Energetic Deficiency Research Articles

Heart Failure: A Deficiency of Energy—A Path Yet to Discover and Walk

Heart failure is a complex syndrome and our understanding and therapeutic approach relies mostly on its phenotypic presentation. Notably, the heart is characterized as the most energy-consuming organ, being both a producer and consumer, in order to satisfy multiple cardiac functions: ion exchange, electromechanical coordination, excitation–contraction coupling, etc. By obtaining further knowledge of the cardiac energy field, we can probably better characterize the basic pathophysiological events occurring in heart disease patients and understand the metabolic substance changes, the relationship between the alteration of energy production/consumption, and hence energetic deficiency not only in the heart as a whole but in every single cardiac territory, which will hopefully provide us with the opportunity to uncover the beginning of the heart failure process. In this respect, using (a) newer imaging techniques, (b) biomedicine, (c) nanotechnology, and (d) artificial intelligence, we can gain a deeper understanding of this complex syndrome. This, in turn, can lead to earlier and more effective therapeutic approaches, ultimately improving human health. To date, the scientific community has not given sufficient attention to the energetic starvation model. In our view, this review aims to encourage scientists and the medical community to conduct studies for a better understanding and treatment of this syndrome.

Mitochondrial function is abnormal in circulating blood monocytes of patients with chronic heart failure

Abstract Background Cardiac mitochondrial function is abnormal in heart failure (HF) and is likely to contribute to disease progression. We previously showed that in dogs with HF mitochondrial functional abnormalities exist in both failing cardiomyocytes and in circulating blood monocytes, and to similar extent. This finding suggested the possibility that mitochondrial function in circulating monocytes can serve as a surrogate for cardiac mitochondrial function. We also showed that mitochondrial abnormalities exist in cardiomyocytes of patients with chronic HF. Purpose In the present study we sought to test the difference between patients with advanced HF and age-matched controls in terms of circulating monocyte mitochondrial function. Methods We examined circulating blood monocytes from 10 patients evaluated in our advanced HF clinic and with left ventricular ejection fraction <35%. compared to 10 age-matched control persons without cardiac disease (CON). Peripheral blood samples (15 ml) were obtained from each participant and monocytes were isolated using standard Ficoll-Paque gradient centrifugation. Isolated monocytes were suspended in Agilent XF-DMEM base buffer for quantification of mitochondrial function with Seahorse XFe96 analyzer. The following key mitochondrial functional parameters were determined: basal respiration (BASEresp), ATP production-linked respiration (ATPresp), maximal respiration (MAXresp) and respiratory capacity (RC). Results BASEresp, ATPresp, MAXresp and RC were significantly lower in monocytes of patients with HF compared to NL subjects (BASEresp 2.7 ± 0.7 vs. 5.2 ± 1.6, p<0.05; ATPresp 10.0 ± 0.8 vs. 15.9 ± 1.0, p<0.05; MAXresp 36.5 ± 5.9 vs. 69.3 ± 3.8, p<0.05; RC 26.5 ± 5.5 vs. 53.5 ± 3.5, p<0.05). Conclusions Mitochondrial dysfunction is present in circulating blood monocytes of patients with chronic HF. These findings coupled to those in dogs with HF suggest the possibility that determination of mitochondrial function in peripheral monocytes may identify those patients with HF with cardiac energetic deficiencies. If validated this technique could help illuminate how cardiac energy deprivation relates to disease progression and potentially enable targeted therapies directed at mitochondria dysfunction.

Regulation of NAD Metabolism in Diastolic Dysfunction Induced by Metabolic Stress

