Tissue Bioenergetics Research Articles

Myoglobin: A versatile age-old oxygen carrying hemoprotein and its emerging role in metabolite regulation in diverse tissues

Myoglobin (Mb) is an age-old heme containing cytoplasmic protein primarily expressed in heart and skeletal muscles, which is capable of rapid release of O2 during the periods of hypoxia or anoxia. The canonical view of the primary physiological function of Mb is that it is a tissue oxygen (O2) storage protein supporting mitochondrial oxidative phosphorylation especially as the tissue O2 partial pressure ( pO2) drops and Mb increasingly offloads O2. For the past 50 years, many investigators are constantly exploring wide-range of physiological functions and metabolic regulation activities of Mb. Advanced genetic engineering tools and molecular techniques revealed important new insights and provided additional functions of Mb. However, accumulating evidence indicates that this paradigm is too narrow, especially in light of recent findings supporting plausible functions for Mb in lipid traffcking and sequestration, binding of small molecules such as lactate (LAC), pyruvate (PYR), glucose (GLU), polyamines, and glutathione (GSH), and “ectopic” expression in some types of cancer cells. Data from Mb knockout mice (Mb−/−) and biochemical models suggest additional metabolic roles for Mb, especially regulation of nitric oxide (NO) pools and modulation of thermogenic brown adipose tissue (BAT) bioenergetics and lipid storage phenotypes. From these and other findings in the literature over many decades, it may be contemplated that the primary role for Mb under most conditions for Mb besides delivering O2 in support of oxidative phosphorylation, but also serve as an O2-sensor that modulates intracellular O2- and NO-responsive molecular signaling pathways. This paradigm shift reflect a fundamental change in how oxidative metabolism and cell regulation are viewed in Mb-expressing cells such as skeletal muscle, heart, brown adipocytes, and select cancer cells. Herein, we present historic and emerging views related to the physiological roles for Mb, and working models illustrating the possible importance of interactions between Mb, gases, and small molecule metabolites in regulation of cell signaling and bioenergetics. USDA-ARS project 6026-51000-010-06S, Sturgis Foundation Grant AWD00054750 and ACRI-ABI Investigator Initiated Grant Award GR037175-4450S ABI. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of six-month creatine supplementation on patient- and clinician-reported outcomes, and tissue creatine levels in patients with post-COVID-19 fatigue syndrome.

Dietary creatine has been recently put forward as a possible intervention strategy to reduce post-COVID-19 fatigue syndrome yet no clinical study so far evaluated its efficacy and safety for this perplexing condition. In this parallel-group, randomized placebo-controlled double-blind trial, we analyzed the effects of 6-month creatine supplementation (4 g of creatine monohydrate per day) on various patient- and clinician-reported outcomes, and tissue creatine levels in 12 patients with post-COVID-19 fatigue syndrome. Creatine intake induced a significant increase in tissue creatine levels in vastus medialis muscle and right parietal white matter compared to the baseline values at both 3-month and 6-month follow-ups (p < .05). Two-way analysis of variance with repeated measures revealed a significant difference (treatment vs. time interaction) between interventions in tissue creatine levels (p < .05), with the creatine group was superior to placebo to augment creatine levels at vastus medialis muscle, left frontal white matter, and right parietal white matter. Creatine supplementation induced a significant reduction in general fatigue after 3 months of intake compared to baseline values (p = .04), and significantly improved scores for several post-COVID-19 fatigue syndrome-related symptoms (e.g., ageusia, breathing difficulties, body aches, headache, and difficulties concentrating) at 6-month follow-up (p < .05). Taking creatine for 6 months appears to improve tissue bioenergetics and attenuate clinical features of post-COVID-19 fatigue syndrome; additional studies are warranted to confirm our findings in various post-COVID-19 cohorts.

Circadian mechanisms in adipose tissue bioenergetics and plasticity.

The circadian clock plays an essential role in coordinating feeding and metabolic rhythms with the light/dark cycle. Disruption of clocks is associated with increased adiposity and metabolic disorders, whereas aligning feeding time with cell-autonomous rhythms in metabolism improves health. Here, we provide a comprehensive overview of recent literature in adipose tissue biology as well as our understanding of molecular mechanisms underlying the circadian regulation of transcription, metabolism, and inflammation in adipose tissue. We highlight recent efforts to uncover the mechanistic links between clocks and adipocyte metabolism, as well as its application to dietary and behavioral interventions to improve health and mitigate obesity.

