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1.
Molecular correlates of MRS-based 31 phosphocreatine muscle resynthesis rate in healthy adults.
Darpolor, MM, Singh, M, Covington, J, Hanet, S, Ravussin, E, Carmichael, OT
NMR in biomedicine. 2021;(1):e4402
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Abstract
Dynamic phosphorus MRS (31 P-MRS) is a method used for in vivo studies of skeletal muscle energetics including measurements of phosphocreatine (PCr) resynthesis rate during recovery of submaximal exercise. However, the molecular events associated with the PCr resynthesis rate are still under debate. We assessed vastus lateralis PCr resynthesis rate from 31 P-MRS spectra collected from healthy adults as part of the CALERIE II study (caloric restriction), and assessed associations between PCr resynthesis and muscle mitochondrial signature transcripts and proteins (NAMPT, NQO1, PGC-1α, and SIRT1). Regression analysis indicated that higher concentration of nicotinamide phosphoribosyltransferase (NAMPT) protein, a mitochondrial capacity marker, was associated with faster PCr resynthesis. However, PCr resynthesis was not associated with greater physical fitness (VO2 peak) or messenger ribonucleic acid levels of mitochondrial function markers such as NQO1, PGC-1α, and SIRT1, suggesting that the impact of these molecular signatures on PCr resynthesis may be minimal in the context of an acute exercise bout. Together, these findings suggest that 31 P-MRS based PCr resynthesis may represent a valid non-invasive surrogate marker of mitochondrial NAMPT in human skeletal muscle.
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Targeting phosphocreatine metabolism in relapsing-remitting multiple sclerosis: evaluation with brain MRI, 1H and 31P MRS, and clinical and cognitive testing.
Cambron, M, Reynders, T, Debruyne, J, Reyngoudt, H, Ribbens, A, Achten, E, Laureys, G
Journal of neurology. 2018;(11):2614-2624
Abstract
BACKGROUND/OBJECTIVES Fluoxetine and prucalopride might change phosphocreatine (PCr) levels via the cAMP-PKA pathway, an interesting target in the neurodegenerative mechanisms of MS. METHODS We conducted a two-center double-blind, placebo-controlled, randomized trial including 48 relapsing-remitting MS patients. Patients were randomized to receive placebo (n = 13), fluoxetine (n = 15), or prucalopride (n = 14) for 6 weeks. Proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) as well as volumetric and perfusion MR imaging were performed at weeks 0, 2, and 6. Clinical and cognitive testing were evaluated at weeks 0 and 6. RESULTS No significant changes were observed for both 31P and 1H MRS indices. We found a significant effect on white matter volume and a trend towards an increase in grey matter and whole brain volume in the fluoxetine group at week 2; however, these effects were not sustained at week 6 for white matter and whole brain volume. Fluoxetine and prucalopride showed a positive effect on 9-HPT, depression, and fatigue scores. CONCLUSION Both fluoxetine and prucalopride had a symptomatic effect on upper limb function, fatigue, and depression, but this should be interpreted with caution. No effect of treatment was found on 31P and 1H MRS parameters, suggesting that these molecules do not influence the PCr metabolism.
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Phosphocreatine in Cardiac Surgery Patients: A Meta-Analysis of Randomized Controlled Trials.
Mingxing, F, Landoni, G, Zangrillo, A, Monaco, F, Lomivorotov, VV, Hui, C, Novikov, M, Nepomniashchikh, V, Fominskiy, E
Journal of cardiothoracic and vascular anesthesia. 2018;(2):762-770
Abstract
OBJECTIVE There is experimental evidence that phosphocreatine (PCr) can decrease ischemia/reperfusion injury of the heart. The authors investigated if PCr would improve heart performance as compared with standard treatment in cardiac surgery. DESIGN Meta-analysis of randomized controlled trials. SETTING Hospitals. PARTICIPANTS Adult and pediatric patients undergoing cardiac surgery. INTERVENTIONS The ability of PCr to improve cardiac outcomes as compared with standard treatment was investigated. MEASUREMENTS AND MAIN RESULTS PubMed/Medline, Embase, Scopus, Cochrane Library, China National Knowledge Infrastructure, WANGFANG DATA, and VIP Paper Check System were searched to March 1 2017. The authors included 26 randomized controlled trials comprising 1,948 patients. Random and fixed-effects models were used to estimate odds ratio (OR) and mean difference (MD) with 95% confidence interval (CI). PCr use was associated with reduced rates of intraoperative inotropic support (27% v 44%; OR 0.47, 95% CI 0.35-0.61; p < 0.001), major arrhythmias (16% v 28%; OR 0.44, 95% CI 0.27-0.69; p < 0.001), as well as increased spontaneous recovery of the cardiac rhythm immediately after aortic declamping (50% v 34%; OR 2.45, 95% CI 1.82-3.30; p < 0.001) as compared with standard treatment. The use of PCr decreased myocardial damage and augmented left ventricular ejection fraction in the postoperative period; however, MD for these outcomes were small and do not seem to be clinically significant. CONCLUSIONS In randomized trials, PCr administration was associated with reduced rates of intraoperative inotropic support and major arrhythmias, and increased spontaneous recovery of the cardiac rhythm after aortic declamping. Large multicenter evidence is needed to validate these findings.
