Energy Metabolism Gene Expression Research Articles

Pharmacological inhibition of ENT1 enhances the impact of specific dietary fats on energy metabolism gene expression

Medium chain fatty acids are commonly consumed as part of diets for endurance sports and as medical treatment in ketogenic diets where these diets regulate energy metabolism and increase adenosine levels. However, the role of the equilibrative nucleoside transporter 1 (ENT1), which is responsible for adenosine transport across membranes in this process, is not well understood. Here, we investigate ENT1 activity in controlling the effects of two dietary medium chain fatty acids (decanoic and octanoic acid), employing the tractable model system Dictyostelium. We show that genetic ablation of three ENT1 orthologues unexpectedly improves cell proliferation specifically following decanoic acid treatment. This effect is not caused by increased adenosine levels triggered by both fatty acids in the presence of ENT1 activity. Instead, we show that decanoic acid increases expression of energy-related genes relevant for fatty acid β-oxidation, and that pharmacological inhibition of ENT1 activity leads to an enhanced effect of decanoic acid to increase expression of tricarboxylicacid cycle and oxidative phosphorylation components. Importantly, similar transcriptional changes have been shown in the rat hippocampus during ketogenic diet treatment. We validated these changes by showing enhanced mitochondria load and reduced lipid droplets. Thus, our data show that ENT1 regulates the medium chain fatty acid-induced increase in cellular adenosine levels and the decanoic acid-induced expression of important metabolic enzymes in energy provision, identifying a key role for ENT1 proteins in metabolic effects of medium chain fatty acids.

In-depth transcriptome and physiological function analysis reveals the toxicology of sodium fluoride in the fall webworm Hyphantria cunea

Fluoride is an environmental pollutant that severely injures various organisms in ecosystems. Herein, the non-target organism, fall webworm (Hyphantria cunea), was used to determine the toxicological mechanism of NaF exposure. In this study, H. cunea exposed to NaF showed significant declines in growth and reproduction. The authors conducted RNA sequencing on adipose bodies and midgut tissues from NaF-exposed H. cunea larvae to uncover the toxicological mechanisms. The results showed that extracellular matrix-receptor interaction, pentose and glucuronate interconversions, fatty acid biosynthesis, and ferroptosis might contribute to NaF stress. NaF significantly decreased the antioxidant level, nitrous oxide synthase activity, and NO content, while significantly increasing lipid peroxidation. NaF induced significant changes in the expression of energy metabolism genes. However, the triglyceride content was significantly decreased and the lipase enzyme activity was significantly increased. Moreover, the expression levels of light and heavy chains of ferritin were inhibited in NaF-exposed H. cunea. NaF caused ferritin Fe2+overload in FerHCH1 and FerLCH knockdown H. cunea larvae, activated reactive oxygen species, and reduced the total iron content, eventually increasing the mortality H. cunea larvae. This study identified the toxicological mechanisms of NaF in lipid synthesis and energy metabolism in H. cunea, providing a basis for understanding the molecular mechanisms of NaF toxicity and developing pollution control strategies.

Mitochondrial dysfunction of peripheral blood mononuclear cells is associated with lung carcinogenesis

The composition, quantity, and function of peripheral blood mononuclear cells (PBMCs) are closely correlated with tumorigenesis. However, the mechanisms of PBMCs in lung cancer are not clear. Mitochondria are energy factories of cells, and almost all cellular functions rely on their energy metabolism level. The present study aimed to test whether the mitochondrial function of PBMCs directly determines their tumor immune monitoring function. We recruited 211 subjects, including 105 healthy controls and 106 patients with recently diagnosed with lung cancer. The model of lung carcinogenesis induced by BaP was used in animal experiment, and the Bap carcinogenic metabolite, Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE), was used in cell experiment. We found that mitochondrial function of PBMCs decreased significantly in patients with new lung cancer, regardless of age. In vivo, BaP caused PBMC mitochondrial dysfunction in mice before the appearance of visible malignant tissue. Moreover, mitochondrial function decreased significantly in mice with lung cancers induced by BaP compared to those without lung cancer after BaP intervention. In vitro, BPDE also induced mitochondrial dysfunction and reduced the aggressiveness of PBMCs toward cancer cells. Furthermore, the changes in mitochondrial energy metabolism gene expression caused by BPDE are involved in this process. Thus, the mitochondrial function of PBMCs is a potential prognostic biomarker or therapeutic target to improve clinical outcomes in patients with lung cancer.