Patients of heart failure with preserved ejection fraction (HFpEF) have diastolic dysfunction. Intervention targeting mechanisms of diastolic dysfunction is lacking, leading to a growing population of patients with HFpEF. Diabetes and obesity are key risk factors of HFpEF. NAD depletion is associated with heart failure, diabetes and obesity, and is due to NAD redox imbalance, suppressed synthesis and/or activated consumption pathways. Here, we used mouse models manipulating NAD redox balance and hydrolysis to determine their roles in metabolic cardiomyopathy. Cardiac Ndufs4‐KO mice (cKO) have lowered cardiac NAD/NADH ratio, normal baseline function, geometry and energetics. Chronic diabetic stress induced by streptozotocin (STZ) or diet‐induced obesity (DIO) in wild type (WT) mice promoted diastolic dysfunction, which was further exacerbated in cKO mice with latent cardiac NAD redox imbalance. Elevated oxidative stress by SOD2 acetylation and increased TnI‐S150 phosphorylation by energetic deficiency in diabetic cKO hearts led to exacerbated diastolic dysfunction. Elevation of cardiac NAD levels normalized NAD/NADH ratio, ameliorated these pathogenic mechanisms and diastolic dysfunction in metabolically stressed mice. These results supported the causal role of NAD redox imbalance in metabolic cardiomyopathy.Next, we tested whether deficiency of SARM1, an intracellular NAD hydrolase, will ameliorate diastolic dysfunction induced by metabolic stresses. WT and total SARM1‐KO mice were challenged with diabetic stress or DIO. These metabolic stresses led to a decline in diastolic function, which was improved in SARM1‐KO mice. DIO also promoted cardiac hypertrophy that was ameliorated by SARM1 deficiency. To determine that the improvement of diastolic function by SARM1 deficiency was not due to a reversal of systemic metabolic state, a comprehensive plasma metabolomic analyses was performed. Hyperglycemia was similar in diabetic WT and SARM1‐KO plasma. Metabolomic analyses showed significant changes in 58 out of 298 aqueous metabolites and in 26 out of 85 lipid species measured, when comparing non‐diabetic WT to diabetic WT plasma. When comparing the 84 metabolites with diabetic changes from diabetic WT and diabetic SARM1‐KO plasma, only one of the lipid metabolites (PC 16:0/16:0) showed a mild further decrease in SARM1‐KO plasma. The metabolomic data suggest that WT and SARM1‐KO hearts experienced similar metabolic stress, and that the improvement of diastolic dysfunction by SARM1 deficiency was due to the reversal of cardiac pathogenic mechanisms.To determine how SARM1 deficiency affected cardiac NAD metabolism, transcript levels of genes in NAD metabolic pathways were assessed. Expressions of Bst1 and Cd38 NAD hydrolases did not change in SARM1‐KO hearts, suggesting that SARM1 deficiency did not induce compensatory changes in expression of the other NAD hydrolases. SARM1‐KO hearts showed lower expressions in several other NAD consuming genes (e.g. Sirtuins) and NAD synthesis genes (e.g. Nmnats). Cardiac fibrosis, pro‐fibrotic genes (e.g. ctgf) and Nppb expression were induced in diabetic WT hearts and were suppressed by SARM1 deficiency. In summary, our data support the critical roles of NAD redox imbalance and SARM1 in diastolic dysfunction induced by metabolic stress.

Elimination of AKT in Cardiomyocytes Causes Complex Reorganization of Signal Transduction leading to AMPK Inhibition and Fatal Cardiac Atrophy

