High-energy Phosphate Metabolism Research Articles

Abstract 16878: Exercise Intolerance in Heart Failure With Preserved Ejection Fraction is More Closely Related to Energetic Decline During Exercise Than to Mitochondrial Oxidative Capacity in Recovery

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with severe exercise intolerance (EI) and exertional fatigue. Impaired skeletal muscle high-energy phosphate metabolism has been reported in HFpEF patients and postulated as a potential contributor to EI. However, whether EI is more closely related to rapid energetic decline during exercise, or reduced mitochondrial oxidative capacity remains unknown. Hypothesis: We hypothesized that six-minute walk distance (6MWD) is more closely related to the rate of skeletal muscle energetic decline during exercise than mitochondrial oxidative capacity in HFpEF. Methods: Calf muscle energetics were measured by phosphorus magnetic resonance spectroscopy ( 31 PMRS). The rate of phosphocreatine (PCr) decline normalized to work performed during graded plantar flexion exercise to volitional fatigue and the time for PCr post-exercise recovery, an established metric inversely related to mitochondrial oxidative capacity, were measured in 64 HFpEF patients (age: 65 ± 11 years; 53% women). Results: The mean rate of PCr decline, PCr recovery time, and 6MWD were 52 ± 108 μmol/g wet weight/KJ, 80 ± 45 seconds, and 296 ± 109 meters, respectively. The 6MWD was inversely related to the rate of PCr decline (r = -0.46; P = 0.0002; Figure, A ) but not significantly related to the PCr recovery time (r = -0.06; P = 0.66; Figure, B ), as determined by Pearson’s correlation coefficients. Conclusions: EI, as measured by 6MWD, in HFpEF patients is closely associated with impaired skeletal muscle metabolism, specifically rapid skeletal muscle PCr decline during exercise rather than mitochondrial oxidative capacity. This suggests that impaired glycolytic metabolism and substrate delivery may contribute metabolically to EI in HFpEF patients.

Abstract 13305: Energetic Basis of Recovered Ejection Fraction in Human Heart Failure

Introduction: Left ventricular ejection fraction (LVEF) improvement in HFrEF patients is classified as heart failure with improved ejection fraction (HFimpEF) and is associated with better long-term outcomes than persistent HFrEF. HFimpEF is difficult to predict and underlying mechanisms remain poorly understood. Hypothesis: Better myocardial high-energy phosphate metabolism at baseline predicts future LVEF recovery and outcomes in a general HFrEF population Methods: We measured cardiac energetics, the ratio of the two main high-energy phosphates, phosphocreatine and ATP (PCr/ATP), and the rate of ATP synthesis through the primary cardiac energy reserve reaction creatine kinase (“CK flux”), in 37 nonischemic HFrEF patients (LVEF ≤40%) with 31 P cardiac magnetic resonance spectroscopy (MRS) at 3T. Baseline transthoracic echocardiogram (TTE) was obtained prior to 31 P MRS and follow-up consecutive TTEs with the two highest LVEFs meeting HFimpEF criteria (LVEF >40% and ≥10% increase over baseline LVEF) over a median follow-up of 6.9 years were averaged and used to classify HFimpEF. Results: There were no significant differences in demographics, HF etiology, baseline TTE metrics, or medications between persistent HFrEF (n=22) and eventual HFimpEF (n=15). Cardiac CK flux was significantly higher at baseline in patients who later recovered to HFimpEF than in those who remained HFrEF (p=0.031). Better baseline cardiac CK flux was associated with increases in LVEF (p=0.025) and decreases in LV end-diastolic diameter (p=0.016) over time. By both dichotomous and continuous metrics, better preserved CK flux was associated with future HFimpEF. Fourteen subjects (38%), all persistent HFrEF, experienced cardiac death, transplant, or LVAD and had significantly lower baseline CK flux than outcome-free patients (p=0.017). Cardiac PCr/ATP was not associated with eventual HFimpEF, outcomes, or changes in TTE indices. Conclusion: Better preserved cardiac CK flux is associated with future LVEF recovery and LV reverse remodeling while lower CK flux is associated with worse cardiac outcomes in HFrEF patients. Interventions restoring CK flux, and possibly other energy-generating metabolic reactions, may elicit myocardial recovery in HFrEF patients.