Transcriptomics-Based Subphenotyping of the Human Placenta Enabled by Weighted Correlation Network Analysis in Early-Onset Preeclampsia With and Without Fetal Growth Restriction.

Placental disorders contribute to pregnancy complications, including preeclampsia and fetal growth restriction (FGR), but debate regarding their specific pathobiology persists. Our objective was to apply transcriptomics with weighted gene correlation network analysis to further clarify the placental dysfunction in these conditions. We performed RNA sequencing with weighted gene correlation network analysis using human placental samples (n=30), separated into villous tissue and decidua basalis, and clinically grouped as follows: (1) early-onset preeclampsia (EOPE)+FGR (n=7); (2) normotensive, nonanomalous preterm FGR (n=5); (2) EOPE without FGR (n=8); (4) spontaneous idiopathic preterm birth (n=5) matched for gestational age; and (5) uncomplicated term births (n=5). Our data was compared with RNA sequencing data sets from public databases (GSE114691, GSE148241, and PRJEB30656; n=130 samples). We identified 14 correlated gene modules in our specimens, of which most were significantly correlated with birthweight and maternal blood pressure. Of the 3 network modules consistently predictive of EOPE±FGR across data sets, we prioritized a coexpression gene group enriched for hypoxia-response and metabolic pathways for further investigation. Cluster analysis based on transcripts from this module and the glycolysis/gluconeogenesis metabolic pathway consistently distinguished a subset of EOPE±FGR samples with an expression signature suggesting modified tissue bioenergetics. We demonstrated that the expression ratios of LDHA/LDHB and PDK1/GOT1 could be used as surrogate indices for the larger panels of genes in identifying this subgroup. We provide novel evidence for a molecular subphenotype consistent with a glycolytic metabolic shift that occurs more frequently but not universally in placental specimens of EOPE±FGR.

Visceral Adipose Tissue Bioenergetics Varies According to Individuals' Obesity Class.

Obesity is associated with complex adipose tissue energy metabolism remodeling. Whether AT metabolic reprogramming differs according to body mass index (BMI) and across different obesity classes is unknown. This study’s purpose was to evaluate and compare bioenergetics and energy substrate preference of visceral adipose tissue (VAT) pertaining to individuals with obesity class 2 and class 3. VAT obtained from patients with obesity (n = 15) class 2 (n = 7; BMI 37.53 ± 0.58 kg/m2) or class 3 (n = 8; BMI 47.79 ± 1.52 kg/m2) was used to assess oxygen consumption rate (OCR) bioenergetics and mitochondrial substrate preferences. VAT of patients with obesity class 3 presented significantly higher non-mitochondrial oxygen consumption (p < 0.05). In VAT of patients with obesity class 2, inhibition of pyruvate and glutamine metabolism significantly decreased maximal respiration and spare respiratory capacity (p < 0.05), while pyruvate and fatty acid metabolism inhibition, which renders glutamine the only available substrate, increased the proton leak with a protective role against oxidative stress (p < 0.05). In conclusion, VAT bioenergetics of patients with obesity class 2 depicts a greater dependence on glucose/pyruvate and glutamine metabolism, suggesting that patients within this BMI range are more likely to be responsive to interventions based on energetic substrate modulation for obesity treatment.

A review on use of computational biology in testing of skeletal muscle function in COPD patients

Computer biology and bioinformatics are interdisciplinary fields that develop and apply computational methods to analyse large amounts of biological data, such as genetic sequences, cell populations, or protein samples, in order to make new predictions or find novel biology. Analytical approaches, mathematical modelling, and simulation are among the computational methods employed.Chronic Obstructive Pulmonary Disease (COPD) is a lung inflammatory disease that causes persistent airflow restriction. These individuals frequently have extensive systemic consequences, such as skeletal muscle dysfunction, which severely restrict their life expectancy. Despite extensive research, the molecular basis of muscle deterioration in COPD remains a matter of contention. We used a network biology approach to investigate the link between the molecular and physiological responses of muscles to training and systemic inflammatory mediators in this study. Failure to coordinately activate expression of various tissue remodelling and bioenergetics pathways is a distinctive feature of COPD diseased muscles, according to our model. Our findings also point to a relationship between this phenomena and aberrant expression of a number of histone modifiers, which we discovered associated with oxygen utilisation. These findings highlighted the intriguing hypothesis that cell hypoxia is a crucial contributor in COPD patients' skeletal muscle.