Akt1 and Akt2 are the main protein kinase B (Akt) isoforms expressed in the mammalian heart. Tamoxifen(OHTx) ‐inducible, cardiomyocyte‐specific Akt1/ Akt2 double knockout mice (iCM‐Akt12) show progressive cardiac atrophy and loss of contractile function leading to terminal heart failure 23.9 ± 2 days after first OHTx injection.TUNEL staining of iCM‐Akt12 hearts revealed that cardiomyocyte apoptosis did not contribute substantially to cardiac atrophy. Rather, cellular atrophy caused the loss of cardiac mass. The cellular area (a), width (w), and length (l) declined between day 9 and day 14 [‐18 (a)/‐18 (w)/‐9% (l)] as compared to WT controls. This size reduction was retarded between d14 and d21 (‐20 (a)/‐24 (w)/‐8% (l). In vivo 31P‐imaging identified a progressive energetic deficiency of iCM‐Akt12 hearts on d15 and d20 after OHTx injection.Further analyses showed that in the early phase up to day 14 increased autophagic activity and reduced de novo protein synthesis seemed to cause cellular atrophy. As expected, deletion of Akt led to impaired mTORC1 signaling indicated by reduced phosphorylation of S6K, RPS6, 4E‐BP1, all involved in translation. Concomitantly, we measured reduced protein synthesis. Autophagy was increased in iCM‐Akt12 hearts, as shown by increased LC3‐II/I ratio and higher expression of autophagic genes.From day 14 after KO induction (late phase), protein synthesis appeared to increase and mTORC1 substrates involved in translation (S6K, RPS6 and 4E‐BP1) were higher phosphorylated. Of note, also a higher phosphorylation of the inhibitory mTORC1 target site in the central autophagy kinase Ulk1 (S757) was found. Moreover, autophagy appeared to be disturbed, as p62 accumulated.Despite increasing energetic depletion, the cellular energy sensor AMPK was not activated in iCM‐Akt12 hearts. Rather, AMPK was inhibited by phosphorylation of the α‐subunit on serine 485/491. The S485/491 phosphorylation has been attributed to several kinases (Akt, PKD1, S6K, PKC, PKA). Akt deletion led to a pronounced hyperactivation of Pdk1 signaling upstream of Akt, causing an activation of protein kinases regulated by Pdk1 (S6K, PKA, PKC, PKD). This was demonstrated by increased phosphorylation of specific kinase substrates and consensus motifs in late iCM‐Akt12 hearts and might promote the AMPK inactivation.To test to what extent a non‐inhibitable AMPK might attenuate the fatal phenotype of cardiac Akt loss, AAV‐mediated infection of iCM‐Akt12 mice with a phospho‐defective AMPKα2 S491A mutant prior to KO induction was performed. This led to an increased survival and improved heart function, demonstrating that the AMPK inhibition contributes to the lethal phenotype.In conclusion, loss of Akt signaling leads to a widespread dysregulation of intracellular signal transduction. Whereas enhanced autophagy and inhibition of mTORC1 are direct consequences of Akt deletion, the later reactivation of mTORC1 and inhibition of AMPK causes attenuation of autophagy, increased translation, deceleration of cellular atrophy, worsenes energetic shortage, and aggravates cardiac dysfunction.

Proteomic quantitative study of dorsal root ganglia and sciatic nerve in type 2 diabetic mice

ObjectivePeripheral neuropathy is the most common and debilitating complication of type 2 diabetes, leading to sensory loss, dysautonomia, hyperalgesia, and spontaneous noxious sensations. Despite the clinical and economic burden of diabetic neuropathy, no effective treatment is available. More preclinical research must be conducted in order to gain further understanding of the aetiology of the disease and elucidate new therapeutic targets. MethodsThe proteome of lumbar dorsal root ganglia and sciatic nerve of BKS-db/db mice, which contain a mutation of the leptin receptor and are an established type 2 diabetes model, was characterized for the first time by tandem mass tag labelling and mass spectrometry analysis. ResultsProteomic analysis showed differentially expressed proteins grouped into functional clusters in db/db peripheral nerves compared to control mice, underlining reduced glycolytic and TCA cycle metabolism, higher lipid catabolism, upregulation of muscle-like proteins in DRG and downregulation in SCN, increased cytoskeleton-related proteins, a mild dysregulation of folding chaperones, activation of acute-phase and inflammatory response, and alterations in glutathione metabolism and oxidative stress related proteins. ConclusionsOur data validate previous transcriptomic and metabolomic results and uncover new pathways altered in diabetic neuropathy. Our results point out that energetic deficiency could represent the main mechanism of neurodegeneration observed in diabetic neuropathy. These findings may provide important information to select appropriate targets to develop new therapeutic strategies.

Molecular Signature of HFpEF: Systems Biology in a Cardiac-Centric Large Animal Model

In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1-month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.

Physical Exercise: A Novel Tool to Protect Mitochondrial Health.

