This study aimed to determine whether electrical stimulation-based twitch exercise is effective in inhibiting the progression of immobilization-induced muscle fibrosis. 19 Wistar rats were randomly divided into a control group (n=6), an immobilization group (n=6; with immobilization only), and a Belt group (n=7; with immobilization and twitch exercise through the belt electrode device, beginning 2 weeks after immobilization). The bilateral soleus muscles were harvested after the experimental period. The right soleus muscles were used for histological analysis, and the left soleus muscles were used for biochemical and molecular biological analysis. As a result, in the picrosirius red images, the perimysium and endomysium were thicker in both the immobilization and Belt groups compared to the control group. However, the perimysium and endomysium thickening were suppressed in the Belt group. The hydroxyproline content and alpha-SMA, TGF-beta1, and HIF-1alpha mRNA expressions were significantly higher in the immobilization and belt groups than in the control group. These expressions were significantly lower in the Belt group than in the immobilization group. The capillary-to-myofiber ratio and the mRNA expressions of VEGF and PGC-1alpha were significantly lower in the immobilization and belt groups than in the control group, these were significantly higher in the Belt group than in the immobilization group. From these results, Electrical stimulation-based twitch exercise using the belt electrode device may prevent the progression of immobilization-induced muscle fibrosis caused by downregulating PGC-1alpha/VEGF pathway, we surmised that this intervention strategy might be effective against the progression of muscle contracture. Keywords: Immobilization, Skeletal muscle, Fibrosis, Electrical stimulation-based twitch exercise, PGC-1alpha/VEGF pathway.
- MeSH
- down regulace * MeSH
- elektrická stimulace MeSH
- elektrostimulační terapie metody MeSH
- fibróza * MeSH
- kondiční příprava zvířat fyziologie MeSH
- kosterní svaly * metabolismus patologie MeSH
- krysa rodu rattus MeSH
- nemoci svalů metabolismus patologie prevence a kontrola etiologie MeSH
- potkani Wistar MeSH
- PPARGC1A * metabolismus MeSH
- progrese nemoci MeSH
- signální transdukce fyziologie MeSH
- vaskulární endoteliální růstový faktor A * metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Although electrical muscle stimulation (EMS) of skeletal muscle effectively prevents muscle atrophy, its effect on the breakdown of muscle component proteins is unknown. In this study, we investigated the biological mechanisms by which EMS-induced muscle contraction inhibits disuse muscle atrophy progression. Experimental animals were divided into a control group and three experimental groups: immobilized (Im; immobilization treatment), low-frequency (LF; immobilization treatment and low-frequency muscle contraction exercise), and high-frequency (HF; immobilization treatment and high-frequency muscle contraction exercise). Following the experimental period, bilateral soleus muscles were collected and analyzed. Atrogin-1 and Muscle RING finger 1 (MuRF-1) mRNA expression levels were significantly higher for the experimental groups than for the control group but were significantly lower for the HF group than for the Im group. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA and protein expression levels in the HF group were significantly higher than those in the Im group, with no significant differences compared to the Con group. Both the Forkhead box O (FoxO)/phosphorylated FoxO and protein kinase B (AKT)/phosphorylated AKT ratios were significantly lower for the Im group than for the control group and significantly higher for the HF group than for the Im group. These results, the suppression of atrogin-1 and MuRF-1 expression for the HF group may be due to decreased nuclear expression of FoxO by AKT phosphorylation and suppression of FoxO transcriptional activity by PGC-1alpha. Furthermore, the number of muscle contractions might be important for effective EMS.