P15.12.A Amine CEST contrast in gliomas to measure metabolic treatment effect at 7T

Abstract Background Chemical exchange saturation transfer (CEST) is an imaging technique that generates contrast based on proton exchange between water and a solute pool of interest. CEST is sensitive to molecules containing amine groups such as glutamate and creatine. Since creatine is a crucial metabolite in cellular metabolism and deregulation in cellular bioenergetics is a hallmark of cancer, CEST could be relevant for glioma imaging, specifically when evaluating treatment response. No clear consensus has been established on its use, therefore we wanted to preliminarily investigate the presence of amine CEST contrast in the contrast enhanced (CE) and non-enhanced (NE) lesions of gliomas, and to assess whether treated tumors would display different CEST contrast compared to treatment naïve tumors. Material and Methods We prospectively scanned 12 glioma patients on a whole-body 7 Tesla Philips Achieva MRI scanner (7 treated glioblastomas; 4 treatment naïve glioblastomas; 1 treatment naïve low-grade astrocytoma). Treatment included surgical resection, chemotherapy and radiotherapy. All patients gave informed consent. CEST images were post-processed, including corrections for B0 and B1 inhomogeneities. The CEST Z-spectra and magnetization transfer ratio (MTR) asymmetry were calculated per voxel. To retrieve the CEST values within the tumor lesions and contralateral white matter for normalization, segmentations were manually delineated on the clinical T2-FLAIR or post contrast 3D-T1. Results Overall we observed a relative increase of amine CEST contrast in the CE (MTRasym: Mean (x̄)=1.32; Standard deviation (σ)= 0.28) compared to a relative decrease (MTRasym: x̄=1.20; σ= 0.35) in the NE lesion. When evaluating the results from the CE and NE lesions for treated and treatment naïve groups individually, we observed a slightly different trend. In the treatment group, the CE lesions showed a higher amine CEST contrast (MTRasym: x̄=1.38; σ= 0.30) than the NE (MTRasym: x̄ = 1.11; σ = 0.302). In contrast, in the treatment naïve group, the CE lesion showed a slightly lower CEST contrast (MTRasym: x̄ = 1.23; σ=0.21) than in the NE group (MTRasym: x̄ = 1.29; σ= 0.38). Conclusion Our results show different amine CEST contrast trends between treated and treatment naïve groups when comparing CE and NE lesions. This suggests that treatment may have an effect on tumor tissue bioenergetics affecting the concentration of creatine. Nevertheless, future work is necessary to verify our results in a larger group of patients.

The mechanism of action of a novel neuroprotective low molecular weight dextran sulphate: New platform therapy for neurodegenerative diseases like Amyotrophic Lateral Sclerosis.

Background: Acute and chronic neurodegenerative diseases represent an immense socioeconomic burden that drives the need for new disease modifying drugs. Common pathogenic mechanisms in these diseases are evident, suggesting that a platform neuroprotective therapy may offer effective treatments. Here we present evidence for the mode of pharmacological action of a novel neuroprotective low molecular weight dextran sulphate drug called ILB®. The working hypothesis was that ILB® acts via the activation of heparin-binding growth factors (HBGF). Methods: Pre-clinical and clinical (healthy people and patients with ALS) in vitro and in vivo studies evaluated the mode of action of ILB®. In vitro binding studies, functional assays and gene expression analyses were followed by the assessment of the drug effects in an animal model of severe traumatic brain injury (sTBI) using gene expression studies followed by functional analysis. Clinical data, to assess the hypothesized mode of action, are also presented from early phase clinical trials. Results: ILB® lengthened APTT time, acted as a competitive inhibitor for HGF-Glypican-3 binding, effected pulse release of heparin-binding growth factors (HBGF) into the circulation and modulated growth factor signaling pathways. Gene expression analysis demonstrated substantial similarities in the functional dysregulation induced by sTBI and various human neurodegenerative conditions and supported a cascading effect of ILB® on growth factor activation, followed by gene expression changes with profound beneficial effect on molecular and cellular functions affected by these diseases. The transcriptional signature of ILB® relevant to cell survival, inflammation, glutamate signaling, metabolism and synaptogenesis, are consistent with the activation of neuroprotective growth factors as was the ability of ILB® to elevate circulating levels of HGF in animal models and humans. Conclusion: ILB® releases, redistributes and modulates the bioactivity of HBGF that target disease compromised nervous tissues to initiate a cascade of transcriptional, metabolic and immunological effects that control glutamate toxicity, normalize tissue bioenergetics, and resolve inflammation to improve tissue function. This unique mechanism of action mobilizes and modulates naturally occurring tissue repair mechanisms to restore cellular homeostasis and function. The identified pharmacological impact of ILB® supports the potential to treat various acute and chronic neurodegenerative disease, including sTBI and ALS.

