Differences In Energy Metabolism Research Articles

Metabolic Profiling in Plasma and Brain Induced by 17β-Estradiol Supplementation in Ovariectomized Mice.

17β-Estradiol is an ovarian hormone that regulates energy circulation and storage by acting on the central nervous system. However, the metabolic differences between the blood and brain when stimulated by 17β-estradiol are poorly understood. Moreover, research using menopause-induced models to investigate primary metabolites in the blood and brain is limited. Thus, this study aimed to identify metabolic changes in the plasma and brain resulting from 17β-estradiol supplementation in an estrogen-deficient mouse model. Three groups of mice were utilized: sham-operated mice (Sham), ovariectomized mice (OVX), and ovariectomized mice that received a weekly supplementation of 17β-estradiol (E2). Plasma and brain samples from these mice were subjected to metabolic analysis using gas chromatography-time-of-flight-mass spectrometry. Compared with the plasma samples from the Sham and OVX groups, the plasma samples from the E2 group contained higher contents of branched-chain amino acids (BCAAs), such as valine, isoleucine, and leucine. Meanwhile, the brain samples from the E2 group contained higher contents of most metabolites, including BCAAs, neurotransmitters, tricarboxylic acid cycle intermediates, and fatty acids, than those from the two other groups. This study is the first to reveal differences in energy metabolism induced by 17β-estradiol supplementation through brain metabolic profiling of ovariectomized mice, emphasizing the importance of brain metabolic profiling in menopausal hormone research.

Decoding the effects of drought stress on popcorn (Zea mays var. everta) flowering combining proteomics and physiological analysis

Under conditions of soil water limitation and adequate irrigation, we conducted an investigation into the growth dynamics, gas exchange performance, and proteomic profiles of two inbred popcorn lines—L71, characterized as drought-tolerant, and L61, identified as drought-sensitive. Our goal was to uncover the mechanisms associated with tolerance to soil water limitation during the flowering. The plants were cultivated until grain filling in a substrate composed of perlite and peat within 150cm long lysimeter, subjected to two water conditions (WC): i) irrigated (WW) at lysimeter capacity (LC - 100%), and ii) water-stressed (WS). Under WS conditions, the plants gradually reached 45% of LC and were maintained at this level for 10 days. Irrespective of the WC, L71 exhibited the highest values of dry biomass in both shoot and root systems, signifying its status as the most robust genotype. The imposed water limitation led to early senescence, chlorophyll degradation, and increased anthocyanin levels, with a more pronounced impact observed in L61. Traits related to gas exchange manifested differences between the lines only under WS conditions. A total of 1838 proteins were identified, with 169 differentially accumulated proteins (DAPs) in the tolerant line and 386 DAPs in the sensitive line. Notably, differences in energy metabolism, photosynthesis, oxidative stress response, and protein synthesis pathways were identified as the key distinctions between L71 and L61. Consequently, our findings offer valuable insights into the alterations in proteomic profiles associated with the adaptation to soil water limitation in popcorn.

The Untargeted Metabolomics Reveals Differences in Energy Metabolism in Patients with Different Subtypes of Ischemic Stroke.

Ischemic stroke (IS) is the most common subtype of stroke. The risk factors and pathogenesis of IS are complex and varied due to different subtypes. Therefore, we used metabolomics technology to investigate the biomarkers and potential pathophysiological mechanisms of different subtypes of IS. We included 126 IS patients and divided them into two groups based on the TOAST classification: large-artery atherosclerosis (LAA) group (n = 87) and small-vessel occlusion (SVO) group (n = 39). Plasma metabolomics analysis was performed using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to identify metabolic profiles in LAA and SVO subtype IS patients and to determine metabolic differences between patients with the two subtypes of IS. We identified 26 differential metabolites between LAA and SVO subtype IS. A multiple prediction model based on the plasm metabolites had good predictive ability for IS subtyping (AUC = 0.822, accuracy = 77.8%), with 12,13-DHOME being the most important differential metabolite in the model. The differential metabolic pathways between the two subtypes of IS patients included tricarboxylic acid (TCA) cycle, alanine, aspartate and glutamate metabolism, and pyruvate metabolism, mainly focused on energy metabolism. 12,13-DHOME emerged as the primary discriminatory metabolite between LAA and SVO subtypes of IS. In LAA subtype IS patients, energy metabolism, encompassing pyruvate metabolism and the TCA cycle, exhibited lower activity levels when compared to patients with the SVO subtype IS. The utilization of targeted metabolomics holds the potential to improve diagnostic accuracy for distinguishing stroke subtypes.