- MeSH
- kosterní svaly metabolismus MeSH
- messenger RNA metabolismus MeSH
- PPAR gama metabolismus MeSH
- PPARGC1A metabolismus MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- svalová atrofie prevence a kontrola genetika metabolismus MeSH
- svalové proteiny metabolismus MeSH
- transkripční faktory * genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Impaired thermogenesis observed in mice with whole-body ablation of peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β; officially known as PPARGC1B) may result from impaired brown fat (brown adipose tissue; BAT) function, but other mechanism(s) could be involved. Here, using adipose-specific PGC-1β knockout mice (PGC-1β-AT-KO mice) we aimed to learn whether specific PGC-1β ablation in adipocytes is sufficient to drive cold sensitivity. Indeed, we found that warm-adapted (30°C) mutant mice were relatively sensitive to acute cold exposure (6°C). When these mice were subjected to cold exposure for 7 days (7-day-CE), adrenergic stimulation of their metabolism was impaired, despite similar levels of thermogenic uncoupling protein 1 in BAT in PGC-1β-AT-KO and wild-type mice. Gene expression in BAT of mutant mice suggested a compensatory increase in lipid metabolism to counteract the thermogenic defect. Interestingly, a reduced number of contacts between mitochondria and lipid droplets associated with low levels of L-form of optic atrophy 1 was found in BAT of PGC-1β-AT-KO mice. These genotypic differences were observed in warm-adapted mutant mice, but they were partially masked by 7-day-CE. Collectively, our results suggest a role for PGC-1β in controlling BAT lipid metabolism and thermogenesis. This article has an associated First Person interview with the first author of the paper.
- MeSH
- hnědá tuková tkáň * MeSH
- lidé MeSH
- myši MeSH
- PPARGC1A metabolismus MeSH
- proteiny vázající RNA metabolismus MeSH
- termogeneze genetika MeSH
- transkripční faktory * metabolismus MeSH
- tukové buňky MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The transcriptional regulator peroxisome proliferator activated receptor gamma coactivator 1A (PGC-1α), encoded by PPARGC1A, has been linked to neurodegenerative diseases. Recently discovered CNS-specific PPARGC1A transcripts are initiated far upstream of the reference promoter, spliced to exon 2 of the reference gene, and are more abundant than reference gene transcripts in post-mortem human brain samples. The proteins translated from the CNS and reference transcripts differ only at their N-terminal regions. To dissect functional differences between CNS-specific isoforms and reference proteins, we used clustered regularly interspaced short palindromic repeats transcriptional activation (CRISPRa) for selective endogenous activation of the CNS or the reference promoters in SH-SY5Y cells. Expression and/or exon usage of the targets was ascertained by RNA sequencing. Compared to controls, more differentially expressed genes were observed after activation of the CNS than the reference gene promoter, while the magnitude of alternative exon usage was comparable between activation of the two promoters. Promoter-selective associations were observed with canonical signaling pathways, mitochondrial and nervous system functions and neurological diseases. The distinct N-terminal as well as the shared downstream regions of PGC-1α isoforms affect the exon usage of numerous genes. Furthermore, associations of risk genes of amyotrophic lateral sclerosis and Parkinson's disease were noted with differentially expressed genes resulting from the activation of the CNS and reference gene promoter, respectively. Thus, CNS-specific isoforms markedly amplify the biological functions of PPARGC1A and CNS-specific isoforms and reference proteins have common, complementary and selective functions relevant for neurodegenerative diseases.
- MeSH
- aktivace transkripce * MeSH
- exony MeSH
- genové regulační sítě * MeSH
- HEK293 buňky MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- neurodegenerativní nemoci genetika MeSH
- neurony metabolismus MeSH
- nukleotidové motivy MeSH
- PPARGC1A genetika metabolismus MeSH
- promotorové oblasti (genetika) * MeSH
- protein - isoformy genetika metabolismus MeSH
- transkriptom MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The skeletal muscles of animals and humans with type 2 diabetes have decreased oxidative capacity. Aerobic exercise can improve muscle oxidative capacity, but no data are available on the amount of exercise required. We investigated the effects of voluntary running exercise and running distance on the skeletal muscle properties of nonobese rats with type 2 diabetes. Six-week-old male diabetic Goto-Kakizaki rats were divided into nonexercised (GK) and exercised (GK-Ex) groups. The rats in the GK-Ex group were permitted voluntary running exercise on wheels for 6 weeks. Age-matched male Wistar rats (WR) were used as nondiabetic controls. Fasting blood glucose and HbA1c levels were higher in the GK and GK-Ex groups than in the WR group and lower in the GK-Ex group than in the GK group. Succinate dehydrogenase (SDH) activity and peroxisome proliferator-activated receptor gamma coactivator-1alpha (Pgc-1alpha) mRNA levels in the soleus and plantaris muscles were higher in the WR and GK-Ex groups than in the GK group. HbA1c and total cholesterol levels were negatively correlated with running distance and SDH activity and Pgc-1alpha mRNA levels in the soleus muscle were positively correlated with running distance. The onset and progression of diabetes in nonobese diabetic rats were effectively inhibited by running longer distances.
