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1.
Arch Biochem Biophys ; 695: 108622, 2020 11 30.
Article in English | MEDLINE | ID: mdl-33053365

ABSTRACT

The unloading of postural muscles leads to the changes in myosins heavy chains isoforms (MyHCs) mRNAs transcription pattern, that cause severe alterations of muscle functioning. Several transcription factors such as NFATc1 and TEAD1 upregulate slow MyHC mRNA transcription, and p38 MAP kinase can phosphorylate NFAT and TEAD1, causing their inactivation. However, the role p38 MAP kinase plays in MyHCs mRNAs transcription regulation in postural soleus muscle during unloading remains unclear. We aimed to investigate whether pharmacological inhibition of p38 MAPK during rat soleus unloading would prevent the unloading-induced slow-type MyHC mRNA transcription decrease by affecting calcineurin/NFATc1 or TEAD1 signaling. Male Wistar rats were randomly assigned to three groups: cage control (C), 3-day hindlimb suspended group (3HS) and 3-day hindlimb suspended group with the daily oral supplementation of 10 mg/kg p38 MAPK inhibitor VX-745 (3HS + VX-745). 3 days of hindlimb suspension caused the significant decreases of slow MyHC and slow-tonic myh7b mRNAs transcription as well as the decrease of NFATc1-dependent MCIP1.4 mRNA transcription in rat soleus muscles compared to the cage control. P38 MAP-kinase inhibition during hindlimb suspension completely prevented slow MyHC mRNA content decrease and partially prevented slow-tonic myh7b and MCIP1.4 mRNAs transcription decreases compared to the 3HS group. We also observed NFATc1 and TEAD1 myonuclear contents increases in the 3HS + VX-745 group compared to both 3HS and C groups (p < 0.05). Therefore, we found that p38 inhibition counteracts the unloading-induced slow MyHC mRNA transcription downregulation and leads to the activation of calcineurin/NFAT signaling cascade in unloaded rat soleus muscles.


Subject(s)
Cardiac Myosins/biosynthesis , MAP Kinase Signaling System , Muscle, Skeletal/enzymology , Myosin Heavy Chains/biosynthesis , RNA, Messenger/biosynthesis , Transcription, Genetic , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , DNA-Binding Proteins/metabolism , Male , Nuclear Proteins/metabolism , Rats , Rats, Wistar , TEA Domain Transcription Factors , Transcription Factors/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
2.
Bull Exp Biol Med ; 169(4): 450-457, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32889570

ABSTRACT

We studied the effect of histone deacetylase 1 (HDAC1) inhibition on titin content and expression of TTN gene in rat m. soleus after 3-day gravitational unloading. Male Wistar rats weighing 210±10 g were randomly divided into 3 groups: control, 3-day hindlimb suspension, and 3-day hindlimb suspension and injection of HDAC1 inhibitor CI-994 (1 mg/kg/day). In hindlimb-suspended rats, the muscle weight/animal body weight ratio was reduced by 13.8% (p<0.05) in comparison with the control, which attested to the development of atrophic changes in the soleus muscle. This was associated with a decrease in the content of NT-isoform of intact titin-1 by 28.6% (p˂0.05) and an increase in TTN gene expression by 1.81 times (p˂0.05) in the soleus muscle. Inhibition of HDAC1 by CI-994 during 3-day hindlimb suspension prevented the decrease in titin content and development of atrophy in rat soleus muscle. No significant differences in the TTN gene expression from the control were found. These results can be used when finding the ways of preventing or reducing the negative changes in the muscle caused by gravitational unloading.


Subject(s)
Benzamides/pharmacology , Connectin/genetics , Histone Deacetylase 1/genetics , Histone Deacetylase Inhibitors/pharmacology , Muscular Atrophy/prevention & control , Phenylenediamines/pharmacology , Animals , Connectin/metabolism , Gene Expression Regulation , Hindlimb , Hindlimb Suspension/adverse effects , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase 1/metabolism , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Atrophy/etiology , Muscular Atrophy/genetics , Muscular Atrophy/metabolism , Organ Size , Protein Isoforms/genetics , Protein Isoforms/metabolism , Rats , Rats, Wistar , Signal Transduction
3.
Dokl Biochem Biophys ; 474(1): 165-167, 2017 May.
Article in English | MEDLINE | ID: mdl-28726101

ABSTRACT

Functional unloading of m. soleus of male Wistar rats was found to cause a reduction in protein synthesis. The level of phosphorylation of the translation elongation factor 2 (eEF2) and the eEF2 kinase (eEF2k) activity in m. soleus after 14 days of unloading were assessed. Rats were divided into the control group (C) and the group with hindlimb unloading for 14 days (HU14). The level of eEF2 phosphorylation in group HU14 was 80%, whereas in the control is was 40%. The indices of eEF2k expression and protein content in group HU14 increased compared to group C.