Диагностическая значимость определения экспрессии генов энергетического метаболизма при задержке роста плода

Диагностическая значимость определения экспрессии генов энергетического метаболизма при задержке роста плода

Acute environmental hypoxia induced changes of tissue morphology, antioxidant capacity, immune response and energy metabolism in Marsupenaeus japonicus

The current study was to investigate the influence of acute hypoxia on the tissue morphology, antioxidant capacity, immune response and energy metabolism in Marsupenaeus japonicus. A total of 180 shrimp were cultured and sampled at 0 h, 2 h, 4 h, 6 h, 10 h after hypoxia. Our findings revealed that acute hypoxia occurred, which was confirmed by darken serum color, increased hepatopancreas hemocyanin and hypoxia-inducible factor 1 expression. Inter-tissue differences existed in gene expression relating to the antioxidant capacity, immune response, and energy metabolism. Expression levels of the above index showed inconsistent trends in the hepatopancreas, while muscle gene expression showed an overall trend of first increasing and then decreasing. Muscle gene expression of energy metabolism (except for glycogen phosphorylase gene) reached the highest value (7.33–227.92 times) after hypoxic for 2 h, and the response was earlier and larger than that of hepatopancreas. Taken together, our results demonstrated that hypoxia could change serum color, influence antioxidant capacity, immune response and energy metabolism n M.japonicus. The response mechanism was tissue-specific and muscle might be the target response tissue for energy metabolism in M.japonicus.

Mutation of gdpS gene induces a viable but non-culturable state in Staphylococcus epidermidis and changes in the global transcriptional profile

BackgroundIn the genome of staphylococci, only the gdpS gene encodes the conserved GGDEF domain, which is the characteristic of diguanylate cyclases. In our previous study, we have demonstrated that the gdpS gene can modulate biofilm formation by positively regulating the expression of ica operon in Staphylococcus epidermidis. Moreover, this regulation seems to be independent of the c-di-GMP signaling pathway and the protein-coding function of this gene. Therefore, the biological function of the gdpS gene remains to be further investigated.ResultsIn the present study, it was observed that mutation of the gdpS gene induced S. epidermidis to enter into a presumed viable but nonculturable state (VBNC) after cryopreservation with glycerol. Similarly, when moved from liquid to solid culture medium, the gdpS mutant strain also exhibited a VBNC state. Compared with the wild-type strain, the gdpS mutant strain autolyzed more quickly during storage at 4℃, indicating its increased susceptibility to low temperature. Transcriptional profiling analysis showed that the gdpS mutation affected the transcription of 188 genes (92 genes were upregulated and 96 genes were downregulated). Specifically, genes responsible for glycerol metabolism were most markedly upregulated and most of the altered genes in the mutant strain are those involved in nitrogen metabolism. In addition, the most significantly downregulated genes included the betB gene, whose product catalyzes the synthesis of glycine betaine and confers tolerance to cold.ConclusionThe preliminary results suggest that the gdpS gene may participate in VBNC formation of S. epidermidis in face of adverse environmental factors, which is probably achieved by regulating expression of energy metabolism genes. Besides, the gdpS gene is critical for S. epidermidis to survive low temperature, and the underlying mechanism may be partly explained by its influence on expression of betB gene.