- MeSH
- diabetes mellitus 2. typu metabolismus rehabilitace MeSH
- kondiční příprava zvířat * MeSH
- kosterní svaly fyziologie MeSH
- krevní glukóza metabolismus MeSH
- krysa rodu rattus MeSH
- PPARGC1A metabolismus MeSH
- sukcinátdehydrogenasa metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
This study aimed at achieving the molecular characterization of peroxisome proliferator-activated receptor-gamma coactivator 1β (PGC-1β) and exploring its modulatory roles in mitochondria biogenesis in blunt snout bream (Megalobrama amblycephala). A full-length cDNA of PGC-1β was cloned from liver which covered 3110 bp encoding 859 amino acids. The conserved motifs of PGC-1β family proteins were gained by MEME software, and the phylogenetic analyses showed motif loss and rearrangement of PGC-1β in fish. The function of PGC-1β was evaluated through overexpression and knockdown of PGC-1β in primary hepatocytes of blunt snout bream. We observed overexpression of PGC-1β along with enhanced mitochondrial transcription factor A (TFAM) expression and mtDNA copies in hepatocytes, and its knockdown led to slightly reduced NRF1 expression. However, knockdown of PGC-1β did not significantly influence TFAM expression or mtDNA copies. The alterations in mitochondria biogenesis were assessed following high-fat intake, and the results showed that it induces downregulation of PGC-1β. Furthermore, significant decreases in mitochondrial respiratory chain activities and mitochondria biogenesis were observed by high-fat intake. Our findings demonstrated that overexpression of PGC-1β induces the enhancement of TFAM expression and mtDNA amount but not NRF-1. Therefore, it could be concluded that PGC-1β is involved in mitochondrial biogenesis in blunt snout bream but not through PGC-1β/NRF-1 pathway.
- MeSH
- aminokyseliny MeSH
- biogeneze organel MeSH
- Cyprinidae genetika fyziologie MeSH
- DNA vazebné proteiny genetika MeSH
- fylogeneze MeSH
- hepatocyty fyziologie MeSH
- játra MeSH
- mitochondriální DNA genetika MeSH
- mitochondriální proteiny genetika MeSH
- mitochondrie genetika fyziologie MeSH
- PPARGC1A genetika MeSH
- signální transdukce genetika MeSH
- transkripční faktory genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the fourth most frequent cause of cancer-related death worldwide. Sorafenib is the first line recommended therapy for patients with locally advanced/metastatic HCC. The low response rate is attributed to intrinsic resistance of HCC cells to Sorafenib. The potential resistance to Sorafenib-induced cell death is multifactorial and involves all hallmarks of cancer. However, the presence of sub-therapeutic dose can negatively influence the antitumoral properties of the drug. In this sense, the present study showed that the sub-optimal Sorafenib concentration (10 nM) was associated with activation of caspase-9, AMP-activated protein kinase (AMPK), sustained autophagy, peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α) and mitochondrial function in HepG2 cells. The increased mitochondrial respiration by Sorafenib (10 nM) was also observed in permeabilized HepG2 cells, but not in isolated rat mitochondria, which suggests the involvement of an upstream component in this regulatory mechanism. The basal glycolysis was dose dependently increased at early time point studied (6 h). Interestingly, Sorafenib increased nitric oxide (NO) generation that played an inhibitory role in mitochondrial respiration in sub-therapeutic dose of Sorafenib. The administration of sustained therapeutic dose of Sorafenib (10 µM, 24 h) induced mitochondrial dysfunction and dropped basal glycolysis derived acidification, as well as increased oxidative stress and apoptosis in HepG2. In conclusion, the accurate control of the administered dose of Sorafenib is relevant for the potential prosurvival or proapoptotic properties induced by the drug in liver cancer cells.