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Creatine Phosphate Administration in Cell Energy Impairment Conditions: A Summary of Past and Present Research.
Gaddi, AV, Galuppo, P, Yang, J
Heart, lung & circulation. 2017;(10):1026-1035
Abstract
BACKGROUND Creatine phosphate (CrP) plays a fundamental physiological role by providing chemical energy for cell viability and activity, especially in muscle tissue. Numerous pathological conditions, caused by acute or chronic ischaemic situations, are related to its deficiency. For these reasons, it has been used as a cardioprotective agent in heart surgery and medical cardiology for many years. OBJECTIVE This article gives a brief overview of the main characteristics of exogenous CrP. METHODS Previous review articles on CrP were screened for relevant information and references. Results from selected studies were reviewed and classified according to the topics in this review article and provided further interesting information on the pharmacological role of this molecule. RESULTS Besides CrP's well known cell energy and function restoring properties, new evidence is emerging regarding its antioxidant and anti-apoptotic properties. Use of CrP is well established clinically as an intraoperative and perioperative adjuvant in heart operations (valve replacement, coronary artery bypass grafting, congenital heart defect repair), and as an additional agent in medical cardiology therapy for acute myocardial infarction and acute and chronic heart failure. In particular, there are promising potential new CrP uses in neurology, such as in cerebral ischaemia and hypoxic ischaemic encephalopathy. CONCLUSIONS This review article describes the role of CrP treatment in cardiological indications, such as cardioprotection in cardioplegia and in myocardiopathies of various etiopathogenesis, as well as in other clinical indications such as skeletal muscle rehabilitation and neurological conditions.
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Role of Exogenous Phosphocreatine in Chemotherapy-induced Cardiomyopathy.
Parve, S, Aliakberova, GI, Gylmanov, AA, Abdulganieva, DI
Reviews in cardiovascular medicine. 2017;(2):82-87
Abstract
The 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen is widely used in the management of breast cancer. The common cardiotoxic effects of doxorubicin include congestive heart failure and left ventricular dysfunction, and those of cyclophosphamide include pericarditis, myocarditis, and congestive heart failure. It has been postulated that cardiotoxicity of 5-fluorouracil presents as coronary artery diseases (eg, angina). Cardiomyopathy is a common outcome following treatment with the FAC regimen. We report on a 52-year-old woman with cardiomyopathy following chemotherapy and radiation therapy. The patient did not respond well to b-blockers and angiotensin-converting enzyme inhibitors. After the addition of exogenous phosphocreatine, the patient's cardiac condition improved significantly.
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The association among skeletal muscle phosphocreatine recovery, adiposity, and insulin resistance in children.