Maternal dietary methionine restriction alters the expression of energy metabolism genes in the duckling liver

BackgroundIn mammals, the nutritional status experienced during embryonic development shapes key metabolic pathways and influences the health and phenotype of the future individual, a phenomenon known as nutritional programming. In farmed birds as well, the quantity and quality of feed offered to the dam can impact the phenotype of the offspring. We have previously reported that a 38% reduction in the intake of the methyl donor methionine in the diet of 30 female ducks during the growing and laying periods - from 10 to 51 weeks of age - reduced the body weight of their 180 mule ducklings compared to that of 190 ducklings from 30 control females. The maternal dietary methionine restriction also altered the hepatic energy metabolism studied in 30 of their ducklings. Thus, their plasma glucose and triglyceride concentrations were higher while their plasma free fatty acid level was lower than those measured in the plasma of 30 ducklings from the control group. The objective of this new study was to better understand how maternal dietary methionine restriction affected the livers of their newly hatched male and female ducklings by investigating the hepatic expression levels of 100 genes primarily targeting energy metabolism, amino acid transport, oxidative stress, apoptotic activity and susceptibility to liver injury.ResultsSixteen of the genes studied were differentially expressed between the ducklings from the two groups. Maternal dietary methionine restriction affected the mRNA levels of genes involved in different pathways related to energy metabolism such as glycolysis, lipogenesis or electron transport. Moreover, the mRNA levels of the nuclear receptors PPARGC1B, PPARG and RXRA were also affected.ConclusionsOur results show that the 38% reduction in methionine intake in the diet of female ducks during the growing and egg-laying periods impacted the liver transcriptome of their offspring, which may explain the previously observed differences in their liver energy metabolism. These changes in mRNA levels, together with the observed phenotypic data, suggest an early modulation in the establishment of metabolic pathways.

Association between a low baseline level of gene expression of energy metabolism in the blood and the development of clinical remission in response to tofacitinib therapy in patients with rheumatoid arthritis

Background. Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, characterized by erosive arthritis (synovitis) and systemic inflammation. Janus kinase (JAK) inhibitors (JAKi) are small molecules that block major signal pathways of many cytokines a growth factors, associated with RA. Identification of patients sensitive to JAKi before treatment could significantly improve therapy outcomes. Currently it is not possible to predict JAKi efficacy in every patient, while some patients are non-responsive to the drug, other develop adverse effects. JAKi effect in RA patients has been recently associated with alterations in mitochondrial function and ATP production. Therefore, we hypothesized that baseline metabolic status of RA patients prior to drug administration can predict the therapeutic outcome.Objective: to investigate the predictive value of baseline expression of genes involved in energy generation in the blood of RA patients, for treatment response to JAKi.Patients and methods. We examined peripheral blood of 28 RA patients aged 52.2±15.6 years, average disease duration 3.5 years (range 0.6–19), treated with Tofacitinib (TOFA, 5–10 mg twice a day) during three months and 26 healthy age-matched control subjects. Clinical response was assessed by disease activity score (DAS28-ESR), immunological status by measurements of serum levels of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), and C-reactive protein (CRP). Gene expression was assessed in peripheral blood cells by realtime reverse-transcription polymerase chain reaction (RT-PCR). At baseline all patients had Steinbrocker radiographic stage II–III. Most patients (85.7%) were ACPA and RF positive. Thirteen patients had medium, others – high RA activity.Results and discussion. JAKi treatment significantly decreased the inflammatory disease activity according to DAS28. At the end of the study 17 patients demonstrated moderate disease activity (3.2<DAS28<5.1), 4 patients retained high disease activity while 7, attained remission (DAS28 <2.6). Disease remission, achieved on TOFA treatment, was accompanied by significant decrease in CRP and the number of swollen and tender joints. ESR values were not changed significantly. Gene expression analysis revealed that RA patients, which attained clinical remission after TOFA treatment, demonstrated significantly lower baseline expression of genes associated with glycolysis (pyruvate kinase, PKM2) and oxidative phosphorylation (succinate dehydrogenase, SDHB) compared to other examined RA patients, but higher expression of the abovementioned genes compared to control subjects. Moreover, RA patients who attained clinical remission demonstrated a trend to increase of these gene expressions within follow-up period, while in the rest of patients these gene expression was tending to downregulate.Conclusion. Clinical remission in RA patients treated with JAKi is associated with significantly lower baseline expression of genes associated with energy generation pathways (PKM2 and SDHB) compared to other examined subjects.