Sex differences in energy metabolism: natural selection, mechanisms and consequences.

Metabolic homeostasis operates differently in men and women. This sex asymmetry is the result of evolutionary adaptations that enable women to resist loss of energy stores and protein mass while remaining fertile in times of energy deficit. During starvation or prolonged exercise, women rely on oxidation of lipids, which are a more efficient energy source than carbohydrates, to preserve glucose for neuronal and placental function and spare proteins necessary for organ function. Carbohydrate reliance in men could be an evolutionary adaptation related to defence and hunting, as glucose, unlike lipids, can be used as a fuel for anaerobic high-exertion muscle activity. The larger subcutaneous adipose tissue depots in healthy women than in healthy men provide a mechanism for lipid storage. As female mitochondria have higher functional capacity and greater resistance to oxidative damage than male mitochondria, uniparental inheritance of female mitochondria may reduce the transmission of metabolic disorders. However, in women, starvation resistance and propensity to obesity have evolved in tandem, and the current prevalence of obesity is greater in women than in men. The combination of genetic sex, programming by developmental testosterone in males, and pubertal sex hormones defines sex-specific biological systems in adults that produce phenotypic sex differences in energy homeostasis, metabolic disease and drug responses.

Regional sex differences in neurochemical profiles of healthy mice measured by magnetic resonance spectroscopy at 9.4 tesla

ObjectiveTo determine sex differences in the neurochemical concentrations measured by in vivo proton magnetic resonance spectroscopy (1H MRS) of healthy mice on a genetic background commonly used for neurodegenerative disease models.Methods1H MRS data collected from wild type mice with C57BL/6 or related genetic backgrounds in seven prior studies were used in this retrospective analysis. To be included, data had to be collected at 9.4 tesla magnetic field using advanced 1H MRS protocols, with isoflurane anesthesia and similar animal handling protocols, and a similar number of datasets from male and female mice had to be available for the brain regions analyzed. Overall, 155 spectra from female mice and 166 spectra from male mice (321 in total), collected from six brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, and striatum) at various ages were included.ResultsConcentrations of taurine, total creatine (creatine + phosphocreatine), ascorbate, glucose and glutamate were consistently higher in male vs. female mice in most brain regions. Striatum was an exception with similar total creatine in male and female mice. The sex difference pattern in the hypothalamus was notably different from other regions. Interaction between sex and age was significant for total creatine and taurine in the cerebellum and hippocampus.ConclusionSex differences in regional neurochemical levels are small but significant and age-dependent, with consistent male–female differences across most brain regions. The neuroendocrine region hypothalamus displays a different pattern of sex differences in neurochemical levels. Differences in energy metabolism and cellular density may underlie the differences, with higher metabolic rates in females and higher osmoregulatory and antioxidant capacity in males.

Quantitative proteomic analysis of cattle-yak and yak longissimus thoracis provides insights into the differential mechanisms of meat quality

In this study, proteins of cattle-yak longissimus thoracis (CYLT) and yak longissimus thoracis (YLT) were compared using tandem mass tag-labeled quantitative proteomic analysis. A total of 157 proteins were screened as differentially abundant proteins (DAPs) derived from 1551 quantitative proteins. Bioinformatics analysis revealed that the upregulated DAPs in CYLT were mainly involved in energy metabolism, oxidative stress, muscle fiber structure, and extracellular matrix (ECM), while the downregulated DAPs were mainly involved in energy metabolism and ECM function. The upregulated myoglobin, downregulation of NADH dehydrogenase, and upregulation of cytochrome oxidase indicated that CYLT initiates compensatory regulation in response to hypoxic high-altitude environments. Two differentially abundant myosins and five collagens suggested that CYLT and YLT may have distinct differences in the assembly structure of muscle fibers and connective tissue. These differences in energy metabolism and muscle structure will inevitably affect the postmortem physiology of “muscle to meat” and consequently the meat qualities. Therefore, our results will provide important clues to gain insight into the potential causes of meat quality differences between cattle-yak and yak based on high-altitude response.

