from HS.

scholarly journals Role of Translation Initiation Factor 2B in Control of Cell Survival by the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3β Signaling Pathway

2002 ◽  
Vol 22 (2) ◽  
pp. 578-586 ◽  
Author(s):  
Marianna Pap ◽  
Geoffrey M. Cooper
Keyword(s):  
Protein Synthesis ◽  
Cell Survival ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Akt Signaling ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Gsk 3Β

ABSTRACT The phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling pathway is an important mediator of growth factor-dependent survival of mammalian cells. A variety of targets of the Akt protein kinase have been implicated in cell survival, including the protein kinase glycogen synthase kinase 3β (GSK-3β). One of the targets of GSK-3β is translation initiation factor 2B (eIF2B), linking global regulation of protein synthesis to PI 3-kinase/Akt signaling. Because of the central role of protein synthesis, we have investigated the involvement of eIF2B, which is inhibited as a result of GSK-3β phosphorylation, in programmed cell death. We demonstrate that expression of eIF2B mutants lacking the GSK-3β phosphorylation or priming sites is sufficient to protect both Rat-1 and PC12 cells from apoptosis induced by overexpression of GSK-3β, inhibition of PI 3-kinase, or growth factor deprivation. Consistent with these effects on cell survival, expression of nonphosphorylatable eIF2B prevented inhibition of protein synthesis following treatment of cells with the PI 3-kinase inhibitor LY294002. Conversely, cycloheximide induced apoptosis of PC12 and Rat-1 cells, further indicating that protein synthesis was required for cell survival. Inhibition of translation resulting from treatment with cycloheximide led to the release of cytochrome c from mitochondria, similar to the effects of inhibition of PI 3-kinase. Expression of nonphosphorylatable eIF2B prevented cytochrome c release resulting from PI 3-kinase inhibition but did not affect cytochrome c release or apoptosis induced by cycloheximide. Regulation of translation resulting from phosphorylation of eIF2B by GSK-3β thus appears to contribute to the control of cell survival by the PI 3-kinase/Akt signaling pathway, acting upstream of mitochondrial cytochrome c release.

scholarly journals An Anabolic Signaling Response of Rat Soleus Muscle to Eccentric Contractions Following Hindlimb Unloading: A Potential Role of Stretch-Activated Ion Channels

2019 ◽  
Vol 20 (5) ◽  
pp. 1165 ◽  
Author(s):  
Sergey Tyganov ◽  
Timur Mirzoev ◽  
Boris Shenkman
Keyword(s):  
Ion Channels ◽  
Potential Role ◽  
Hindlimb Unloading ◽  
Eccentric Contractions ◽  
Temporal Response ◽  
Mtorc1 Signaling ◽  
Mechanical Signal ◽  
Rat Soleus Muscle ◽  
Stretch Activated Ion Channels

Mechanisms that convert a mechanical signal into a biochemical response in an atrophied skeletal muscle remain poorly understood. The aims of the study were to evaluate a temporal response of anabolic signaling and protein synthesis (PS) to eccentric contractions (EC) in rat soleus during hindlimb unloading (HU); and to assess a possible role of stretch-activated ion channels (SAC) in the propagation of a mechanical signal to mTORC1 following HU. Following HU, an isolated soleus was subjected to EC. Upon completion of EC, muscles were collected for western blot analyses to determine the content/phosphorylation of the key anabolic markers. We found that a degree of EC-induced p70S6K phosphorylation and the rate of PS in the soleus of 3- and 7-day unloaded rats was significantly less than that in control. A decrease in EC-induced phosphorylation of p70S6K, RPS6 and PS in the 7-day unloaded soleus treated with SAC inhibitor did not differ from that of the 7-day unloaded soleus without SAC blockade. The results of the study suggest that (i) HU results in a blunted anabolic response to a bout of EC, (ii) attenuation of mTORC1-signaling and PS in response to EC in unloaded soleus may be associated with inactivation of SAC.

scholarly journals Foot-and-Mouth Disease Virus Viroporin 2B Antagonizes RIG-I-Mediated Antiviral Effects by Inhibition of Its Protein Expression

2016 ◽  
Vol 90 (24) ◽  
pp. 11106-11121 ◽  
Author(s):  
Zixiang Zhu ◽  
Guoqing Wang ◽  
Fan Yang ◽  
Weijun Cao ◽  
Ruoqing Mao ◽  
...  
Keyword(s):  
Protein Expression ◽  
Foot And Mouth Disease ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Mouth Disease Virus ◽  
2B Protein ◽  
Eukaryotic Translation Initiation ◽  
Cellular Apoptosis