Wells, GD, Banks, L, Caterini, JE, Thompson, S, Noseworthy, MD, Rayner, T, Syme, C, McCrindle, BW, Hamilton, J
Pediatric obesity. 2017;(2):163-170
Abstract
BACKGROUND Obesity is associated with cardiometabolic disturbances, which may have significant implications for musculoskeletal health and exercise tolerance. OBJECTIVE We sought to determine the association between muscle structure, function, and metabolism in adolescents across the weight spectrum. METHODS This cross-sectional case-control study included overweight and obese participants (n = 24) 8-18 years of age with a body mass index (BMI) ≥ 85th percentile for age and gender, and non-obese participants (n = 24) with a BMI < 85th percentile. Body composition, physical activity, peak aerobic capacity, cardiometabolic blood markers and insulin resistance (measured by the homeostatic model assessment of insulin resistance, HOMA-IR), skeletal muscle mitochondrial oxidative capacity (via 31 Phosphorous-Magnetic Resonance Spectroscopy, 31 P-MRS, to assess phosphocreatine (PCr) recovery after exercise), and extramyocellular and intramyocellular lipid (IMCL) levels (via 1 Hydrogen-MRS) were assessed. Stepwise regression was performed to examine the factors associated with oxidative capacity. RESULTS bese and overweight patients had similar age, height, and physical activity to non-obese controls, but obese and overweight participants exhibited higher insulin resistance. Obese and overweight participants had longer PCr recovery than non-obese controls following 5x30s of moderate-intensity exercise (51.2 ± 20.1 s vs. 23.9 ± 7.5 s, p = 0.004). In univariate correlation analysis, impaired PCr recovery was associated with a higher BMI z-score (rs = 0.51, p < 0.001), circulating triglycerides (rs = 0.41, p = 0.005), and HOMA-IR (rs = 0.46, p = 0.001). In stepwise multivariate regression analysis, impaired PCr recovery was associated with a higher BMI z-score (β = 0.47, p = 0.002), but not insulin resistance (β = 0.07, p = 0.07) or circulating triglycerides (β = 0.16 p = 0.33). CONCLUSION A slower phosphocreatine recovery following aerobic exercise is strongly associated with increasing adiposity. A slower metabolic recovery following aerobic exercise stress suggests that endurance exercise training in obese adolescents may be an optimal strategy to target exercise intolerance in this cohort.
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Monitoring creatine and phosphocreatine by (13)C MR spectroscopic imaging during and after (13)C4 creatine loading: a feasibility study.
Janssen, BH, Lassche, S, Hopman, MT, Wevers, RA, van Engelen, BG, Heerschap, A
Amino acids. 2016;(8):1857-66
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Abstract
Creatine (Cr) supplementation to enhance muscle performance shows variable responses among individuals and different muscles. Direct monitoring of the supplied Cr in muscles would address these differences. In this feasibility study, we introduce in vivo 3D (13)C MR spectroscopic imaging (MRSI) of the leg with oral ingestion of (13)C4-creatine to observe simultaneously Cr and phosphocreatine (PCr) for assessing Cr uptake, turnover, and the ratio PCr over total Cr (TCr) in individual muscles. (13)C MRSI was performed of five muscles in the posterior thigh in seven subjects (two males and two females of ~20 years, one 82-year-old male, and two neuromuscular patients) with a (1)H/(13)C coil in a 3T MR system before, during and after intake of 15 % (13)C4-enriched Cr. Subjects ingested 20 g Cr/day for 4 days in four 5 g doses at equal time intervals. The PCr/TCr did not vary significantly during supplementation and was similar for all subjects and investigated muscles (average 0.71 ± 0.07), except for the adductor magnus (0.64 ± 0.03). The average Cr turnover rate, assessed in male muscles, was 2.1 ± 0.7 %/day. The linear uptake rates of Cr were variable between muscles, although not significantly different. This assessment was possible in all investigated muscles of young male volunteers, but less so in muscles of the other subjects due to lower signal-to-noise ratio. Improvements for future studies are discussed. In vivo (13)C MRSI after (13)C-Cr ingestion is demonstrated for longitudinal studies of Cr uptake, turnover, and PCr/TCr ratios of individual muscles in one exam.
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Cardiac protection with phosphocreatine: a meta-analysis.