Magnetic Resonance Spectroscopy Studies of Brain Energy Metabolism in Schizophrenia: Progression from Prodrome to Chronic Psychosis.

Schizophrenia (SZ) is a debilitating mental illness; existing treatments are partially effective and associated with significant side effect burden, largely due to our limited understanding of disease mechanisms and the trajectory of disease progression. Accumulating evidence suggests that metabolic changes associated with glucose metabolism, mitochondrial dysfunction, and redox imbalance play an important role in the pathophysiology of schizophrenia. However, the molecular mechanisms associated with these abnormalities in the brains of schizophrenia patients and the ways in which they change over time remain unclear. This paper aims to review the current literature on molecular mechanisms and in vivo magnetic resonance spectroscopy (MRS) studies of impaired energy metabolism in patients at clinical high risk for psychosis, with first-episode SZ, and with chronic SZ. Our review covers research related to high-energy phosphate metabolism, lactate, intracellular pH, redox ratio, and the antioxidant glutathione. Both first-episode and chronic SZ patients display a significant reduction in creatine kinase reaction activity and redox (NAD + /NADH) ratio in the prefrontal cortex. Chronic, but not first-episode, SZ patients also show a trend toward increased lactate levels and decreased pH value. These findings suggest a progressive shift from oxidative phosphorylation to glycolysis for energy production over the course of SZ, which is associated with redox imbalance and mitochondrial dysfunction. Accumulating evidence indicates that aberrant brain energy metabolism associated with mitochondrial dysfunction and redox imbalance plays a critical role in SZ and will be a promising target for future treatments.

Circulating metabolic signatures of heart failure in precision cardiology.

Precision cardiology aims to implement personalized health care and precise medical decisions based on the specific characteristics of individuals. Metabolic remodeling plays a causal role in the pathogenesis of heart failure (HF). Changes in metabolic pathways such as substrate preference, high-energy phosphate metabolism and amino acid metabolism, are involved in pathological structural remodeling and functional impairment. These metabolic alterations are usually not restricted in the cardiac tissue, but also manifest in circulation. In clinical practice, blood sample is routinely used for HF screening. Metabolomics is an emerging omics technology that provides an efficient way to acquire dynamic metabolic profiles in circulation. An increasing number of metabolic biomarkers have been implicated in disease progression, making it possible to fight HF in a more effective and precise way. This review summarizes the modern analytical techniques in metabolomics as well as emerging circulating metabolites during the pathogenesis of HF, aiming to provide new insights into the prevention, diagnosis and treatment of HF in the era of precision medicine.

Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy.

Pelizaeus–Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus–Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus–Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P < 0.0001 and P = 0.0002) and phosphocreatine levels were significantly higher (P < 0.0001) in Pelizaeus–Merzbacher disease patients compared with controls. Additionally, there was a significant group-by-brain area interaction for phosphocreatine with post-hoc analyses demonstrating significantly higher phosphocreatine levels in patients with Pelizaeus–Merzbacher disease compared with controls across multiple brain areas (anterior and posterior white matter, superior parietal lobe, posterior cingulate cortex, hippocampus, occipital cortex, striatum and thalamus; all P ≤ 0.0042). Phosphoethanolamine, glycerophosphoethanolamine and adenosine triphosphate levels were not significantly different between groups. For the first-time, widespread alterations in phosphorus magnetic resonance spectroscopy metabolite levels of Pelizaeus–Merzbacher disease patients are being reported. Specifically, increased high-energy phosphate storage levels of phosphocreatine concomitant with decreased inorganic orthophosphate across multiple areas suggest a widespread reduction in the high-energy phosphate utilization in Pelizaeus–Merzbacher disease, and the membrane phospholipid metabolite deficits suggest a widespread degradation in the neuropil content/maintenance of patients with Pelizaeus–Merzbacher disease which includes axons, dendrites and astrocytes within cortex and the myelin microstructure and oligodendrocytes within white matter. These results provide greater insight into the neuropathology of Pelizaeus–Merzbacher disease both in terms of energy expenditure and membrane phospholipid metabolites. Future longitudinal studies are warranted to investigate the utility of phosphorus magnetic resonance spectroscopy as surrogate biomarkers in monitoring treatment intervention for Pelizaeus–Merzbacher disease.

Magnetic field therapy enhances muscle mitochondrial bioenergetics and attenuates systemic ceramide levels following ACL reconstruction: Southeast Asian randomized-controlled pilot trial.