Epithelial Ovarian Cancer microenvironment regulates Myeloid cell metabolism to confer immunosuppression via glutamine metabolism.

Abstract Myeloid Cells are a major constituent of epithelial ovarian cancer (EOC) microenvironment that confer immunosuppression and promote tumor growth. Using the syngeneic ID8 EOC model we show that its microenvironment is enriched in myeloid cell recruiting factors like GM-CSF, G-CSF, VEGF, TNF-a, IL-1b and IL-6. Tumor microenvironment (TME) exposed myeloid cells are highly immunosuppressive as seen by increased expression of CSF-R, S100a9, STAT-3, VEGF, TNF-a, iNOS, STAT-3 and T-cell suppression activity. TME exposed myeloid cells exhibited an activated metabolic phenotype that was fueled by glutamine dependent oxidative phosphorylation as assessed by XFe seahorse analyzer and targeted metabolomics. Deprivation of glutamine or use of a glutaminase inhibitor, BPTES reduced oxidative phosphorylation, decreased immunosuppressive markers and protected from T-cell suppression. Targeted energy metabolism gene expression arrays revealed that the mitochondrial enzyme, dihydrolipoamide succinyl transferase (DLST), a component of alpha-ketoglutarate dehydrogenase (a-KG) complex in TCA cycle, was elevated in TME exposed myeloid cells. Glutamine deprivation reduced DLST expression, suggesting that DLST expression is dependent on availability of glutamine. A novel small molecule inhibitor of a-KG complex, 3-methyl 2-oxalo valeric acid, regressed EOC growth, reversed myeloid cell energy phenotype and alleviated T-cell suppression. We propose that EOC induced expression of DLST metabolically regulates the immunosuppressive function of myeloid cells and targeting DLST may represent a new strategy to reduce immunosuppressive environment plaguing ovarian cancer.

Effects of nanoplastics on energy metabolism in the oriental river prawn (Macrobrachium nipponense).

Nanoplastics are common pollutants in aquatic environments and have attracted widespread research attention. However, few studies focus on the effects of nanoplastic exposure on energy metabolism in crustaceans. Accordingly, we exposed juvenile oriental river prawns (Macrobrachium nipponense) to different concentrations of 75-nm polystyrene nanoplastics (0, 5, 10, 20, and 40mg/L) for 7, 14, 21, or 28 days. Thereafter, the effects of nanoplastic exposure on metabolite content, energy metabolism-related enzyme activity, and gene expression were evaluated. Our results showed that (1) with increasing nanoplastic concentration and exposure time, the survival rate decreased, while weight gain rate and molting number increased and then decreased; glycogen, triglyceride, and total cholesterol content all declined while lactic acid content increased with higher exposure to nanoplastic concentrations; (2) the activities of acetyl-CoA carboxylase (ACC), hexokinase (HK), carnitine palmitoyl transferase-1, pyruvate kinase (PK), lipase, and fatty acid synthase tended to decrease, while the activity of lactate dehydrogenase (LDH) increased. In particular, the activity of 6-phosphofructokinase exposed to 5mg/L nanoplastics increased significantly (P<0.05). (3) Expression of the metabolism-related genes 6-phosphate glucokinase (G-6-Pase), HK, PK, ACC, Acetyl-CoA-binding protein (ACBP), CPT-1, and fatty-acid-binding protein 10 (FABP 10) increased and then decreased, while expression of the LDH gene showed an upward trend. These results indicate that nanoplastics affect growth, enzyme activity, and the gene expression of energy metabolism in M. nipponense, and that high concentrations of nanoplastics have a negative impact on energy metabolism.