How can we assess "thrifty" and "spendthrift" phenotypes?

There is a large inter-individual variability in the magnitude of body weight change that cannot be fully explained by differences in daily energy intake and physical activity levels and that can be attributed to differences in energy metabolism. Measuring the short-term metabolic response to acute changes in energy intake can better uncover this inter-individual variability and quantify the degree of metabolic thriftiness that characterizes an individual's susceptibility to weight gain and resistance to weight loss. This review summarizes the methods used to identify the individual-specific metabolic phenotype (thrifty vs. spendthrift) in research and clinical settings. The metabolic responses to short-term fasting, protein-imbalanced overfeeding, and mild cold exposure constitute quantitative factors that characterize metabolic thriftiness. The energy expenditure response to prolonged fasting is considered the most accurate and reproducible measure of metabolic thriftiness, likely because the largest energy deficit best captures interindividual differences in the extent of metabolic slowing. However, all the other dietary/environmental challenges can be used to quantify the degree of thriftiness using whole-room indirect calorimetry. Efforts are underway to identify alternative methods to assess metabolic phenotypes in clinical and outpatient settings such as the hormonal response to low-protein meals.

Protein profiles identified by LC-MS/MS demonstrate change in beta oxidation, ketogenesis, and propionate metabolism in rumen epithelium with different additives

Replacement of ionophore feed additives by essential oils demonstrates differences in energy metabolism. The mechanism of action of essential oils depends on the ruminal pH, therefore, feedlot diets with high starch inclusions tend to show greater effectiveness of these natural additives. The aim of this study is to map the proteome of the ruminal epithelium of feedlot Nellore cattle (n = 60) with different additives (monensin, blend of essential oils + exogenous α-amylase) and varying levels of starch (25% and 45%) Two-dimensional polyacrylamide gel electrophoresis was used to separate the proteome of ruminal epithelium. The differentially expressed protein spots were characterized by isoelectric point, molecular mass, volume, and intensity of the spots and identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Diets using an essential oil blend associated with exogenous amylase promoted greater expression of macromolecules from the degradation of carbohydrates through the glycolytic and ketogenesis pathway. Fourteen proteins were identified in upregulation and the presence of proteins involved in glucose oxidation as well as HydroxymethylglutarylCoA lyase (HMGCL), which catalyzes part of the metabolic intermediate metabolism—a key step in ketogenesis. Our results suggest that there was an increase in glycolysis from the oxidation of Glyceraldehyde-3-phosphate dehydrogenase (GAPDH GAPD), which participates in the first step of acetate and butyrate production and the oxidative decarboxylation of the ruminal epithelium of feedlot Nellore cattle. Monensin increased precursors of propionate, such as methylmalonyl-CoA mutase (MUT), which suggests greater synthesis of propionate via propionyl-CoA upon entry into the citric acid cycle as succinyl-CoA, which can increase feed efficiency and reduces feed intake.

Differential energy expenditure is involved in the difference in activity levels between the Djungarian hamster (Phodopus sungorus) and the Roborovskii hamster (P. roborovskii)

The Djungarian hamster (Phodopus sungorus) shows calm behavior, while the Roborovskii hamster (P. roborovskii) exhibits hyperactivity. Even though they belong to the same genus, Phodopus, these two species are quite different. The current study investigated the relationship between energy expenditure and the markedly different levels of activity shown by these hamsters. Roborovskii hamsters showed significantly higher energy expenditure than Djungarian hamsters under both feeding and fasting conditions during darkness. Roborovskii hamsters showed a repeated increase and decrease in energy expenditure under the feeding condition; however, this changed under the fasting condition, during which the repeated increase and decrease in energy expenditure corresponded to the repeated active and sleeping conditions. Djungarian hamsters had a tendency to keep their energy expenditure constant during the fasting condition, while Roborovskii hamsters moved around a lot to find food. The respiratory quotient (RQ) values in Djungarian hamsters were relatively constant. However, Roborovskii hamsters showed a wide variation in RQ. In particular, the RQ value declined immediately before a dark phase commenced, indicating a switchover from the utilization of glucose to that of lipids as a substrate for energy production. In conclusion, Djungarian hamsters and Roborovskii hamsters showed different behavioral patterns that were related to differences in energy metabolism.