Mitochondrial dysfunction is a crucial contributor to heart diseases. Alterations in energetic metabolism affect crucial homeostatic processes, such asATP production, the generation of reactive oxygen species, and the release of pro-apoptotic factors, associated with metabolic abnormalities. In response to energetic deficiency, the cardiomyocytes activate the Mitochondrial Quality Control (MQC), a critical process in maintaining mitochondrial health. This process is compromised in cardiovascular diseases depending on the pathology’s severity and represents, therefore, a potential therapeutic target. Several potential targeting molecules within this process have been identified in the last years, and therapeutic strategies have been proposed to ameliorate mitochondria monitoring and function. In this context, physical exercise is considered a non-pharmacological strategy to protect mitochondrial health. Physical exercise regulates MQC allowing the repair/elimination of damaged mitochondria and synthesizing new ones, thus recovering the metabolic state. In this review, we will deal with the effect of physical exercise on cardiac mitochondrial function tracing its ability to modulate specific steps in MQC both in physiologic and pathologic conditions.

Mitochondrial morphology, bioenergetics and proteomic responses in fatty acid oxidation disorders

Mutations in nuclear genes encoding for mitochondrial proteins very long-chain acyl-CoA dehydrogenase (VLCAD) and trifunctional protein (TFP) cause rare autosomal recessive disorders. Studies in fibroblasts derived from patients with mutations in VLCAD and TFP exhibit mitochondrial defects. To gain insights on pathological changes that account for the mitochondrial deficits we performed quantitative proteomic, biochemical, and morphometric analyses in fibroblasts derived from subjects with three different VLCAD and three different TFP mutations. Proteomic data that was corroborated by antibody-based detection, indicated reduced levels of VLCAD and TFP protein in cells with VLCAD and TFP mutations respectively, which in part accounted for the diminished fatty acid oxidation capacity. Decreased mitochondrial respiratory capacity in cells with VLCAD and TFP mutations was quantified after glucose removal and cells with TFP mutations had lower levels of glycogen. Despite these energetic deficiencies, the cells with VLCAD and TFP mutations did not exhibit changes in mitochondria morphology, distribution, fusion and fission, quantified by either confocal or transmission electron microscopy and corroborated by proteomic and antibody-based protein analysis. Fibroblasts with VLCAD and to a lesser extend cells with TFP mutations had increased levels of mitochondrial respiratory chain proteins and proteins that facilitate the assembly of respiratory complexes. With the exception of reduced levels of catalase and glutathione S-transferase theta-1 in cells with TFP mutations, the levels of 45 proteins across all major intracellular antioxidant networks were similar between cells with VLCAD and TFP mutations and non-disease controls. Collectively the data indicate that despite the metabolic deficits, cells with VLCAD and TFP mutations maintain their proteomic integrity to preserve cellular and mitochondria architecture, support energy production and protect against oxidative stress.

251 Impacts of different levels of dietary zinc oxide on mitochondrial energy metabolism and oxidative stress conditions in post-weaned piglets

Abstract Zinc oxide (ZnO) is commonly added to weanling piglet diets for its documented benefits as growth promoting agent and usefulness for preventing diarrhea. We have recently reported the occurrence of mitochondrial energetic deficiencies and oxidative stress conditions in post-weaned piglets. In cells, Zn is known to be primarily located in mitochondria, where it is involved in mitochondrial function. The objective of this study was to determine the impacts of different levels of dietary ZnO on mitochondrial function and oxidative stress. One hundred twenty suckling piglets (5.65 ± 0.68 kg) were selected at d14. After weaning (d21), they were fed a basal diet supplemented with 100 mg/kg (low; L), 1000 mg/kg (medium; M) or 3000 mg/kg (high; H) of ZnO until d42 (n = 40/treatment). Piglets were sacrificed at d21, d23, d35, and d42 of age (n = 10/treatment/d) for sample collection. Mitochondrial respiration was evaluated using an extracellular flux analyzer and our results showed higher oxygen consumption rates in liver mitochondria from H group (P < 0.05) at d42. The cellular energy status was characterized by measuring liver adenosine 5’-triphosphate (ATP) content, and lower levels were reported in H group (P < 0.01) at d42. These observations were concomitant with a decrease in activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) in cytosol and mitochondria. Quantitative RT-PCR analyses revealed that expression of genes implicated in oxidative stress response such as glutathione synthase (GSS), heme oxygenase 1 (HO1) and metallothionein 3 (MT3) is increased in H group at d42 (P < 0.05). In plasma, GPx activity and oxidative damage to proteins (carbonyls) was higher in H group (P < 0.05). These findings indicate that ZnO affects mitochondrial function and oxidative stress in post-weaned piglets and provide insights to guide the prophylactic practices using high levels of dietary ZnO.