Role of exercise and rapamycin on the expression of energy metabolism genes in liver tissues of rats fed a high‑fat diet.

The mTOR pathway serves an important role in the development of insulin resistance induced by obesity. Exercise improves obesity-associated insulin resistance and hepatic energy metabolism; however, the precise mechanism of this process remains unknown. Therefore, the present study investigated the role of rapamycin, an inhibitor of mTOR, on exercise-induced expression of hepatic energy metabolism genes in rats fed a high-fat diet (HFD). A total of 30 male rats were divided into the following groups: Normal group (n=6) fed chow diets and HFD group (n=24) fed an HFD for 6 weeks. The HFD rats performed exercise adaptation for 1 week and were randomly divided into the four following groups (each containing six rats): i) Group of HFD rats with sedentary (H group); ii) group of HFD rats with exercise (HE group); iii) group of HFD rats with rapamycin (HR group); and iv) group of HFD rats with exercise and rapamycin (HER group). Both HE and HER rats were placed on incremental treadmill training for 4 weeks (from week 8–11). Both HR and HER rats were injected with rapamycin intraperitoneally at the dose of 2 mg/kg once a day for 2 weeks (from week 10–11). All rats were sacrificed following a 12–16 h fasting period at the end of week 11. The levels of mitochondrial and oxidative enzyme activities, as well as of the expression of genes involved in energy metabolism were assessed in liver tissues. Biochemical assays and oil red staining were used to assess the content of hepatic triglycerides (TGs). The results indicated that exercise, but not rapamycin, reduced TG content in the liver of HFD rats. Further analysis indicated that rapamycin reduced the activity of cytochrome c oxidase, but not the activities of succinate dehydrogenase and β-hydroxyacyl-CoA dehydrogenase in the liver of HFD rats. Exercise significantly upregulated the mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1 β, while rapamycin exhibited no effect on the mRNA expression levels of hepatic transcription factors associated with energy metabolism enzymes in the liver of HFD rats. Collectively, the results indicated that exercise reduced TG content and upregulated mitochondrial metabolic gene expression in the liver of HFD rats. Moreover, this mechanism may not involve the mTOR pathway.

Binding of Phage-Encoded FlaGrab to Motile Campylobacter jejuni Flagella Inhibits Growth, Downregulates Energy Metabolism, and Requires Specific Flagellar Glycans.

Many bacterial pathogens display glycosylated surface structures that contribute to virulence, and targeting these structures is a viable strategy for pathogen control. The foodborne pathogen Campylobacter jejuni expresses a vast diversity of flagellar glycans, and flagellar glycosylation is essential for its virulence. Little is known about why C. jejuni encodes such a diverse set of flagellar glycans, but it has been hypothesized that evolutionary pressure from bacteriophages (phages) may have contributed to this diversity. However, interactions between Campylobacter phages and host flagellar glycans have not been characterized in detail. Previously, we observed that Gp047 (now renamed FlaGrab), a conserved Campylobacter phage protein, binds to C. jejuni flagella displaying the nine-carbon monosaccharide 7-acetamidino-pseudaminic acid, and that this binding partially inhibits cell growth. However, the mechanism of this growth inhibition, as well as how C. jejuni might resist this activity, are not well-understood. Here we use RNA-Seq to show that FlaGrab exposure leads C. jejuni 11168 cells to downregulate expression of energy metabolism genes, and that FlaGrab-induced growth inhibition is dependent on motile flagella. Our results are consistent with a model whereby FlaGrab binding transmits a signal through flagella that leads to retarded cell growth. To evaluate mechanisms of FlaGrab resistance in C. jejuni, we characterized the flagellar glycans and flagellar glycosylation loci of two C. jejuni strains naturally resistant to FlaGrab binding. Our results point toward flagellar glycan diversity as the mechanism of resistance to FlaGrab. Overall, we have further characterized the interaction between this phage-encoded flagellar glycan-binding protein and C. jejuni, both in terms of mechanism of action and mechanism of resistance. Our results suggest that C. jejuni encodes as-yet unidentified mechanisms for generating flagellar glycan diversity, and point to phage proteins as exciting lenses through which to study bacterial surface glycans.

Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment

Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.

Genome-wide analyses reveal the role of noncoding variation in complex traits during rice domestication.

Genomes carry millions of noncoding variants, and identifying the tiny fraction with functional consequences is a major challenge for genomics. We assessed the role of selection on long noncoding RNAs (lncRNAs) for domestication-related changes in rice grains. Among 3363 lncRNA transcripts identified in early developing panicles, 95% of those with differential expression (329 lncRNAs) between Oryza sativa ssp. japonica and wild rice were significantly down-regulated in the domestication event. Joint genome and transcriptome analyses reveal that directional selection on lncRNAs altered the expression of energy metabolism genes during domestication. Transgenic experiments and population analyses with three focal lncRNAs illustrate that selection on these loci led to increased starch content and grain weight. Together, our findings indicate that genome-wide selection for lncRNA down-regulation was an important mechanism for the emergence of rice domestication traits.

White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy.

Neurocognitive impairment (NCI) remains a significant cause of morbidity in human immunodeficiency virus (HIV)-positive individuals despite highly active antiretroviral therapy (HAART). White matter abnormalities have emerged as a key component of age-related neurodegeneration, and accumulating evidence suggests they play a role in HIV-associated neurocognitive disorders. Viral persistence in the brain induces chronic inflammation associated with lymphocytic infiltration, microglial proliferation, myelin loss, and cerebrovascular lesions. In this study, gene expression profiling was performed on frontal white matter from 34 older HIV+ individuals on HAART (18 with NCI) and 24 HIV-negative controls. We used the NanoString nCounter platform to evaluate 933 probes targeting inflammation, interferon and stress responses, energy metabolism, and central nervous system-related genes. Viral loads were measured using single-copy assays. Compared to HIV- controls, HIV+ individuals exhibited increased expression of genes related to interferon, MHC-1, and stress responses, myeloid cells, and T cells and decreased expression of genes associated with oligodendrocytes and energy metabolism in white matter. These findings correlated with increased white matter inflammation and myelin pallor, suggesting interferon (IRFs, IFITM1, ISG15, MX1, OAS3) and stress response (ATF4, XBP1, CHOP, CASP1, WARS) gene expression changes are associated with decreased energy metabolism (SREBF1, SREBF2, PARK2, TXNIP) and oligodendrocyte myelin production (MAG, MOG), leading to white matter dysfunction. Machine learning identified a 15-gene signature predictive of HIV status that was validated in an independent cohort. No specific gene expression patterns were associated with NCI. These findings suggest therapies that decrease chronic inflammation while protecting mitochondrial function may help to preserve white matter integrity in older HIV+ individuals.

Effects of cross-fostering and developmental exposure to mixtures of environmental contaminants on hepatic gene expression in prepubertal 21 days old and adult male Sprague-Dawley rats

ABSTRACTThe notion that adverse health effects produced by exposure to environmental contaminants (EC) may be modulated by the presence of non-chemical stressors is gaining attention. Previously, our lab demonstrated that cross-fostering (adoption of a litter at birth) acted as a non-chemical stressor that amplified the influence of developmental exposure to EC on the glucocorticoid stress-response in adult rats. Using liver from the same rats, the aim of the current study was to investigate whether cross-fostering might also modulate EC-induced alterations in hepatic gene expression profiles. During pregnancy and nursing, Sprague-Dawley dams were fed cookies laced with corn oil (control, C) or a chemical mixture (M) composed of polychlorinated biphenyls (PCB), organochlorine pesticides (OCP), and methylmercury (MeHg), at 1 mg/kg/day. This mixture simulated the contaminant profile reported in maternal human blood. At birth, some control and M treated litters were cross-fostered to form two additional groups with different biological/nursing mothers (CC and MM). The hepatic transcriptome was analyzed by DNA microarray in male offspring at postnatal days 21 and 78–86. Mixture exposure altered the expression of detoxification and energy metabolism genes in both age groups, but with different sets of genes affected at day 21 and 78–86. Cross-fostering modulated the effects of M on gene expression pattern (MM vs M), as well as expression of energy metabolism genes between control groups (CC vs C). In conclusion, while describing short and long-term effects of developmental exposure to EC on hepatic transcriptomes, these cross-fostering results further support the consideration of non-chemical stressors in EC risk assessments.