BackgroundMetabolic disruption commonly follows Anterior Cruciate Ligament Reconstruction (ACLR) surgery. Brief exposure to low amplitude and frequency pulsed electromagnetic fields (PEMFs) has been shown to promote in vitro and in vivo murine myogeneses via the activation of a calcium–mitochondrial axis conferring systemic metabolic adaptations. This randomized-controlled pilot trial sought to detect local changes in muscle structure and function using MRI, and systemic changes in metabolism using plasma biomarker analyses resulting from ACLR, with or without accompanying PEMF therapy.Methods20 patients requiring ACLR were randomized into two groups either undergoing PEMF or sham exposure for 16 weeks following surgery. The operated thighs of 10 patients were exposed weekly to PEMFs (1 ​mT for 10 ​min) for 4 months following surgery. Another 10 patients were subjected to sham exposure and served as controls to allow assessment of the metabolic repercussions of ACLR and PEMF therapy. Blood samples were collected prior to surgery and at 16 weeks for plasma analyses. Magnetic resonance data were acquired at 1 and 16 weeks post-surgery using a Siemens 3T Tim Trio system. Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS) was utilized to monitor changes in high-energy phosphate metabolism (inorganic phosphate (Pi), adenosine triphosphate (ATP) and phosphocreatine (PCr)) as well as markers of membrane synthesis and breakdown (phosphomonoesters (PME) and phosphodiester (PDE)). Quantitative Magnetization Transfer (qMT) imaging was used to elucidate changes in the underlying tissue structure, with T1-weighted and 2-point Dixon imaging used to calculate muscle volumes and muscle fat content.ResultsImprovements in markers of high-energy phosphate metabolism including reductions in ΔPi/ATP, Pi/PCr and (Pi ​+ ​PCr)/ATP, and membrane kinetics, including reductions in PDE/ATP were detected in the PEMF-treated cohort relative to the control cohort at study termination. These were associated with reductions in the plasma levels of certain ceramides and lysophosphatidylcholine species. The plasma levels of biomarkers predictive of muscle regeneration and degeneration, including osteopontin and TNNT1, respectively, were improved, whilst changes in follistatin failed to achieve statistical significance. Liquid chromatography with tandem mass spectrometry revealed reductions in small molecule biomarkers of metabolic disruption, including cysteine, homocysteine, and methionine in the PEMF-treated cohort relative to the control cohort at study termination. Differences in measurements of force, muscle and fat volumes did not achieve statistical significance between the cohorts after 16 weeks post-ACLR.ConclusionThe detected changes suggest improvements in systemic metabolism in the post-surgical PEMF-treated cohort that accords with previous preclinical murine studies. PEMF-based therapies may potentially serve as a manner to ameliorate post-surgery metabolic disruptions and warrant future examination in more adequately powered clinical trials.The Translational Potential of this ArticleSome degree of physical immobilisation must inevitably follow orthopaedic surgical intervention. The clinical paradox of such a scenario is that the regenerative potential of the muscle mitochondrial pool is silenced. The unmet need was hence a manner to maintain mitochondrial activation when movement is restricted and without producing potentially damaging mechanical stress. PEMF-based therapies may satisfy the requirement of non-invasively activating the requisite mitochondrial respiration when mobility is restricted for improved metabolic and regenerative recovery.

Guanidinoacetic Acid as a Nutritional Adjuvant to Multiple Sclerosis Therapy.

Tackling impaired bioenergetics in multiple sclerosis (MS) has been recently recognized as an innovative approach with therapeutic potential. Guanidinoacetic acid (GAA) is an experimental nutrient that plays a significant role in high-energy phosphate metabolism. The preliminary trials suggest beneficial effects of supplemental GAA in MS, with GAA augments biomarkers of brain energy metabolism and improves patient-reported features of the disease. GAA can also impact other metabolic footprints of MS, including demyelination, oxidative stress, and GABA-glutamate imbalance. In this mini-review article, we summarize studies evaluating GAA effectiveness in MS, explore mechanisms of GAA action, and discuss the challenges of using dietary GAA as an element of MS therapy.

Anti-Inflammatory and Anti-Catabolic Effects of Creatine Supplementation: A Brief Review.