Energetic Interactions Between Subcellular Organelles in Striated Muscles.

Adult striated muscle cells present highly organized structure with densely packed intracellular organelles and a very sparse cytosol accounting for only few percent of cell volume. These cells have a high and fluctuating energy demand that, in continuously working oxidative muscles, is fulfilled mainly by oxidative metabolism. ATP produced by mitochondria should be directed to the main energy consumers, ATPases of the excitation-contraction system; at the same time, ADP near ATPases should rapidly be eliminated. This is achieved by phosphotransfer kinases, the most important being creatine kinase (CK). Specific CK isoenzymes are located in mitochondria and in close proximity to ATPases, forming efficient energy shuttle between these structures. In addition to phosphotransfer kinases, ATP/ADP can be directly channeled between mitochondria co-localized with ATPases in a process called “direct adenine nucleotide channeling, DANC.” This process is highly plastic so that inactivation of the CK system increases the participation of DANC to energy supply owing to the rearrangement of cell structure. The machinery for DANC is built during postnatal development in parallel with the increase in mitochondrial mass, organization, and complexification of the cell structure. Disorganization of cell architecture remodels the mitochondrial network and decreases the efficacy of DANC, showing that this process is intimately linked to cardiomyocyte structure. Accordingly, in heart failure, disorganization of the cell structure along with decrease in mitochondrial mass reduces the efficacy of DANC and together with alteration of the CK shuttle participates in energetic deficiency contributing to contractile failure.

Extreme environmental conditions reduce coral reef fish biodiversity and productivity

Tropical ectotherms are hypothesized to be vulnerable to environmental changes, but cascading effects of organismal tolerances on the assembly and functioning of reef fish communities are largely unknown. Here, we examine differences in organismal traits, assemblage structure, and productivity of cryptobenthic reef fishes between the world’s hottest, most extreme coral reefs in the southern Arabian Gulf and the nearby, but more environmentally benign, Gulf of Oman. We show that assemblages in the Arabian Gulf are half as diverse and less than 25% as abundant as in the Gulf of Oman, despite comparable benthic composition and live coral cover. This pattern appears to be driven by energetic deficiencies caused by responses to environmental extremes and distinct prey resource availability rather than absolute thermal tolerances. As a consequence, production, transfer, and replenishment of biomass through cryptobenthic fish assemblages is greatly reduced on Earth’s hottest coral reefs. Extreme environmental conditions, as predicted for the end of the 21st century, could thus disrupt the community structure and productivity of a critical functional group, independent of live coral loss.

Pericytes in Neurometabolic Diseases

Since brain pericytes guarantee appropriate development and maintenance of the cerebrovascular system, we reviewed their role in neurometabolic diseases (NMDs), a subclass of inborn errors of metabolism that selectively cause neurological sequels and widespread cerebrovascular alterations. Main findings about pericyte involvement in NMDs arise from glutaric acidemia type I (GA-I) models. In this regard, we found that (i) a single intracisternal injection of the main accumulated metabolite (glutaric acid, GA) in rat neonates disturbed the neurovascular unit (NVU) as evidenced by blood-brain barrier hyperpermeability, and altered immunoreactivity of pericyte and astrocyte markers surrounding brain microvessels; (ii) GA-elicited capillary constriction near pericyte somata likely inducing reduced brain blood flow as reported in GA-I patients; (iii) GA-elicited pericyte contraction probably results from a defective interplay among NVU components and could be relevant in case of metabolic decompensation or energetic deficiency. Although pericyte pathological features have been studied in few NMDs, their involvement in NMD pathophysiology is largely unknown. Thus, further studies are needed to identify their roles and therapeutic potentiality.