The Effect of Lipolysis Inhibitor Acipimox on Brown Adipose Tissue Bioenergetics and Uncoupling Protein Abundance in Severely Burned Rats

IntroductionUncoupling protein 1 (UCP1) activation in brown adipose tissue (BAT) contributes to the hypermetabolic stress response to burn trauma. Strategies that target BAT UCP1 could be beneficial in controlling burn‐induced hypermetabolism. Acipimox, an inhibitor of adipose tissue lipolysis, has been shown to be effective at blunting burn‐induced lipolysis and expression of UCP1 protein in rodent white adipose tissue. The impact of acipimox on BAT bioenergetics and uncoupling protein abundance is currently unknown. We hypothesized that acipimox would blunt burn‐induced UCP‐1 dependent respiration and UCP‐1 protein levels in BAT.MethodsSixty‐four male Sprague‐Dawley rats received a 60% TBSA scald burn (n=32) or sham procedure (n=32) and were subsequently randomized to receive either acipimox (n=16/group; 50 mg/kg/day i.p.) or vehicle (n=16/group) daily for 7d. BAT was harvested from the interscapular fat pad on day 7 after burn and mitochondrial respiratory function assessed by high‐resolution respirometry. GDP‐sensitive respiration was assayed as a direct measure of UCP1 function. UCP1 and adenine nucleotide translocator (ANT2) protein levels were determined by western blot.ResultsUCP1‐dependent and UCP1‐independent uncoupled respiration in BAT was reduced at 7d after severe burn, independent of treatment (injury effect, P&lt;0.01). Post‐burn, UCP1‐dependent respiration accounted for 65% of total uncoupled respiration compared to 59% in sham rats (injury effect, P&lt;0.05), independent of treatment. Acipimox appeared to exert a lowering effect on UCP1‐dependent respiration (treatment effect, P=0.07) but not on UCP1‐independent respiration. Neither burn nor treatment with acipimox had a significant effect on UCP1 protein levels. Protein levels of ANT2, a carrier protein involved in fatty acid‐induced uncoupling, were greater in response to acipimox (treatment effect, P&lt;0.05).ConclusionBAT UCP1 function than UCP1 protein content is greater in severely burned rats. Acipimox appears to reduce UCP1‐dependent respiration, independent of UCP1 protein levels. The effect of acipimox on BAT ANT2 protein content may partly explain the absence of an effect on UCP1‐independent respiration, but this warrants further investigation.The protocol was approved by the University of Texas Medical Branch IACUC.

Housing Temperature Alters Energy Expenditure and Adipose Tissue Bioenergetics in Mice