It is well established that creatine supplementation, primarily when combined with resistance training, significantly increases measures of muscle mass and performance (primarily strength). Emerging research also indicates that creatine supplementation may have favorable effects on measures of bone biology. These anabolic adaptations may be related to creatine influencing cellular hydration status, high-energy phosphate metabolism, growth factors, muscle protein kinetics, and the bone remodeling process. Accumulating research also suggests that creatine supplementation has anti-inflammatory and anti-catabolic properties, which may help create a favorable environment for muscle and bone accretion and recovery from exercise. Creatine supplementation has the ability to decrease markers of inflammation and possibly attenuate cancerous tumor growth progression. From a musculoskeletal perspective, there is some evidence to show that creatine supplementation reduces measures of muscle protein catabolism (primarily in males) and bone resorption when combined with resistance training. The purpose of this brief review is to summarize the current body of literature examining the potential anti-inflammatory and anti-catabolic effects of creatine supplementation across various research populations.

Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation

Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case–control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor. Thirteen iron-deficient (ID) individuals and thirteen iron-replete (IR) control participants each underwent 31P-magnetic resonance spectroscopy of exercising calf muscle to investigate differences in oxidative phosphorylation, followed by whole-body cardiopulmonary exercise testing. Thereafter, individuals were given an intravenous (IV) infusion, randomised to either iron or saline, and the assessments repeated ~ 1 week later. Neither baseline iron status nor IV iron significantly influenced high-energy phosphate metabolism. During submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was diminished in the ID group (P = 0.005). Intravenous iron corrected this abnormality. Furthermore, IV iron increased lactate threshold during maximal cardiopulmonary exercise by ~ 10%, regardless of baseline iron status. These findings demonstrate abnormal whole-body energy metabolism in iron-deficient but otherwise healthy humans. Iron deficiency promotes a more glycolytic phenotype without having a detectable effect on mitochondrial bioenergetics.

Abstract 10080: Myocardial Physiological Responses to the Third Trimester of Healthy Pregnancy

Background: Pregnancy requires significant cardiometabolic adaptation and is therefore considered a “stress test” for future cardiovascular disease. Cardiovascular magnetic resonance (CMR) allows evaluation of cardiac structure, function and tissue characteristics with excellent reproducibility. There is scarcity of CMR data on pregnancy-associated cardiovascular adaptive changes. Moreover, no studies to date assessed the physiological impact of pregnancy on cardiac high energy phosphate metabolism, measured as the phosphocreatine (PCr)/ATP ratio, using 31 Phosphorus magnetic resonance spectroscopy ( 31 P-MRS). Objectives: We aimed to investigate the physiological effects of pregnancy in women in the third trimester of a healthy singleton pregnancy on cardiac energetics, function and tissue characteristics using 31 P-MRS and CMR at 3T. Methods: Thirty pregnant women and fifteen age-matching nulliparous healthy female controls were recruited. Results: Clinical characteristics and CMR/ 31 P-MRS results are provided in Table1.Resting heart rates and cardiac output were higher in pregnancy, with no significant differences in left-ventricular volumes, mass or ejection fraction, diastolic function (mitral in-flow E/A), global longitudinal strain or MAPSE. There were subtle reductions in cardiac PCr/ATP in pregnancy. Compared to non-pregnant controls, myocardial T1 was 2% higher in pregnant women, whilst T2 was 5% lower. Conclusions: Healthy pregnancy was associated with no significant changes in cardiac size, mass or function. Consistent with the haemodynamic changes in pregnancy, subtle reductions in cardiac energetics were detected, though these remained within normal range.CMR is well tolerated in pregnancy and may play a role in assessing cardiac involvement in women at risk of perinatal complications, offering the opportunity of early initiation of risk modifying treatment and prevention of adverse maternal cardiovascular outcomes.

Myocardial glucose and fatty acid metabolism is altered and associated with lower cardiac function in young adults with Barth syndrome

BackgroundBarth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function. Methods/ResultsYoung adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15O-water and 1-11C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 μmol·g−1·min−1, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g−1·min−1, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS. ConclusionsMyocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS.Clinical Trials #: NCT01625663.

Association between cardiac high-energy phosphate metabolism and whole body metabolism in healthy female adults.