Differential gene expression in the Longissimus dorsi of Nguni and Bonsmara bulls finished on low and high energy diets

Objectives of this research were to examine differential gene expression profiles of Nguni and Bonsmara cattle fed diets differing in their energy density. The ultimate goal was to improve understanding of the mechanisms that underlie differences between these breeds and the potential interactions of the differences between breeds with the nutritive environment. The experiment was designed as a 2 × 2 factorial arrangement of breed and diet (12.5 MJ/kg DM vs. 10.9 MJ/kg DM). The initial feeding trial had 10 bull calves per treatment. However, financial constraints limited RNA sequencing to six animals per treatment and the RNA generated from one animal was of insufficient quality to be useful. Transcripts with false discovery rate P-values <0.05 and fold-changes >2.0 were considered significant. Bonsmara had a faster growth rate, heavier live and carcass weights, and better feed conversion compared to Nguni. However, lower levels of fat were observed in Nguni. Twenty different genes were differentially expressed, with three exhibiting interaction effects and all 20 having differences in transcript abundance between the breeds. A dietary effect was only observed for the one gene and that gene was also subject to an interaction effect with breed. Observed differences in gene expression between Bonsmara and Nguni by several genes affecting the structure or function of the mitochondria imply differences in energy metabolism between the breeds. Interaction effects on the abundance of some gene transcripts indicate the need to consider the diet when evaluating breed differences and conversely, consider breed when evaluating diets.

Comparative transcriptome analysis revealed genes involved in the sexual size dimorphisms and expressed sequence tag-Simple Sequence Repeat loci validation in Odorrana graminea

Sexual size dimorphism (SSD) is widespread among animals and is characterized by differences in body size between sexes. Previous studies suggested SSD might reflect the adaptations of particular sexes to their specific reproductive or ecological roles. The large green cascade frogs (Odorrana graminea) exhibit obvious SSD that females are nearly twice the body size of males. However, the molecular mechanisms underlying SSD of O. graminea are still unknown. In the present study, we first obtained nearly 5 Gb of the transcriptome data through Illumina sequencing, and the de novo transcriptome assembly produced 189,868 unigenes of O. graminea. A total of 774 significantly sex-differentially expressed genes (DEGs) were identified. Of which, 436 DEGs showed significantly higher expression levels in females than those in males, whereas 338 DEGs showed significantly lower expression in females than those in males. We also found 10 sex-differentially expressed genes related to energy metabolism between sexes of O. graminea, and these DEGs were related to the estrogen signaling pathway, oxidative phosphorylation, fatty acid biosynthesis, gastric acid secretion, and nitrogen metabolism. We found that the differences in energy metabolism and steroid hormone synthesis might be the main driving force leading to the sexual growth dimorphism of O. graminea. In addition, a total of 63,269 potential EST-SSR loci and 4,669 EST-SSR loci were detected and validated in different populations of O. graminea and other species within Odorrana. The assembled transcriptome will facilitate functional genomic studies of O. graminea and the developed EST-SSR markers will contribute to the population genetics of the species within Odorrana. The sex-differentially expressed genes involved in energy metabolism might provide insights into the genetic mechanisms underlying the SSD of O. graminea.

Sex differences in body composition and serum metabolome responses to sustained, physical training suggest enhanced fat oxidation in women compared with men.