PO-264 Target Mitochondria Metabolism and Energy Expenditure in Muscle Atrophy, Sarcopenia and Cachexia

Objective Muscle atrophy is a common and clinically important outcome of many diseases and hospitalization bed rest. Mechanical unloading of skeletal muscles may result in a rapid loss of muscle mass and mitochondria dysfunction. And the recovery from disuse muscle atrophy is usually complete in young healthy adults but is delayed and often incomplete in older patients. However, the mechanisms underlying poor recovery of aged muscle following disuse remain to be delineated. Recent evidence suggests that mitochondrial energetics play an important role in regulation of muscle mass. To this end, we employed multiple approaches to address the role of mitochondrial function and metabolism in muscle atrophy and sarcopenia. And we are also engaged to develop novel mitochondria-targeted antioxidant peptides to mitigate this mitochondria-related functional impairment by ROS and improve the recovery from muscle atrophy and cachexia.&#x0D; Methods Tail Suspension Hind Limb Unloading for adult mice (6-month-old) and aged mice (22-24month old). Cardiometabolic Phenotyping：Measurement of fat and lean mass (g) is accomplished using a LF90II TD-NMR (Bruker, Madison, WI). Locomotor activity measurements are obtained using a Promethion Mouse Multiplexed Metabolic System(Sable Systems International, Las Vegas, NV).Mitochondrial Respiration :Respirometry assays were conducted using an Oxygraph-2k (Oroboros Instruments, Innsbruck, Austria), Mitochondria H2O2 emission was measured with Amplex Red reagent which reacts with H2O2 to produce the stable fluorescent compound resorufin. Resorufin fluorescence was monitored using a Fluorescence. A continuous, spectrophotometric assay was utilized to measure mitochondrial calcium retention capacity (CRC) within soleus fiber bundles. RNA Sequencing and Informatics, KEGG Pathway and Upstream Regulator Analysis, Real-Time Quantitative-PCR. Multidimensional mass spectrometry-based shotgun lipidomics was employed to measure and characterize the lipid patterns inmouse soleus muscle. Metabolomics Acylcarnitines A panel of acylcarnitines was quantitated by LC/ MS/MS (Agilent 1290 HPLC/6490 triple quadrupole mass spectrometer). Amino Acids. Quantitation of amino acids was achieved using LC/MS/MS (Agilent 1290 HPLC/6490 triple quadrupole mass spectrometer).&#x0D; Results Old mice have impaired early recovery of soleus mass following unloading induced muscle atrophy. And mitochondrial function and metabolism does not Improve during early recovery in aged Mice. Divergent metabolomic response was found between adult and aged Mice during unloading and recovery. However, transcriptomic response to unloading and reloading is similar in adult and aged Mice.&#x0D; Conclusions Here, we report that aged mice with low muscle mass and low glucose clearance rate also display poor early recovery of muscle mass after disuse muscle atrophy. We used unbiased and targeted approaches to identify changes in energy metabolism gene expression, metabolite pools and mitochondrial phenotype and show for the first time that persistent mitochondrial dysfunction, dysregulated fatty acid β-oxidation and elevated H2O2 emission occur concomitantly with poor early recovery of muscle mass following a period of disuse in old mice. Importantly, this is linked to more severe whole-body insulin resistance, as determined by insulin tolerance test. Our findings also showed cellular metabolic changes during muscle atrophy and sarcopenia may induce higher production of oxygen radicals that play a significant role in the progression of age-related sarcopenia. These findings suggest that muscle fuel metabolism and mitochondrial energetics could be a focus for mining therapeutic targets to improve recovery of muscle mass following periods of disuse. We are engaged to develop novel mitochondria-targeted antioxidant peptides to mitigate this mitochondria-related functional impairment by ROS and improve the recovery from muscle atrophy and cachexia. Co-administration of other targeted compounds was also promising to improve recovery from muscle atrophy and cachexia.&#x0D;