Landoni, G, Zangrillo, A, Lomivorotov, VV, Likhvantsev, V, Ma, J, De Simone, F, Fominskiy, E
Interactive cardiovascular and thoracic surgery. 2016;(4):637-46
Abstract
Phosphocreatine (PCr) plays an important role in the energy metabolism of the heart and a decrease in its intracellular concentration results in alteration of myocardium energetics and work. We conducted a meta-analysis of all randomized and matched trials that compared PCr with placebo or standard treatment in patients with coronary artery disease or chronic heart failure or in those undergoing cardiac surgery. We systematically searched PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials and Google Scholar up to 1 November 2015, for pertinent trials. The primary outcome was all-cause mortality. Secondary outcomes included inotrope use, ejection fraction (EF), peak creatinine kinase-myocardial band (CK-MB) release and the incidence of major arrhythmias, as well as spontaneous recovery of the heart performance in the subgroup of patients undergoing cardiac surgery with cardiopulmonary bypass. We pooled odds ratio (OR) and mean difference (MD) using fixed- and random effects models. We identified 41 controlled trials, of them 32 were randomized. Patients receiving PCr had lower all-cause mortality when compared with the control group [61/1731 (3.5%) vs 177/1667 (10.6%); OR: 0.71, 95% CI: 0.51-0.99; P = 0.04; I(2) = 0%; with 3400 patients and 22 trials included]. Phosphocreatine administration was associated with higher LVEF (MD: 3.82, 95% CI: 1.18-6.46; P = 0.005; I(2) = 98%), lower peak CK-MB release (MD: -6.08, 95% CI: -8.01, -4.15; P < 0.001; I(2) = 97%), lower rate of major arrhythmias (OR: 0.42; 95% CI: 0.27-0.66; P < 0.001; I(2) = 0%), lower incidence of inotropic support (OR: 0.39, 95% CI: 0.25-0.61; P < 0.001; I(2) = 56%) and a higher level of spontaneous recovery of the heart performance after cardiopulmonary bypass (OR: 3.49, 95% CI: 2.28-5.35; P < 0.001; I(2) = 49%) when compared with the control group. In a mixed population of patients with coronary artery disease, chronic heart failure or in those undergoing cardiac surgery, PCr may reduce all-cause short-term mortality. In addition, PCr administration was associated with improved cardiac outcomes. Owing to the pharmacological plausibility of this effect and to the concordance of the beneficial effects of PCr on several secondary but important outcomes and survival, there is urgent need for a large multicentre randomized trial to confirm these findings.
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Regulation of metabolism: the work-to-rest transition in skeletal muscle.
Wilson, DF
American journal of physiology. Endocrinology and metabolism. 2016;(8):E633-E642
Abstract
The behavior of oxidative phosphorylation predicted by a model for the mechanism and kinetics of cytochrome c oxidase is compared with the experimentally observed behavior during the work-to-rest transition in skeletal muscle. For both experiment and model, when work stops, the increase in creatine phosphate and decrease in creatine and inorganic phosphate concentrations ([CrP], [Cr], and [Pi]) begin immediately. The rate of change for each is maximal and then progressively slows as the increasing energy state ([ATP]/[ADP][Pi]) suppresses the rate of oxidative phosphorylation. The time courses can be reasonably fitted to single exponential curves with similar time constants. The energy state in the working and resting steady states at constant Po2 are dependent on the intramitochondrial [NAD+]/[NADH], mitochondrial content, and size of the creatine pool ([CrP] + [Cr]). The rate of change in [CrP] is linearly correlated with [CrP] and with [Pi] and [Cr]. The time constant for [CrP] increase in the resting and working steady states, and the rate of decrease in oxygen consumption are similarly dependent on the Po2 in the inspired gas (experimental) or tissue Po2 (model). Myoglobin strongly buffers intracellular Po2 below ∼15 torr, truncating the low end of the oxygen distribution in the tissue and suppressing intra- and intermyocyte oxygen gradients. The predictions of the model are consistent with the experimental data throughout the work/rest transition, providing valuable insights into the regulation of cellular and tissue metabolism.
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The effect of exogenous creatine phosphate on myocardial injury after percutaneous coronary intervention.
Ke-Wu, D, Xu-Bo, S, Ying-Xin, Z, Shi-Wei, Y, Yu-Jie, Z, Dong-Mei, S, Yu-Yang, L, De-An, J, Zhe, F, Zhi-Ming, Z, et al
Angiology. 2015;(2):163-8
Abstract
OBJECTIVE To evaluate the effect of exogenous creatine phosphate (CP) on myocardial injury after percutaneous coronary intervention (PCI). METHOD Four hundred patients were divided to receive conventional therapy (control group) or 3-day intravenous infusion of CP after PCI (CP group). Levels of creatine kinase MB (CK-MB) and troponin I (TnI) were measured before and on postprocedural day 3. RESULTS Postprocedural CK-MB and TnI in the CP group were significantly increased compared to the control group. In the CP group, 8.0% and 5.0% of patients had an increase in CK-MB 1 to 3 times and >3 times, respectively, which were significantly lower than that of the control group (19.0% and 9.0%, respectively); 12.0% and 10.0% of patients had an increase in TnI 1 to 3 times and >3 times, respectively, which were significantly lower than that of the control group (21.0% and 18.0%, respectively). CONCLUSION Exogenous CP was helpful to reduce myocardial injury after PCI.