Sex differences in energy metabolism during acute, sub-maximal exercise are well documented. Whether these sex differences influence metabolic and physiologic responses to sustained, physically demanding activities is not well characterized. This study aimed to identify sex differences within changes in the serum metabolome in relation to changes in body composition, physical performance, and circulating markers of endocrine and metabolic status during a 17-day military training exercise. Blood was collected, and body composition and lower-body power measured before and after training on 72 cadets (18 women). Total daily energy expenditure (TDEE) was assessed using doubly labeled water in a subset. TDEE was greater in men (4,085±482kcal/d) than women (2,982±472kcal/d, p<0.001), but not after adjustment for dry lean mass (DLM). Men tended to lose more DLM than women (-0.2[-0.3,-0.1] vs. -0.0[-0.0,0.0] kg, p=0.063, Cohen's d=0.50) and have greater reductions in lower body power (-244[-314,-174] vs. -130[-209,-51] Watts, p=0.085, d=0.49). Reductions in DLM and lower body power were correlated (r=0.325, p=0.006). Women demonstrated greater fat oxidation than men (Δfat mass/DLM: -0.20[-0.24,-0.17] vs. -0.15[-0.17,-0.13] kg, p=0.012, d=0.64). Metabolites within pathways of fatty acid, endocannabinoid, lysophospholipid, phosphatidylcholine, phosphatidylethanolamine, and plasmalogen metabolism increased in women relative to men. Independent of sex, changes in metabolites related to lipid metabolism were inversely associated with changes in body mass and positively associated with changes in endocrine and metabolic status. These data suggest that during sustained military training, women preferentially mobilize fat stores compared with men, which may be beneficial for mitigating loss of lean mass and lower body power.

What Maintains the Metabolic Cost at Peak Anaerobic Test in Elite Young and Master Male Cyclists?

Purpose: The present study investigated the effect of aging on the oxygen utilization in healthy well-trained elite cyclists males young and masters at peak Wingate Anaerobic Test. Methods:Twenty young 21.21±1 and twenty masters 57.6±3.4 years were studied by Echocardiography performed with the subject sitting on a bicycle ergometry. Arterial oxygen was defined from echocardiographic measurements and venous oxygen content. Results: At peak Wingate Anaerobic Test, in young compare to masters, cardiac output (18.2±0.6 and 17.1±0.4 L•min-1 respectively), and stroke volume&nbsp;(84.0±5.0 and 78.2±6.1 mL respectively) were significantly (P &lt; 0.05) higher, (a-v)O2 was significantly (P &lt; 0.05) lower (122.5±2.9 and 126.1±3.1 mLO2 respectively) while %VO2 out of total energy utilized did not differ between groups. &nbsp;Conclusions: This study suggests that elite cyclist athlete young and masters respond to the Wingate Anaerobic Test by reducing their left ventricular systolic function in the face of increased afterload. The lack of differences at peak exercise in the oxygen utilization may be attributed to differences in energy metabolism, namely higher oxygen extraction in the masters, compensating for the lower oxygen delivery.

Increased adiposity is associated with altered skeletal muscle energetics.

The objective of this pilot study was to characterize relationships between skeletal muscle energy metabolism and body composition in healthy adults with varied amounts and distribution of adipose tissue. In vivo muscle energetics were quantified using dynamic 31P magnetic resonance spectroscopy with knee extension exercise standardized to subject lean body mass. Spearman's correlation analysis examined relationships between muscle metabolism indices and measures of adiposity including body mass index (BMI), total body fat, and quadriceps intermuscular adipose tissue (IMAT). Post hoc partial correlations were examined controlling for additional body composition measures. Kruskal-Wallis tests with Dunn-Sidak post hoc comparisons evaluated group differences in energy metabolism based on body composition profiles (i.e., lean, normal-weight obese, and overweight-obese) and IMAT tertiles. BMI negatively correlated with end-exercise muscle pH after correcting for IMAT and total body fat (r = -0.46, P = 0.034). Total adiposity negatively correlated with maximum oxidative capacity after correcting for IMAT (r = -0.54, P = 0.013). IMAT positively correlated with muscle proton buffering capacity after correcting for total body fat (r = 0.53, P = 0.023). Body composition groups showed differences in end-exercise fall in [PCr] with normalized workload (P = 0.036; post hoc: overweight-obese < lean, P = 0.029) and maximum oxidative capacity (P = 0.021; post hoc: normal-weight obese < lean, P = 0.016). IMAT tertiles showed differences in end-exercise fall in [PCr] with normalized workload (P = 0.035; post hoc: 3rd < 1st, P = 0.047). Taken together, these results support increased adiposity is associated with reduced muscle energetic efficiency with more reliance on glycolysis, and when accompanied with reduced lean mass, is associated with reduced maximum oxidative capacity.NEW & NOTEWORTHY Skeletal muscle energy production is influenced by both lean body mass and adipose tissue but the effect of their distribution on energy metabolism is unclear. This study examined variations in quadriceps muscle energy metabolism in healthy adults with varied relative amounts of lean and adipose tissue. Results suggest increased adiposity is associated with reduced muscle energetic efficiency with more reliance on glycolysis, and when accompanied with reduced lean mass, is associated with reduced maximum oxidative capacity.