Decline in cardiac high-energy phosphate metabolism [phosphocreatine-to-ATP (PCr/ATP) ratio] and whole body metabolism increase the risk of heart failure and metabolic diseases. The aim of the present study was to assess the relationship between PCr/ATP ratio and measures of body metabolic function. A total of 35 healthy women (56+/-14.0 years of age) underwent cardiac 31P magnetic resonance spectroscopy to assess PCr/ATP ratio - an index of cardiac high-energy phosphate metabolism. Fasting and 2-hour glucose levels were assessed using oral glucose tolerance test. Indirect calorimetry was performed to determine oxygen consumption and resting metabolic rate. There were no significant relationships between PCr/ATP ratio and resting metabolic rate (r=-0.09, p=0.62), oxygen consumption (r=-0.11, p=0.54), fasting glucose levels (r=-0.31, p=0.07), and 2-hour plasma glucose (r=-0.10, p=0.58). Adjusted analysis for covariates including age, body mass index, fat mass, and physical activity, had no significant influence on the relationship between PCr/ATP ratio and body metabolism. In conclusion, the lack of relationship between cardiac PCr/ATP ratio, glucose control and metabolic rate may suggest that overall metabolic function does not influence cardiac high-energy phosphate metabolism.

Altered phospholipid and high-energy phosphate metabolism in the basal ganglia and thalamus of severe obsessive compulsive patients with treatment resistance: A phosphorus 31 nuclear magnetic resonance spectroscopy study.

Cerebral metabolism in obsessive-compulsive-disorder(OCD) has been the subject of numerous studies using proton magnetic resonance spectroscopy(MRS). Despite heterogeneous results, some studies have unraveled membrane turnover and energy metabolism abnormalities in different brain regions, suggesting that alterations in these processes may contribute to the pathophysiology. So far, no authors have explored phospholipids and high-energy phosphate metabolism using 31P-MRS, which allows in vivo quantification of phosphorus metabolites that are considered to be related to membrane turnover and energy metabolism. The aim of our study was to describe and compare brain metabolic changes using 31P-MRS in the striatum and the thalamus, between 23 severe OCD patients and 22 healthy controls. All subject underwent a clinical examination and a same 31P-MRS protocol. Significantly, increased concentrations of PC, PDE,PME,GPC,PME/PCr,PDE/PCr were found in patients compared to controls in the striatum and the thalamus. PCr and tATP were decreased in the striatum. Finally, significant correlations were found in the striatum and the thalamus between illness duration and some specific measured parameters. Our results showed significant modifications of the membrane and energy metabolism in the basal ganglia of severe OCD patients and suggests a link between energetic buffer and serotonin metabolism disorder.

Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty.

BACKGROUNDPhysical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown.METHODSHere, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 ± 2.7 years, mean ± SEM), nonfrail older (NFO) individuals (79 ± 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 ± 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO2).RESULTSDuring graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by 31P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing (P < 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.CONCLUSIONSeveral-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.FUNDINGThis work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins.

Non-invasive investigation of myocardial energetics in cardiac disease using 31P magnetic resonance spectroscopy.

Cardiac metabolism and function are intrinsically linked. High-energy phosphates occupy a central and obligate position in cardiac metabolism, coupling oxygen and substrate fuel delivery to the myocardium with external work. This insight underlies the widespread clinical use of ischaemia testing. However, other deficits in high-energy phosphate metabolism (not secondary to supply-demand mismatch of oxygen and substrate fuels) may also be documented, and are of particular interest when found in the context of structural heart disease. This review introduces the scope of deficits in high-energy phosphate metabolism that may be observed in the myocardium, how to assess for them, and how they might be interpreted.

Dynamic magnetic resonance measurements of calf muscle oxygenation and energy metabolism in peripheral artery disease.