- MeSH
- autofagie účinky léků MeSH
- buněčná smrt účinky léků MeSH
- buňky Hep G2 MeSH
- chemorezistence účinky léků MeSH
- hepatocelulární karcinom metabolismus patologie MeSH
- jaterní mitochondrie účinky léků metabolismus MeSH
- kaspasa 9 metabolismus MeSH
- lidé MeSH
- nádory jater metabolismus patologie MeSH
- oxid dusnatý metabolismus MeSH
- potkani Wistar MeSH
- PPARGC1A metabolismus MeSH
- proteinkinasy aktivované AMP metabolismus MeSH
- protinádorové látky farmakologie MeSH
- signální transdukce účinky léků MeSH
- sorafenib farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Although the scientific literature regarding sports genomics has grown during the last decade, some genes, such as peroxisome proliferator activated receptors (PPARs), have not been fully described in terms of their role in achieving extraordinary sports performance. Therefore, the purpose of this systematic review was to determine which elite sports performance constraints are positively influenced by PPARs and their coactivators. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used, with a combination of PPAR and sports keywords. RESULTS: In total, 27 studies that referred to PPARs in elite athletes were included, where the Ala allele in PPARG rs1801282 was associated with strength and power elite athlete status in comparison to subelite athlete status. The C allele in PPARA rs4253778 was associated with soccer, and the G allele PPARA rs4253778 was associated with endurance elite athlete status. Other elite status endurance alleles were the Gly allele in PPARGC1A rs8192678 and the C allele PPARD rs2016520. CONCLUSIONS: PPARs can be used for estimating the potential to achieve elite status in human physical performance in strength and power, team, and aerobic sports disciplines. Carrying specific PPAR alleles can provide a partial benefit to achieving elite sports status, but does not preclude achieving elite status if they are absent.
BACKGROUND: The peroxisome proliferator-activated receptors (PPARA, PPARG, PPARD) and their transcriptional coactivators' (PPARGC1A, PPARGC1B) gene polymorphisms have been associated with muscle morphology, oxygen uptake, power output and endurance performance. The purpose of this review is to determine whether the PPARs and/or their coactivators' polymorphisms can predict the training response to specific training stimuli. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses, a literature review has been run for a combination of PPARs and physical activity key words. RESULTS: All ten of the included studies were performed using aerobic training in general, sedentary or elderly populations from 21 to 75 years of age. The non-responders for aerobic training (VO₂peak increase, slow muscle fiber increase and low-density lipoprotein decrease) are the carriers of PPARGC1A rs8192678 Ser/Ser. The negative responders for aerobic training (decrease in VO₂peak) are carriers of the PPARD rs2267668 G allele. The negative responders for aerobic training (decreased glucose tolerance and insulin response) are subjects with the PPARG rs1801282 Pro/Pro genotype. The best responders to aerobic training are PPARGC1A rs8192678 Gly/Gly, PPARD rs1053049 TT, PPARD rs2267668 AA and PPARG rs1801282 Ala carriers. CONCLUSIONS: The human response for aerobic training is significantly influenced by PPARs' gene polymorphism and their coactivators, where aerobic training can negatively influence glucose metabolism and VO₂peak in some genetically-predisposed individuals.
- MeSH
- dospělí MeSH
- jednonukleotidový polymorfismus * MeSH
- kondiční příprava * MeSH
- kosterní svaly metabolismus fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- PPARGC1A genetika MeSH
- receptory aktivované proliferátory peroxizomů genetika MeSH
- senioři MeSH
- spotřeba kyslíku MeSH
- transportní proteiny genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
The aging process is associated with a decline in mitochondrial functions. Mitochondria dysfunction is involved in initiation and progression of many health problems including neuromuscular, metabolic and cardiovascular diseases. It is well known that endurance exercise improves mitochondrial function, especially in the elderly. However, recent studies have demonstrated that resistance training lead also to substantial increases in mitochondrial function in skeletal muscle. A comprehensive understanding of the cellular mechanisms involved in the skeletal muscle mitochondrial adaptations to exercise training in healthy elderly subjects, can help practitioners to design and prescribe more effective exercise trainings.
- MeSH
- cvičení fyziologie MeSH
- fyzická vytrvalost fyziologie MeSH
- fyziologická adaptace fyziologie MeSH
- kosterní svaly metabolismus MeSH
- lidé MeSH
- PPARGC1A metabolismus MeSH
- stárnutí metabolismus MeSH
- svalové mitochondrie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