Meta-analysis across Nellore cattle populations identifies common metabolic mechanisms that regulate feed efficiency-related traits

BackgroundFeed efficiency (FE) related traits play a key role in the economy and sustainability of beef cattle production systems. The accurate knowledge of the physiologic background for FE-related traits can help the development of more efficient selection strategies for them. Hence, multi-trait weighted GWAS (MTwGWAS) and meta-analyze were used to find genomic regions associated with average daily gain (ADG), dry matter intake (DMI), feed conversion ratio (FCR), feed efficiency (FE), and residual feed intake (RFI). The FE-related traits and genomic information belong to two breeding programs that perform the FE test at different ages: post-weaning (1,024 animals IZ population) and post-yearling (918 animals for the QLT population).ResultsThe meta-analyze MTwGWAS identified 14 genomic regions (-log10(p -value) > 5) regions mapped on BTA 1, 2, 3, 4, 7, 8, 11, 14, 15, 18, 21, and 29. These regions explained a large proportion of the total genetic variance for FE-related traits across-population ranging from 20% (FCR) to 36% (DMI) in the IZ population and from 22% (RFI) to 28% (ADG) in the QLT population. Relevant candidate genes within these regions (LIPE, LPL, IGF1R, IGF1, IGFBP5, IGF2, INS, INSR, LEPR, LEPROT, POMC, NPY, AGRP, TGFB1, GHSR, JAK1, LYN, MOS, PLAG1, CHCD7, LCAT, and PLA2G15) highlighted that the physiological mechanisms related to neuropeptides and the metabolic signals controlling the body's energy balance are responsible for leading to greater feed efficiency. Integrated meta-analysis results and functional pathway enrichment analysis highlighted the major effect of biological functions linked to energy, lipid metabolism, and hormone signaling that mediates the effects of peptide signals in the hypothalamus and whole-body energy homeostasis affecting the genetic control of FE-related traits in Nellore cattle.ConclusionsGenes and pathways associated with common signals for feed efficiency-related traits provide better knowledge about regions with biological relevance in physiological mechanisms associated with differences in energy metabolism and hypothalamus signaling. These pleiotropic regions would support the selection for feed efficiency-related traits, incorporating and pondering causal variations assigning prior weights in genomic selection approaches.

Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes.

The way in which brain morphology and proteome are remodeled during embryonal development, and how they are linked to the cellular metabolism, could be a key for elucidating the pathological mechanisms of certain neurodevelopmental disorders. Cerebral organoids derived from autism spectrum disorder (ASD) patients were generated to capture critical time-points in the neuronal development, and metabolism and protein expression were investigated. The early stages of development, when neurogenesis commences (day in vitro 39), appeared to be a critical timepoint in pathogenesis. In the first month of development, increased size in ASD-derived organoids were detected in comparison to the controls. The size of the organoids correlates with the number of proliferating cells (Ki-67 positive cells). A significant difference in energy metabolism and proteome phenotype was also observed in ASD organoids at this time point, specifically, prevalence of glycolysis over oxidative phosphorylation, decreased ATP production and mitochondrial respiratory chain activity, differently expressed cell adhesion proteins, cell cycle (spindle formation), cytoskeleton, and several transcription factors. Finally, ASD patients and controls derived organoids were clustered based on a differential expression of ten proteins-heat shock protein 27 (hsp27) phospho Ser 15, Pyk (FAK2), Elk-1, Rac1/cdc42, S6 ribosomal protein phospho Ser 240/Ser 244, Ha-ras, mTOR (FRAP) phospho Ser 2448, PKCα, FoxO3a, Src family phospho Tyr 416-at day 39 which could be defined as potential biomarkers and further investigated for potential drug development.