BackgroundClinical assessments of peripheral artery disease (PAD) severity are insensitive to pathophysiological changes in muscle tissue oxygenation and energy metabolism distal to the affected artery.PurposeTo quantify the blood oxygenation level‐dependent (BOLD) response and phosphocreatine (PCr) recovery kinetics on a clinical MR system during a single exercise‐recovery session in PAD patients.Study TypeCase–control study.SubjectsFifteen Fontaine stage II patients, and 18 healthy control subjectsField Strength/SequenceInterleaved dynamic multiecho gradient‐echo 1H T2* mapping and adiabatic pulse‐acquire 31P‐MR spectroscopy at 3T.AssessmentBlood pressure in the arms and ankles were measured to determine the ankle‐brachial index (ABI). Subjects performed a plantar flexion exercise‐recovery protocol. The gastrocnemius and soleus muscle BOLD responses were characterized using the T2* maps. High‐energy phosphate metabolite concentrations were quantified by fitting the series of 31P‐MR spectra. The PCr recovery time constant (τPCr) was derived as a measure of in vivo mitochondrial oxidative capacity.Statistical TestsComparisons between groups were performed using two‐sided Mann–Whitney U‐tests. Relations between variables were assessed by Pearson's r correlation coefficients.ResultsThe amplitude of the functional hyperemic BOLD response in the gastrocnemius muscle was higher in PAD patients compared with healthy subjects (–3.8 ± 1.4% vs. –1.4 ± 0.3%; P < 0.001), and correlated with the ABI (r = 0.79; P < 0.001). PCr recovery was slower in PAD patients (τPCr = 52.0 ± 13.5 vs. 30.3 ± 9.7 sec; P < 0.0001), and correlated with the ABI (r = –0.64; P < 0.001). Moreover, τPCr correlated with the hyperemic BOLD response in the gastrocnemius muscle (r = –0.66; P < 0.01).Data ConclusionMR readouts of calf muscle tissue oxygenation and high‐energy phosphate metabolism were acquired essentially simultaneously during a single exercise‐recovery session. A pronounced hypoxia‐triggered vasodilation in PAD is associated with a reduced mitochondrial oxidative capacity. Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:98–107.

Creatine and pregnancy outcomes, a prospective cohort study in low-risk pregnant women: study protocol

IntroductionThe creatine kinase circuit is central to the regulation of high-energy phosphate metabolism and the maintenance of cellular energy turnover. This circuit is fuelled by creatine, an amino acid derivative...

The effect of succinate on brain NADH/NAD+ redox state and high energy phosphate metabolism in acute traumatic brain injury

A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (−13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = −0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.

Metabolic remodeling of substrate utilization during heart failure progression.

Heart failure (HF) is a clinical syndrome caused by a decline in cardiac systolic or diastolic function, which leaves the heart unable to pump enough blood to meet the normal physiological requirements of the human body. It is a serious disease burden worldwide affecting nearly 23 million patients. The concept that heart failure is "an engine out of fuel" has been generally accepted and metabolic remodeling has been recognized as an important aspect of this condition; it is characterized by defects in energy production and changes in metabolic pathways involved in the regulation of essential cellular functions such as the process of substrate utilization, the tricarboxylic acid cycle, oxidative phosphorylation, and high-energy phosphate metabolism. Advances in second-generation sequencing, proteomics, and metabolomics have made it possible to perform comprehensive tests on genes and metabolites that are crucial in the process of HF, thereby providing a clearer and comprehensive understanding of metabolic remodeling during HF. In recent years, new metabolic changes such as ketone bodies and branched-chain amino acids were demonstrated as alternative substrates in end-stage HF. This systematic review focuses on changes in metabolic substrate utilization during the progression of HF and the underlying regulatory mechanisms. Accordingly, the conventional concepts of metabolic remodeling characteristics are reviewed, and the latest developments, particularly multi-omics studies, are compiled.

Altered brain high-energy phosphate metabolism in mild Alzheimer's disease: A 3-dimensional 31P MR spectroscopic imaging study.

In Alzheimer's disease (AD), defects in essential metabolic processes for energy supply and phospholipid membrane function have been implicated in the pathological process. However, post-mortem investigations are generally limited to late stage disease and prone to tissue decay artifacts. In vivo assessments of high energy phosphates, tissue pH and phospholipid metabolites are possible by phosphorus MR spectroscopy (31P–MRS), but so far only small studies, mostly focusing on single brain regions, have been performed. Therefore, we assessed phospholipid and energy metabolism in multiple brain regions of 31 early stage AD patients and 31 age- and gender-matched controls using 31P–MRS imaging. An increase of phosphocreatine (PCr) was found in AD patients compared with controls in the retrosplenial cortex, and both hippocampi, but not in the anterior cingulate cortex. While PCr/inorganic phosphate and pH were also increased in AD, no changes were found for phospholipid metabolites. This study showed that PCr levels are specifically increased in regions that show early degeneration in AD. Together with an increased pH, this indicates an altered energy metabolism in mild AD.