AMPK Preferentially Depresses Retrograde Transport of Axonal Mitochondria during Localized Nutrient Deprivation

Mitochondrial clusters are found at regions of high-energy demand, allowing cells to meet local metabolic requirements while maintaining neuronal homeostasis. AMP-activated protein kinase (AMPK), a key energy stress sensor, responds to increases in AMP/ATP ratio by activating multiple signaling cascades to overcome the energetic deficiency. In many neurologic conditions, the distal axon experiences energetic stress independent of the soma. Here, we used microfluidic devices to physically isolate these two neuronal structures and to investigate whether localized AMPK signaling influenced axonal mitochondrial transport. Nucleofection of primary cortical neurons, derived from E16-18 mouse embryos (both sexes), with mito-GFP allowed monitoring of the transport dynamics of mitochondria within the axon, by confocal microscopy. Pharmacological activation of AMPK at the distal axon (0.1 mm 5-aminoimidazole-4-carboxamide riboside) induced a depression of the mean frequency, velocity, and distance of retrograde mitochondrial transport in the adjacent axon. Anterograde mitochondrial transport was less sensitive to local AMPK stimulus, with the imbalance of bidirectional mitochondrial transport resulting in accumulation of mitochondria at the region of energetic stress signal. Mitochondria in the axon-rich white matter of the brain rely heavily on lactate as a substrate for ATP synthesis. Interestingly, localized inhibition of lactate uptake (10 nm AR-C155858) reduced mitochondrial transport in the adjacent axon in all parameters measured, similar to that observed by 5-aminoimidazole-4-carboxamide riboside treatment. Coaddition of compound C restored all parameters measured to baseline levels, confirming the involvement of AMPK. This study highlights a role of AMPK signaling in the depression of axonal mitochondrial mobility during localized energetic stress.SIGNIFICANCE STATEMENT As the main providers of cellular energy, the dynamic transport of mitochondria within the neuron allows for clustering at regions of high-energy demand. Here we investigate whether acute changes in energetic stress signal in the spatially isolated axon would alter mitochondrial transport in this local region. Both direct and indirect activation of AMP-activated protein kinase isolated to the distal axon induced a rapid, marked depression in local mitochondrial transport. This work highlights the ability of acute localized AMP-activated protein kinase signaling to affect mitochondrial mobility within the axon, with important implications for white matter injury, axonal growth, and axonal degeneration.

Energy balance but not competitive environment corresponds with allostatic load during development in an Old World monkey

Primates develop slowly relative to their body size, a pattern posited to result from ecological risk aversion. Little is known, however, about how energy balance contributes to allostatic load in juveniles. Using data collected over 8 consecutive months, we examined variation in energy balance (as measured by urinary C-peptide) and how energy balance, life history status, and social competition related to allostatic load (as measured by deviation from baseline fecal glucocorticoid metabolites, dfGCs) in 41 wild juvenile blue monkeys from 3 social groups. Juvenile energy balance was higher among females, older juveniles, when ripe fruit was more available, and when rainfall was lower. Energy balance, but not life history or competitive environments, predicted dfGC concentrations, such that juveniles generally had lower mean dfGCs when they had higher energy balance. An additional exploratory analysis of how dfGCs relate to social strategies revealed that subjects had lower dfGCs when they groomed less, and played more. Time spent grooming interacted with energy balance in predicting dfGC concentrations, so that individuals that groomed more actually had higher dfGCs when they had higher energy balance. Together these results reveal that energetic deficiencies are a true ecological risk factor in blue monkeys, and suggest that navigating the social environment via overt affiliative behavior is potentially both a stress-relieving and stress-inducing endeavor during development.

Urinary ketone body loss leads to degeneration of brain white matter in elderly SLC5A8-deficient mice

SLC5A8 is a sodium-coupled monocarboxylate and ketone transporter expressed in various epithelial cells. A putative role of SLC5A8 in neuroenergetics has been also hypothesized. To clarify this issue, we studied the cerebral phenotype of SLC5A8-deficient mice during aging. Elderly SLC5A8-deficient mice presented diffuse leukoencephalopathy characterized by intramyelinic oedema without demyelination suggesting chronic energetic crisis. Hypo-metabolism in the white matter of elderly SLC5A8-deficient mice was found using 99mTc-hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT (SPECT). Since the SLC5A8 protein could not be detected in the mouse brain, it was hypothesized that the leukoencephalopathy of aging SLC5A8-deficient mice was caused by the absence of slc5a8 expression in a peripheral organ, i.e. the kidney, where SLC5A8 is strongly expressed. A hyper-excretion of the ketone β-hydroxybutyrate (BHB) in the urine of SLC5A8-deficient mice was observed and showed that SLC5A8-deficient mice suffered a cerebral BHB insufficiency. Elderly SLC5A8-deficient mice also presented altered glucose metabolism. We propose that the continuous renal loss of BHB leads to a chronic energetic deficiency in the brain of elderly SLC5A8-deficient mice who are unable to counterbalance their glucose deficit. This study highlights the importance of alternative energetic substrates in neuroenergetics especially under conditions of restricted glucose availability.