Pirin: A novel redox-sensitive modulator of primary and secondary metabolism in Streptomyces

Pirins are evolutionarily conserved iron-containing proteins that are found in all kingdoms of life, and have been implicated in diverse molecular processes, mostly associated with cellular stress. In the present study, we started from the evidence that the insertional inactivation of pirin-like gene SAM23877_RS18305 (pirA) by ΦC31 Att/Int system-based vectors in spiramycin-producing strain Streptomyces ambofaciens ATCC 23877 resulted in marked effects on central carbon and energy metabolism gene expression, high sensitivity to oxidative injury and repression of polyketide antibiotic production. By using integrated transcriptomic, proteomic and metabolite profiling, together with genetic complementation, we here show that most of these effects could be traced to the inability of the pirA-defective strain to modulate beta-oxidation pathway, leading to an unbalanced supply of precursor monomers for polyketide biosynthesis. Indeed, in silico protein-protein interaction modeling and in vitro experimental validation allowed us to demonstrate that PirA is a novel redox-sensitive negative modulator of very long-chain acyl-CoA dehydrogenase, which catalyzes the first committed step of the beta-oxidation pathway.

SAT-008 - Intestinal microbiota significantly alters hepatic expression of energy metabolism genes in mice with acute cholestasis

SAT-008 - Intestinal microbiota significantly alters hepatic expression of energy metabolism genes in mice with acute cholestasis

Body weight influences genes related to energy metabolism in human skeletal muscle

Over one third of adults in the United States are obese. Skeletal muscle is a major site of metabolic activity and the most abundant tissue in the human body. For skeletal muscle to function at optimal levels, the efficient activation of processes that regulate muscle development, growth, regeneration and metabolism is required. Mitochondria play a key role in ensuring adequate levels of ATP needed for skeletal muscle contraction. In addition, the capacity of skeletal muscle to contribute to whole‐body energy expenditure is related to the fact that muscle makes up ~40% of total body mass and accounts for 20–30% of total resting oxygen uptake. This indicates that mitochondrial functional capacity is likely to directly affect muscle metabolic function and have a significant impact on whole‐body metabolism. Mitochondria are also important for ensuring muscle is able to modulate substrate oxidation (e.g. lipid and carbohydrate oxidation) following a meal. The objective of this study was to determine if there was an effect of body weight on genes related to mitochondrial function in skeletal muscle from normal weight (NW) and obese/overweight (OW) participants. Muscle biopsies were taken from OW (n=31, ages 48±19) and NW (n=12, ages 43±18) adults. Gene expression was measured using real‐time PCR. There was an increase (p&lt;0.05) in the expression of both PGC1α and PPARγ, which are regulators of mitochondrial biogenesis, in OW vs NW participants. Expression of UCP2, a key regulator involved in ATP synthesis, was higher (p&lt;0.05) in OW participants. In addition, genes related to mitochondrial respiration, mitochondrial DNA replication and transcription, NRF1 and Tfam, had higher (p&lt;0.05) expression in OW. Cpt1a, a gene encoding carnitine palmitoyltransferase 1A, which is necessary for fatty acid oxidation, had lower (p&lt;0.05) expression in OW compared with NW. Conclusively, these data provide a preliminary view of differences in energy metabolism gene expression in obese/overweight versus normal weight individuals.Support or Funding InformationArkansas Biosciences InstituteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.