BackgroundSub‐thermoneutral housing temperatures increase facultative thermogenesis in mice, a process which has been attributed in part to uncoupling protein 1 (UCP1). Typical vivarium temperatures (i.e., ~22‐26°C) likely represent mild cold stress for mice, yet the metabolic impact of modest changes in housing temperature in mice remains unclear. Here, we determined the impact of transitioning mice from 24°C to 30°C on total energy expenditure (TEE) and adipose tissue bioenergetics.MethodsMale and female C57BL/6J mice were studied for 6‐weeks. All mice were housed at 24°C (room temperature, RT) for two weeks, and then either remained at RT (n=16 per group, 8M/8F) or were transitioned to 30°C (thermoneutrality, TN) (n=16 per group, 8M/8F) for 4 weeks. Mice were housed in metabolic cages to determine TEE and its components via respiratory gas exchange. Interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) were harvested at the end of the 6‐week study to assess mitochondrial respiratory function by high resolution respirometry.ResultsCompared to RT, total daily energy expenditure (TEE) was 25% and 16% lower in males and females at TN (M: TN, 8.4±0.6 vs. RT, 11.1±1.0 kcal/day; F: TN, 8.1±0.6 vs. RT, 9.6±1.6 kcal/day; P&lt;0.05), which was partly due to a 36% and 40% decrease in basal metabolic rate (BEE) at TN (M: TN, 3.6±0.2 vs. RT, 5.6±0.8 kcal/day; F: TN, 3.2±0.2 vs. RT, 5.4±0.9 kcal/day; P&lt;0.01). Wheel running distance completed by males was 50% lower at TN versus RT (P&lt;0.05), and female mice ran 101% further than males at TN (P&lt;0.05). iBAT depot mass was 73% and 76% greater at TN versus RT (P&lt;0.01) in males and females, respectively, whereas iWAT mass was similar between conditions. At RT, total iBAT depot UCP1 protein content was 2‐fold greater than that at TN (P&lt;0.01). Further, iBAT depot UCP1 protein content was respectively 20‐ and 40‐fold greater than the iWAT depot at TN and RT (P&lt;0.01). However, iBAT UCP1‐dependent respiration per depot was unaltered by housing temperature, whereas iWAT UCP1‐dependent respiration per depot was 70% and 62% lower in males and females, respectively, at TN versus RT (P&lt;0.01). Still, the absolute thermogenic capacity of UCP1 in the iBAT depot was 45‐ and 16‐fold greater than the iWAT depot at TN and RT, respectively.ConclusionA modest change in housing temperature markedly alters BEE and thus TEE in mice. Cooler housing temperature (even those within the National Research Council’s guide for housing laboratory rodents) results in marked hypermetabolism and recruitment of UCP1 in both iWAT and iBAT. Despite UCP1 recruitment in iWAT, iBAT is the principal site of UCP1‐dependent thermogenesis in mice housed at 24°C. These data may have important implications regarding the optimization of preclinical models of human disease.

Lithium augmentation of ketamine increases insulin signaling and antidepressant-like active stress coping in a rodent model of treatment-resistant depression

Lithium, a mood stabilizer and common adjunctive treatment for refractory depression, shares overlapping mechanisms of action with ketamine and enhances the duration of ketamine’s antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial, lithium co-treatment with ketamine failed to improve antidepressant outcomes in subjects previously shown to respond to ketamine alone. The potential for lithium augmentation to improve antidepressant outcomes in ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of lithium and ketamine co-treatment in a rodent model of antidepressant resistance. Male Wistar rats were administered adrenocorticotropic hormone (ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with ketamine (10 mg/kg; 2 days; n = 12), lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on extracellular signal-regulated kinase (ERK); mammalian target of rapamycin (mTOR), phospho kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with brain-derived neurotrophic factor (BDNF) and tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and insulin were determined using enzyme-linked immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to BDNF or TNFα. Animals receiving both ketamine and lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that lithium augmentation of ketamine in antidepressant nonresponsive animals improves antidepressant-like behavioral responses under stress, together with peripheral insulin efflux and region-specific PFC insulin signaling.

ILB® Attenuates Clinical Symptoms and Serum Biomarkers of Oxidative/Nitrosative Stress and Mitochondrial Dysfunction in Patients with Amyotrophic Lateral Sclerosis.

Oxidative/nitrosative stress and mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal progressive neurodegenerative disease. Here, as an exploratory arm of a phase II clinical trial (EudraCT Number 2017-005065-47), we used high performance liquid chromatography(HPLC) to investigate changes in the metabolic profiles of serum from ALS patients treated weekly for 4 weeks with a repeated sub-cutaneous dose of 1 mg/kg of a proprietary low molecular weight dextran sulphate, called ILB®. A significant normalization of the serum levels of several key metabolites was observed over the treatment period, including N-acetylaspartate (NAA), oxypurines, biomarkers of oxidative/nitrosative stress and antioxidants. An improved serum metabolic profile was accompanied by significant amelioration of the patients’ clinical conditions, indicating a response to ILB® treatment that appears to be mediated by improvement of tissue bioenergetics, decrease of oxidative/nitrosative stress and attenuation of (neuro)inflammatory processes.

Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects.

Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.

Adipose tissue senescence is mediated by increased ATP content after a short-term high-fat diet exposure.

In the context of obesity, senescent cells accumulate in white adipose tissue (WAT). The cellular underpinnings of WAT senescence leading to insulin resistance are not fully elucidated. The objective of the current study was to evaluate the presence of WAT senescence early after initiation of high‐fat diet (HFD, 1–10 weeks) in 5‐month‐old male C57BL/6J mice and the potential role of energy metabolism. We first showed that WAT senescence occurred 2 weeks after HFD as evidenced in whole WAT by increased senescence‐associated ß‐galactosidase activity and cyclin‐dependent kinase inhibitor 1A and 2A expression. WAT senescence affected various WAT cell populations, including preadipocytes, adipose tissue progenitors, and immune cells, together with adipocytes. WAT senescence was associated with higher glycolytic and mitochondrial activity leading to enhanced ATP content in HFD‐derived preadipocytes, as compared with chow diet‐derived preadipocytes. One‐month daily exercise, introduced 5 weeks after HFD, was an effective senostatic strategy, since it reversed WAT cellular senescence, while reducing glycolysis and production of ATP. Interestingly, the beneficial effect of exercise was independent of body weight and fat mass loss. We demonstrated that WAT cellular senescence is one of the earliest events occurring after HFD initiation and is intimately linked to the metabolic state of the cells. Our data uncover a critical role for HFD‐induced elevated ATP as a local danger signal inducing WAT senescence. Exercise exerts beneficial effects on adipose tissue bioenergetics in obesity, reversing cellular senescence, and metabolic abnormalities.

Short-term GAA loading: Responders versus nonresponders analysis.

Dietary guanidinoacetic acid (GAA) has been suggested to be advantageous for favorable changes in tissue bioenergetics in terms of responder versus nonresponder performance, yet no studies so far explored the proportion of two distinct populations following short‐term GAA intervention. A secondary analysis of previously completed guanidinoacetic acid (GAA) trials has been carried out in aim to classify individuals into responders and nonresponders using cut‐off criteria for an increase in intramuscular creatine. A total of 30 individuals (mean age = 34.5 years, women 66.7%) who were supplemented with up to 3 g/day of GAA for at least 28 days with total muscle creatine evaluated using 1.5 T magnetic resonance spectroscopy studies were included in this examination. Pre–post measures included total creatine content (creatine plus phosphocreatine) determined from the quadriceps muscle, with participants were classified by arbitrary cut‐off points in three categories, including responders (>10% increase in total creatine content at follow‐up), quasi‐responders (5%–10% increase), and nonresponders (<5% increase in total intramuscular creatine at postadministration). An average change in total creatine content after GAA supplementation was 22.9%, with 13.3% participants were categorized as nonresponders, 6.6% as quasi‐responders, and 80.0% as responders (p < .001). A fairly high prevalence of individuals sensitive to dietary GAA advances this innovative agent as a rather effective tool to improve muscle creatine levels for at least 10% or more during 28‐day loading.

Transplanting Marginal Organs in the Era of Modern Machine Perfusion and Advanced Organ Monitoring.