Up to a Sign. The Insidious Effects of Energetically Inaccessible Conical Intersections on Unimolecular Reactions.

It is now well established that conical intersections play an essential role in nonadiabatic radiationless decay where their double-cone topography causes them to act as efficient funnels channeling wave packets from the upper to the lower adiabatic state. Until recently, little attention was paid to the effect of conical intersections on dynamics on the lower state, particularly when the total energy involved is significantly below that of the conical intersection seam. This energetic deficiency is routinely used as a sufficient condition to exclude consideration of excited states in ground state dynamics. In this account, we show that, this energy criterion notwithstanding, energy inaccessible conical intersections can and do exert significant influence on lower state dynamics. The origin of this influence is the geometric phase, a signature property of conical intersections, which is the fact that the real-valued electronic wave function changes sign when transported along a loop containing a conical intersection, making the wave function double-valued. This geometric phase is permitted by an often neglected property of the real-valued adiabatic electronic wave function; namely, it is determined only up to an overall sign. Noting that in order to change sign a normalized, continuous function must go through zero, for loops of ever decreasing radii, demonstrating the need for an electronic degeneracy (intersection) to accompany the geometric phase. Since the total wave function must be single-valued a compensating geometry dependent phase needs to be included in the total electronic-nuclear wave function. This Account focuses on how this consequence of the geometric phase can modify nuclear dynamics energetically restricted to the lower state, including tunneling dynamics, in directly measurable ways, including significantly altering tunneling lifetimes, thus confounding the relation between measured lifetimes and barrier heights and widths, and/or completely changing product rotational distributions. Some progress has been made in understanding the origin of this effect. It has emerged that for a system where the lower adiabatic potential energy surface exhibits a topography comprised of two saddle points separated by a high energy conical intersection, the effect of the geometric phase can be quite significant. In this case topologically distinct paths through the two adiabatic saddle points may lead to interference. This was pointed out by Mead and Truhlar almost 50 years ago and denoted the Molecular Aharonov-Bohm effect. Still, the difficulty in anticipating a significant geometric phase effect in tunneling dynamics due to energetically inaccessible conical intersections leads to the attribute insidious that appears in the title of this Account. Since any theory is only as relevant as the prevalence of the systems it describes, we include in this Account examples of real systems where these effects can be observed. The accuracy of the reviewed calculations is high since we use fully quantum mechanical dynamics and construct the geometric phase using an accurate diabatic state fit of high quality ab initio data, energies, energy gradients, and interstate couplings. It remains for future work to establish the prevalence of this phenomenon and its deleterious effects on the conventional wisdom discussed in this work.

RETRACTED: Energy balance but not competitive environment corresponds with allostatic load during development in an Old World monkey

Primates develop slowly relative to their body size, a pattern posited to result from ecological risk aversion. Little is known, however, about how energy balance contributes to allostatic load in juveniles. Using data collected over 8 consecutive months, we examined variation in energy balance (as measured by urinary C-peptide) and how energy balance, life history status, and social competition related to allostatic load (as measured by deviation from baseline fecal glucocorticoid metabolites, dfGCs) in 41 wild juvenile blue monkeys from 3 social groups. Juvenile energy balance was higher among females, when ripe fruit was more available, and when rainfall was lower. Energy balance, but not life history or competitive environments, predicted dfGC concentrations, such that juveniles generally had lower mean dfGCs when they had higher energy balance. An additional exploratory analysis of how dfGCs relate to social strategies revealed that subjects had lower dfGCs when they groomed less, and played more. Time spent grooming interacted with energy balance in predicting dfGC concentrations, so that individuals that groomed more actually had higher dfGCs when they had higher energy balance. Together these results reveal that energetic deficiencies are a true ecological risk factor in blue monkeys, and suggest that navigating the social environment via overt affiliative behavior is potentially both a stress-relieving and stress-inducing endeavor during development.