Mitochondrial bioenergetics in ocular fibroblasts of two myasthenia gravis cases.

Myasthenia gravis (MG) is a rare, treatable, antibody-mediated disease characterized by fatigable muscle weakness of extraocular muscles (EOMs) and non-ocular skeletal muscles. The antibodies are directed against muscle-endplate proteins, most frequently the acetylcholine receptor (AChR) alpha-subunit. Although most MG patients respond to immunosuppressive treatment, some individuals, frequently with African-genetic ancestry, develop treatment-resistant ophthalmoplegia (OP-MG). Although the underlying pathogenetic mechanisms of OP-MG remain unknown, experimental rodent models of MG showed upregulation of genes involved in oxidative metabolism in muscles. EOMs are highly dependent on oxidative metabolism. We opportunistically sampled EOM-tendons of two rare OP-MG patients (and non-MG controls) undergoing re-alignment surgery, and established ocular fibroblast cultures. Metabolic assays were performed on these live cells to assess real-time differences in energy metabolism. To study the cellular bioenergetic profiles in the context of MG, we exposed the cultures to homologous 5% MG sera for 24 h, vs. growth media, from two independent MG patients (with circulating AChR-antibodies) and five controls without MG, and estimated the fold change in oxygen consumption rates in response to three compounds which inhibit different mitochondrial chain complexes. Quantitative PCR (qPCR) was performed in cells before and after MG sera exposure, to assess transcript levels of mitochondrial genes, PDK4, ANGPTL4 and UCP3, which were altered in experimental MG. In response to the mitochondrial stressors, basal oxidative metabolism parameters were similar between OP-MG and control fibroblasts (p = 0.81). However, after exposure to MG sera, bioenergetic parameters (oxygen consumption rate as an indicator of oxidative phosphorylation; extracellular acidification rate as an indicator of glycolysis), were induced to higher levels in OP-MG fibroblasts compared to controls (2.6-fold vs 1.5-fold; p = 0.031) without evidence of mitochondrial insufficiency in the OP-MG ocular fibroblasts. In support of the bioenergetic responses to the same MG sera, gene transcripts of PDK4 and ANGPLT4 in ocular fibroblasts also showed significant upregulation (p ≤ 0.041), but similarly in OP-MG and control cases. Taken together we showed similar basal and metabolic adaptive responses after exposure to mitochondrial inhibitors in ocular fibroblasts derived from OP-MG cases and controls, although the OP-MG cells showed greater activation in response to MG conditions. These pilot results in orbital-derived tissues provide support for myasthenic-induced changes in cellular metabolism and evidence that orbital fibroblasts may be useful for dynamic bioenergetic assessments.

Label-Free Quantitative Proteomic Analysis Provides Insight Into the Differences Between Slow-Twitch Muscle and Fast-Twitch Muscle of Pseudocaranx dentex