Organ transplantation is undergoing profound changes. Contraindications for donation have been revised in order to better meet the organ demand. The use of lower-quality organs and organs with greater preoperative damage, including those from donation after cardiac death (DCD), has become an established routine but increases the risk of graft malfunction. This risk is further aggravated by ischemia and reperfusion injury (IRI) in the process of transplantation. These circumstances demand a preservation technology that ameliorates IRI and allows for assessment of viability and function prior to transplantation. Oxygenated hypothermic and normothermic machine perfusion (MP) have emerged as valid novel modalities for advanced organ preservation and conditioning. Ex vivo prolonged lung preservation has resulted in successful transplantation of high-risk donor lungs. Normothermic MP of hearts and livers has displayed safe (heart) and superior (liver) preservation in randomized controlled trials (RCT). Normothermic kidney preservation for 24 h was recently established. Early clinical outcomes beyond the market entry trials indicate bioenergetics reconditioning, improved preservation of structures subject to IRI, and significant prolongation of the preservation time. The monitoring of perfusion parameters, the biochemical investigation of preservation fluids, and the assessment of tissue viability and bioenergetics function now offer a comprehensive assessment of organ quality and function ex situ. Gene and protein expression profiling, investigation of passenger leukocytes, and advanced imaging may further enhance the understanding of the condition of an organ during MP. In addition, MP offers a platform for organ reconditioning and regeneration and hence catalyzes the clinical realization of tissue engineering. Organ modification may include immunological modification and the generation of chimeric organs. While these ideas are not conceptually new, MP now offers a platform for clinical realization. Defatting of steatotic livers, modulation of inflammation during preservation in lungs, vasodilatation of livers, and hepatitis C elimination have been successfully demonstrated in experimental and clinical trials. Targeted treatment of lesions and surgical treatment or graft modification have been attempted. In this review, we address the current state of MP and advanced organ monitoring and speculate about logical future steps and how this evolution of a novel technology can result in a medial revolution.

Changes in Fat Mass Following Creatine Supplementation and Resistance Training in Adults ≥50 Years of Age: A Meta-Analysis.

Aging is associated with an increase in fat mass which increases the risk for disease, morbidity and premature mortality. Creatine supplementation in combination with resistance training has been shown to increase lean tissue mass in adults ≥50 years of age; however, the synergetic effects of creatine and resistance training on fat mass in this population are unclear. Creatine metabolism plays an important role in adipose tissue bioenergetics and energy expenditure. Thus, the combination of creatine supplementation and resistance training may decrease fat mass more than resistance training alone. The purpose of this review is two-fold: (1) to perform meta-analyses on studies involving creatine supplementation during resistance training on fat mass in adults ≥50 years of age, and (2) to discuss possible mechanistic actions of creatine on reducing fat mass. Nineteen studies were included in our meta-analysis with 609 participants. Results from the meta-analyses showed that adults ≥50 years of age who supplemented with creatine during resistance training experienced a greater reduction in body fat percentage (0.55%, p = 0.04) compared to those on placebo during resistance training. Despite no statistical difference (p = 0.13), adults supplementing with creatine lost ~0.5 kg more fat mass compared to those on placebo. Interestingly, there are studies which have linked mechanism(s) explaining how creatine may influence fat mass, and these data are also discussed.

Dose-Dependent Acute Circulatory Fates Elicited by Cadmium Are Mediated by Differential Engagements of Cardiovascular Regulatory Mechanisms in Brain.

Whereas cadmium is a toxicant that has been shown to cause cardiovascular toxicity and mortality in mammals, few mechanistic studies address its acute circulatory actions. The present study assessed the hypothesis that cadmium effects dose-dependent acute circulatory fates via differential participation of the cardiovascular regulatory mechanisms in brain. In Sprague-Dawley rats maintained under propofol anesthesia, cadmium acetate (8 mg/kg, iv) induced significantly high mortality rate within 10 min, concomitant with progressive decline toward zero level of mean arterial pressure (MAP), heart rate (HR), baroreflex-mediated sympathetic vasomotor tone, and carotid blood flow (CBF). There were concurrent tissue anoxia, cessation of microvascular perfusion, reduction of mitochondrial membrane potential and ATP production, and necrotic cell death in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone. On the other hand, a lower-dose of cadmium (4 mg/kg, iv) resulted in only a transient decrease in MAP that was mirrored by an increase in CBF and baroreflex-mediated sympathetic vasomotor tone, minor changes in HR, along with transient hypoxia, and apoptotic cell death in RVLM. We conclude that cadmium elicits dose-dependent acute cardiovascular effects with differential underlying biochemical and neural mechanisms. At a higher-dose, cadmium induces high mortality by effecting acute cardiovascular collapse via anoxia, diminished tissue perfusion, mitochondrial dysfunction and bioenergetics failure that echo failure of cerebral autoregulation, leading to necrosis, and loss of functionality in RVLM. On the other hand, a lower-dose of cadmium elicits low mortality, transient decrease in arterial pressure, and hypoxia and apoptosis in RVLM that reflect sustained cerebral autoregulation.