ABSTRACTThe role of retinoic acid-inducible gene I (RIG-I) in foot-and-mouth disease virus (FMDV)-infected cells remains unknown. Here, we showed that RIG-I inhibits FMDV replication in host cells. FMDV infection increased the transcription of RIG-I, while it decreased RIG-I protein expression. A detailed analysis revealed that FMDV leader proteinase (Lpro), as well as 3C proteinase (3Cpro) and 2B protein, decreased RIG-I protein expression. Lproand 3Cproare viral proteinases that can cleave various host proteins and are responsible for several of the viral polyprotein cleavages. However, for the first time, we observed 2B-induced reduction of host protein. Further studies showed that 2B-mediated reduction of RIG-I is specific to FMDV, but not other picornaviruses, including encephalomyocarditis virus, enterovirus 71, and coxsackievirus A16. Moreover, we found the decreased protein level of RIG-I is independent of the cleavage of eukaryotic translation initiation factor 4 gamma, the induction of cellular apoptosis, or the association of proteasome, lysosome, and caspase pathways. A direct interaction was observed between RIG-I and 2B. The carboxyl-terminal amino acids 105 to 114 and amino acids 135 to 144 of 2B were essential for the reduction of RIG-I, while residues 105 to 114 were required for the interaction. These data suggest the antiviral role of RIG-I against FMDV and a novel antagonistic mechanism of FMDV that is mediated by 2B protein.IMPORTANCEThis study demonstrated that RIG-I could suppress FMDV replication during virus infection. FMDV infection increased the transcriptional expression of RIG-I, while it decreased RIG-I protein expression. FMDV 2B protein interacted with RIG-I and induced reduction of RIG-I. 2B-induced reduction of RIG-I was independent of the induction of the cleavage of eukaryotic translation initiation factor 4 gamma or cellular apoptosis. In addition, proteasome, lysosome, and caspase pathways were not involved in this process. This study provides new insight into the immune evasion mediated by FMDV and identifies 2B as an antagonistic factor for FMDV to evade the antiviral response.

Increased coronary perfusion augments cardiac contractility in the rat through stretch-activated ion channels

2002 ◽  
Vol 282 (4) ◽  
pp. H1334-H1340 ◽  
Author(s):  
R. R. Lamberts ◽  
M. H. P. van Rijen ◽  
P. Sipkema ◽  
P. Fransen ◽  
S. U. Sys ◽  
...  
Keyword(s):  
Ion Channels ◽  
Perfusion Pressure ◽  
Cardiac Contractility ◽  
No Synthase ◽  
Coronary Perfusion ◽  
Channel Blockade ◽  
No Release ◽  
Sustained Increase ◽  
Stretch Activated Ion Channels

The role of stretch-activated ion channels (SACs) in coronary perfusion-induced increase in cardiac contractility was investigated in isolated isometrically contracting perfused papillary muscles from Wistar rats. A brief increase in perfusion pressure (3–4 s, perfusion pulse, n = 7), 10 repetitive perfusion pulses ( n = 4), or a sustained increase in perfusion pressure (150–200 s, perfusion step, n = 7) increase developed force by 2.7 ± 1.1, 7.7 ± 2.2, and 8.3 ± 2.5 mN/mm2 (means ± SE, P < 0.05), respectively. The increase in developed force after a perfusion pulse is transient, whereas developed force during a perfusion step remains increased by 5.1 ± 2.5 mN/mm2 ( P < 0.05) in the steady state. Inhibition of SACs by addition of gadolinium (10 μmol/l) or streptomycin (40 and 100 μmol/l) blunts the perfusion-induced increase in developed force. Incubation with 100 μmol/l N ω-nitro-l-arginine [nitric oxide (NO) synthase inhibition], 10 μmol/l sodium nitroprusside (NO donation) and 0.1 μmol/l verapamil (L-type Ca2+ channel blockade) are without effect on the perfusion-induced increase of developed force. We conclude that brief, repetitive, or sustained increases in coronary perfusion augment cardiac contractility through activation of stretch-activated ion channels, whereas endothelial NO release and L-type Ca2+channels are not involved.

scholarly journals 4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

2021 ◽  
Vol 118 (15) ◽  
pp. e2025522118
Author(s):  
Vijendra Sharma ◽  
Rapita Sood ◽  
Danning Lou ◽  
Tzu-Yu Hung ◽  
Maxime Lévesque ◽  
...  
Keyword(s):  
Animal Models ◽  
Mammalian Target Of Rapamycin ◽  
Neuronal Cell ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Inhibitory Neurons ◽  
Initiation Factor ◽  
Seizure Threshold ◽  
Parvalbumin Neurons

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

scholarly journals Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss of TSC1

2020 ◽  
Author(s):  
Mayukh Choudhury ◽  
Clara A. Amegandjin ◽  
Vidya Jadhav ◽  
Josianne Nunes Carriço ◽  
Ariane Quintal ◽  
...  
Keyword(s):  
Social Behavior ◽  
Time Course ◽  
Cell Types ◽  
Developmental Time ◽  
Adult Mice ◽  
Mtorc1 Signaling ◽  
Pv Cell ◽  
Mechanistic Basis

ABSTRACTMutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear.Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.

scholarly journals The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

2021 ◽  
Vol 13 ◽  
Author(s):  
Nicolás W. Martinez ◽  
Felipe E. Gómez ◽  
Soledad Matus
Keyword(s):  
Protein Kinase ◽  
Pathological Process ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Kinase R ◽  
Eukaryotic Translation ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Initiation Factor 2

There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer’s disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR’s contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

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