Lipid­carbohydrate metabolism and nutrition in the indigenous and non­indigenous population of the north-east of Russia.

Scientific-research center «Arktika» far-eastern branch of the Russian academy of sciences, 685000, Magadan, Russia Young male residents ofMagadan region and Chukotsky Autonomous District aged 17-21, all are representatives of Russia’s northeast ethnic peoples were examined in comparison with Caucasoid subjects born in the north in the p>-2 generation to study the blood lipid and glucose values as well as the dietary structure. In order to ascertain the subjects ’ lipid and carbohydrate basic values, the CardioChek PA biochemical express-analyzer (USA) was used during the study of the capillary blood samples taken from the examinees on empty stomach, 10-12 hours after the last meal. Besides, the program set of “ASPON-nutrition” was used to analyze the subjects ’ daily diets for assessing their dietary structures and nutrition facts. All the examined subjects demonstrated the similar changes in lipid-carbohydrate profile resulted in low fat metabolism and high glucose close to the upper limit of physiological norm. Reliable ethnic and region-related peculiarities in the studied metabolic parameters were found. Of note, that Aboriginal subjects were the highest in the blood glucose. They showed higher values ofLPHD and lower values ofLPLD compared to those of Caucasoid subjects. Significant nutrition irrationalities such as imbalance in macronutrients and energetic deficiency were found. The observed diets contain excess carbohydrates and insufficient protein and fat saturation at lowered daily energetic value for the given age cohort.

MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review.

Heart failure is a major cause of morbidity and mortality in type 2 diabetes. Type 2 diabetes contributes to the development of heart failure through a variety of mechanisms, including disease-specific myocardial structural, functional and metabolic changes. This review will focus on the contemporary contributions of state of the art non-invasive technologies to our understanding of diabetic cardiomyopathy, including data on cardiac disease phenotype, cardiac energy metabolism and energetic deficiency, ectopic and visceral adiposity, diabetic liver disease, metabolic modulation strategies and cardiovascular outcomes with new classes of glucose-lowering therapies.

Decreased ATP production and myocardial contractile reserve in metabolic heart disease

Metabolic syndrome is a cluster of obesity-related metabolic abnormalities that lead to metabolic heart disease (MHD) with left ventricular pump dysfunction. Although MHD is thought to be associated with myocardial energetic deficiency, two key questions have not been answered. First, it is not known whether there is a sufficient energy deficit to contribute to pump dysfunction. Second, the basis for the energy deficit is not clear. To address these questions, mice were fed a high fat, high sucrose (HFHS) ‘Western’ diet to recapitulate the MHD phenotype. In isolated beating hearts, we used 31P NMR spectroscopy with magnetization transfer to determine a) the concentrations of high energy phosphates ([ATP], [ADP], [PCr]), b) the free energy of ATP hydrolysis (∆G~ATP), c) the rate of ATP production and d) flux through the creatine kinase (CK) reaction. At the lowest workload, the diastolic pressure-volume relationship was shifted upward in HFHS hearts, indicative of diastolic dysfunction, whereas systolic function was preserved. At this workload, the rate of ATP synthesis was decreased in HFHS hearts, and was associated with decreases in both [PCr] and ∆G~ATP. Higher work demands unmasked the inability of HFHS hearts to increase systolic function and led to a further decrease in ∆G~ATP to a level that is not sufficient to maintain normal function of sarcoplasmic Ca2+-ATPase (SERCA). While [ATP] was preserved at all work demands in HFHS hearts, the progressive increase in [ADP] led to a decrease in ∆G~ATP with increased work demands. Surprisingly, CK flux, CK activity and total creatine were normal in HFHS hearts. These findings differ from dilated cardiomyopathy, in which the energetic deficiency is associated with decreases in CK flux, CK activity and total creatine. Thus, in HFHS-fed mice with MHD there is a distinct metabolic phenotype of the heart characterized by a decrease in ATP production that leads to a functionally-important energetic deficiency and an elevation of [ADP], with preservation of CK flux.