Integrated Computational Model of Lung Tissue Bioenergetics.

Altered lung tissue bioenergetics plays a key role in the pathogenesis of lung diseases. A wealth of information exists regarding the bioenergetic processes in mitochondria isolated from rat lungs, cultured pulmonary endothelial cells, and intact rat lungs under physiological and pathophysiological conditions. However, the interdependence of those processes makes it difficult to quantify the impact of a change in a single or multiple process(es) on overall lung tissue bioenergetics. Integrated computational modeling provides a mechanistic and quantitative framework for the bioenergetic data at different levels of biological organization. The objective of this study was to develop and validate an integrated computational model of lung bioenergetics using existing experimental data from isolated perfused rat lungs. The model expands our recently developed computational model of the bioenergetics of mitochondria isolated from rat lungs by accounting for glucose uptake and phosphorylation, glycolysis, and the pentose phosphate pathway. For the mitochondrial region of the model, values of kinetic parameters were fixed at those estimated in our recent model of the bioenergetics of mitochondria isolated from rat lungs. For the cytosolic region of the model, intrinsic parameters such as apparent Michaelis constants were determined based on previously published enzyme kinetics data, whereas extrinsic parameters such as maximal reaction and transport velocities were estimated by fitting the model solution to published data from isolated rat lungs. The model was then validated by assessing its ability to predict existing experimental data not used for parameter estimation, including relationships between lung nucleotides content, lung lactate production rate, and lung energy charge under different experimental conditions. In addition, the model was used to gain novel insights on how lung tissue glycolytic rate is regulated by exogenous substrates such as glucose and lactate, and assess differences in the bioenergetics of mitochondria isolated from lung tissue and those of mitochondria in intact lungs. To the best of our knowledge, this is the first model of lung tissue bioenergetics. The model provides a mechanistic and quantitative framework for integrating available lung tissue bioenergetics data, and for testing novel hypotheses regarding the role of different cytosolic and mitochondrial processes in lung tissue bioenergetics.

Integrated Computational Model of Lung Tissue Bioenergetics

Altered lung tissue bioenergetics plays a key role in the pathogenesis of lung diseases. A wealth of information exists regarding the bioenergetic processes in mitochondria isolated from rat lungs, cultured pulmonary endothelial cells, and intact rat lungs under physiological and pathophysiological conditions. However, the interdependence of those processes makes it difficult to quantify the impact of a change in a single or multiple process(es) on overall lung tissue bioenergetics. Integrated computational modeling provides a mechanistic and quantitative framework for the bioenergetic data at different levels of biological organization. The objective of this study was to develop and validate an integrated computational model of lung bioenergetics using existing experimental data from isolated perfused rat lungs. The model expands our recently developed computational model of the bioenergetics of mitochondria isolated from rat lungs by accounting for glucose uptake and phosphorylation, glycolysis, and the pentose phosphate pathway. For the mitochondrial region of the model, values of kinetic parameters were fixed at those estimated in our recent model of the bioenergetics of mitochondria isolated from rat lungs. For the cytosolic region of the model, intrinsic parameters such as apparent Michaelis constants were determined based on previously published enzyme kinetics data, whereas extrinsic parameters such as maximal reaction and transport velocities were estimated by fitting the model solution to published data from isolated rat lungs. The model was then validated by assessing its ability to predict existing experimental data not used for parameter estimation, including relationships between lung nucleotides content, lung lactate production rate, and lung energy charge under different experimental conditions. In addition, the model was used to gain novel insights on how lung tissue glycolytic rate is regulated by exogenous substrates such as glucose and lactate, and assess differences in the bioenergetics of mitochondria isolated from lung tissue and those of mitochondria in intact lungs. To the best of our knowledge, this is the first model of lung tissue bioenergetics. The model provides a mechanistic and quantitative framework for integrating available lung tissue bioenergetics data, and for testing novel hypotheses regarding the role of different cytosolic and mitochondrial processes in lung tissue bioenergetics.