Subject(s)
Elongation Factor 2 Kinase/metabolism , Hindlimb Suspension/adverse effects , Muscle, Skeletal/enzymology , Animals , Elongation Factor 2 Kinase/genetics , Enzyme Activation , Gene Expression Regulation, Neoplastic , Male , Phosphorylation , Rats
5.
Bull Exp Biol Med ; 155(6): 767-70, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24288762

ABSTRACT

Extralife, a Pentaphylloides fruticos extract, in concentrations of 0.005-10 µg/ml dose-dependently increased H2O2 production in rat heart mitochondria in the presence of respiration substrates. Extralife decreased ATP-induced accumulation of H2O2 related to inhibition of mitochondrial ATP-dependent potassium channel. This effect was observed only at low doses of the adaptogen (0.05-3 µg/ml). High doses of the substance (5-10 µg/ml) did not abolish ATP-dependent production of H2O2 and increased the rate of H2O2 generation by the mitochondria. We concluded that Extralife in trace concentrations could activate mitochondrial ATP-dependent potassium channel and decrease H2O2 accumulation in the mitochondria.


Subject(s)
Antioxidants/pharmacology , Hydrogen Peroxide/metabolism , KATP Channels/metabolism , Mitochondria, Heart/metabolism , Plant Extracts/pharmacology , Adenosine Triphosphate/pharmacology , Adenosine Triphosphate/physiology , Animals , Decanoic Acids/pharmacology , Glutamic Acid/pharmacology , Glutamic Acid/physiology , Hydroxy Acids/pharmacology , Malates/pharmacology , Mitochondria, Heart/drug effects , Potassium Channel Blockers/pharmacology , Rats , Rats, Wistar , Rotenone/pharmacology , Succinic Acid/pharmacology
6.
Prikl Biokhim Mikrobiol ; 49(4): 345-52, 2013.
Article in Russian | MEDLINE | ID: mdl-24455859

ABSTRACT

The effect of adaptogens-antihypoxants that participate in the activation of mitochondrial ATP-dependent potassium channels (mitoK(ATP)) at the oxidation of the Amplex Red (AR) fluorescent indicator in a peroxidase system was tested. It was shown that Extralife, Hypoxen, taurine, and synthetic antioxidant ionol can be arranged in the following row, according to the fluorescence inhibition activity: Extralife > Hypoxen > > ionol > taurine; their effect was shown to be concentration-dependent. The calculated K(i) value of fluorescence indicators demonstrate fast and slow phases of inhibition of the AR oxidation by Extralife and Hypoxen. The fast phase occurs in the presence of microdoses (0.05-3 microg/mL) of adaptogens and is related to the competition for H2O2, which is in agreement with our previous data on the mitoK(ATP) activation by doses of adaptogens related to the H2O2 consumption. The slow phase is characteristic of high adaptogen and ionol concentrations and is related to the competition for phenoxyl radicals of resorufin formed during AR oxidation. The obtained results allow one to suggest the application of a highly sensitive model peroxidase system with AR for the preliminary testing of compounds activating mitoK(ATP) channels.


Subject(s)
Antioxidants/chemistry , Butylated Hydroxytoluene/chemistry , Oxazines/analysis , Phenyl Ethers/chemistry , Plant Extracts/chemistry , Taurine/chemistry , Fluorescent Dyes , Humans , Mitochondria/chemistry , Mitochondria/metabolism , Oxazines/chemistry , Potassium Channels/agonists , Potassium Channels/chemistry , Solutions , Spectrometry, Fluorescence
7.
Biofizika ; 57(5): 789-95, 2012.
Article in Russian | MEDLINE | ID: mdl-23136770

ABSTRACT

The mechanisms of cytotoxic effect of uranyl nitrate were studied. It was shown that uranyl nitrate induced HEp-2 cell death, mainly by necrotic way. In the experiments in vitro, uranyl nitrate caused an appearance of 8-oxoguanine in DNA, indicating the induction of oxidative stress. The experiments with isolated rat liver mitochondria revealed that 1 mM uranyl nitrate decreased the respiration rates of mitochondria in state 3 and DNP-induced respiration. At the same time, uranyl nitrate had no influence on the opening of the mitochondrial permeability transition pore and decreased the rate of formation of H2O2 by mitochondria. Possible molecular mechanisms of uranyl-induced necrosis are discussed.


Subject(s)
Cell Respiration/drug effects , Mitochondria, Liver/drug effects , Uranyl Nitrate/pharmacology , 2,4-Dinitrophenol/pharmacology , Animals , Cell Death/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Guanine/analogs & derivatives , Guanine/metabolism , Humans , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/metabolism , Liver/cytology , Liver/drug effects , Liver/metabolism , Male , Mitochondria, Liver/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Oxidative Stress/drug effects , Rats , Reactive Oxygen Species/metabolism
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