Fish skeletal muscles are mainly composed of two distinct types, fast-twitch and slow-twitch muscles, and they play important roles in maintaining movement and energy metabolism. The fast-twitch muscle contracts quickly and is mainly responsible for burst swimming, while the slow-twitch muscle possesses fatigue resistance and supports endurance swimming. To assess the differences in molecular composition and investigate the potential regulatory mechanisms, we performed an integrative study at both proteomic and transcriptomic levels of the fast-twitch and slow-twitch muscles in Pseudocaranx dentex, a pelagic migratory fish with distinctly differentiated skeletal muscle. Label-free proteomics revealed 471 differentially expressed proteins (DEPs), 422 upregulated and 49 downregulated in slow-twitch muscle when compared to fast-twitch muscle. These DEPs were mainly involved in myofibrillary structure and energy metabolism. Integrative analysis of proteomic and transcriptomic data showed that 757 RNA-protein pairs were positively correlated, and 191 RNA-protein pairs were negatively correlated in abundance. Meanwhile, 311 RNA-protein pairs were consistent in fold changes, and 594 RNA-protein pairs exhibited striking differences, which provided an insight into the complex regulation at both transcriptional and post-transcriptional levels that contribute to shaping the different muscle types. The specific expression of multiple myofibrillar proteins, such as myosin, actin, troponin, and tropomyosin, suggested that the distinction in contraction characterizations between slow-twitch and fast-twitch muscles is related to different protein isoforms. Muscle-type specific expression of gene-encoding key enzymes in fatty acid metabolism, glycolysis, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation pathways, such as carnitine palmitoyltransferase (CPT2), phosphofructokinase (Pfkm), pyruvate kinase (Pkmb), citrate synthase (CS), isocitrate dehydrogenase (IDH), and 2-oxoglutarate dehydrogenase complex (Ogdh), may be the molecular basis responsible for the differences in energy metabolism. Overall, this global view of protein and RNA expression levels in P. dentex fast-twitch and slow-twitch muscles reveals the essential roles of transcriptional and post-transcriptional regulation in maintaining muscle structure and function. The identified potential genes that may cause the differences in physiological characteristics will greatly improve our understanding on the molecular basis of skeletal muscle contraction, metabolism, and regulation in teleost.

Age-dependent differences in energy metabolism in the acute phase of critical illness

ObjectivesResting energy expenditure (REE) declines with age in healthy individuals, independent of the age-related decrease in lean body mass. The aim of this study was to evaluate whether this holds true in critically ill medical patients. Moreover, we assessed how measured REE compares with energy requirements calculated by prediction equations in different age groups. MethodsIn this retrospective cohort study, 200 critically ill medical patients with need for mechanical ventilation underwent indirect calorimetry within 72 h of admission after an overnight fast to determine REE. REE was adjusted for body weight (REEaBW). Patients were divided into age quartiles (I: 18–35, n = 21; II: 36–52, n = 43; III 53–69, n = 93; IV = 70–86 y, n = 43). Sex, Simplified Acute Physiology Score II, temperature at time of measurement, height, weight, and body mass index were assessed. We calculated energy requirements by Harris–Benedict and Mifflin–St. Jeor equations. Kruskal–Wallis test was used for group comparisons. Parameters that were significant in univariate regression entered the multivariate regression model. ResultsREE (P = 0.009) and REEaBW (P < 0.001) declined with age in our study population. Multivariate regression reveals age (R = -8.49 (95% CI -8.30- -1.83), P = 0.003), P = 0.004) and body temperature (R = 92.52 (95% CI 40.08-135.97, P < 0.001) as independent predictors for REE. ConclusionREE and REEaBW decrease with age in critically ill medical patients. Age and body temperature are independent predictors of both REE and REEaBW. Prediction equations underestimate energy requirements in critically ill medical patients.

Transcriptomics and Metabolomics Identify Drug Resistance of Dormant Cell in Colorectal Cancer.

Background: Tumor dormancy is an important way to develop drug resistance. This study aimed to identify the characteristics of colorectal cancer (CRC) cell dormancy. Methods: Based on the CRC cohorts, a total of 1,044 CRC patients were included in this study, and divided into a dormant subgroup and proliferous subgroup. Non-negative matrix factorization (NMF) was used to distinguish the dormant subgroup of CRC via transcriptome data of cancer tissues. Gene Set Enrichment Analysis (GSEA) was used to explore the characteristics of dormant CRC. The characteristics were verified in the cell model, which was used to predict key factors driving CRC dormancy. Potential treatments for CRC dormancy were also examined. Results: The dormant subgroup had a poor prognosis and was more likely to relapse. GSEA analysis showed two defining characteristics of the dormant subgroup, a difference in energy metabolism and synergistic effects of cancer-associated fibroblasts (CAFs), which were verified in a dormant cell model. Transcriptome and clinical data identified LMOD1, MAB21L2, and ASPN as important factors associated with cell dormancy and verified that erlotinib, and CB-839 were potential treatment options. Conclusion: Dormant CRC is associated with high glutamine metabolism and synergizes with CAFs in 5-FU resistance, and the key effectors are LMOD1, MAB21L2, and ASPN. Austocystin D, erlotinib, and CB-839 may be useful for dormant CRC.