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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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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.
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Impact of creatine on muscle performance and phosphagen stores after immobilization.
Fransen, JC, Zuhl, M, Kerksick, CM, Cole, N, Altobelli, S, Kuethe, DO, Schneider, S
European journal of applied physiology. 2015;(9):1877-86
Abstract
PURPOSE This study investigated the effect of creatine (CR) supplementation during cast-immobilization to preserve skeletal muscle total work, power and intramuscular phosphocreatine (PCr) kinetics during dynamic exercise. METHODS Twenty-five active individuals (24 ± 4 years,) performed wrist flexion exercise within a 1.9 Tesla superconducting magnet before and after 1 week of cast-immobilization. An incremental protocol to fatigue and two constant load (CL1 and CL2) exercise bouts were performed. While casted, participants consumed either 20 g day(-1) of CR or a placebo (PLA). (31)P magnetic resonance spectroscopy was used to quantify in vivo intramuscular PCr levels. RESULTS No significant group × time interaction effects were found for work or power throughout all exercise bouts. Total work was significantly reduced over time in both groups (p = 0.049) during the incremental exercise bout. Work production in CL1 tended (p = 0.073) to attenuate in the CR group, compared to PLA. No changes were observed in CL2. Baseline PCr significantly decreased with casting in PLA (PRE: 26.6 ± 6.3 vs. POST 22.5 ± 5.6 mM kg(-1) wet muscle, p = 0.003). No change (p = 0.31) was observed in the CR group. Changes in work production were significantly correlated with changes in resting PCr in CR (r = -0.63, p = 0.021) but not PLA (r = -0.36, p = 0.26) group. CONCLUSIONS Results suggest decreases in short-term endurance may be due to alternations of PCr status and/or metabolism. More research is needed to fully determine the efficacy of CR supplementation during short-term immobilization.
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The effects of tesamorelin on phosphocreatine recovery in obese subjects with reduced GH.
Makimura, H, Murphy, CA, Feldpausch, MN, Grinspoon, SK
The Journal of clinical endocrinology and metabolism. 2014;(1):338-43
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Abstract
CONTEXT Few studies have assessed the relationship between GH and mitochondrial function. OBJECTIVE The objective of this study was to determine the effects of improving IGF-I using a GHRH analog, tesamorelin, on mitochondrial function assessed by phosphocreatine (PCr) recovery using (31)P magnetic resonance spectroscopy in obese adults with reduced GH. DESIGN A total of 39 obese men and women with reduced GH secretion as determined by GHRH-arginine stimulation tests underwent magnetic resonance spectroscopy as part of a 12-month, double-blind, randomized, placebo-controlled trial comparing tesamorelin vs placebo. PCr recovery after submaximal exercise was assessed at baseline and at 12 months. RESULTS At baseline, there were no differences in age, sex, race/ethnicity, and GH or PCr parameters between tesamorelin and placebo. After 12 months, tesamorelin treatment led to a significantly greater increase in IGF-I than did placebo treatment (change, 102.9±31.8 μg/L vs 22.8±8.9 μg/L, tesamorelin vs placebo; P=.02). We demonstrated a significant positive relationship between increases in IGF-I and improvements in PCr recovery represented as ViPCr (R=0.56; P=.01). The association between IGF-I and PCr recovery was even stronger among subjects treated with tesamorelin only (ViPCr: R=0.71; P=.03). This association remained significant after controlling for age, sex, race, ethnicity, and parameters of body composition and insulin sensitivity (all P<.05). CONCLUSIONS Increases in IGF-I from 12 months of treatment with tesamorelin were significantly associated with improvements in PCr recovery parameters in obese men and women with reduced GH secretion, suggestive of improvements in mitochondrial function.
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Oxygen uptake kinetics at work onset: role of cardiac output and of phosphocreatine breakdown.
Francescato, MP, Cettolo, V, di Prampero, PE
Respiratory physiology & neurobiology. 2013;(2):287-95
Abstract
The hypothesis that variability in individual's cardiac output response affects the kinetics of pulmonary O₂ uptake (VO₂) was tested by investigating the time constants of cardiac output (Q) adjustment (τ(Q)), of PCr splitting (τ(PCr)), and of phase II pulmonary O₂ uptake (τ(VO₂)) in eight volunteers. VO₂, Q, and gastrocnemius [PCr] (by (31)P-MRS) were measured at rest and during low intensity two-legged exercise. Steady state VO₂ and Q increased (ΔVO₂(s) = 182 ± 58 mL min⁻¹; ΔQ = 1.3 ± 0.4 L min⁻¹), whereas [PCr] decreased significantly (21 ± 8%). τ(VO₂), τ(PCr) and τ(Q) were significantly different from each other (38.3 ± 4.0, 23.9 ± 2.5, 11.6 ± 4.6 s, respectively; p<0.001). τ(PCr) assumed to be equal to the time constant of VO₂ at the muscle level (τ(mVO₂)), was not related to τ(Q), whereas τ(VO₂) and τ(Q) were significantly related (p<0.05) as were τ(VO₂) and τ(PCr) (p<0.05). Venous blood O₂ stores changes, as determined from arterio-to-mixed-venous O₂ content, were essentially equal to those estimated as (τ(VO₂)-τ(PCr))·ΔVO₂(s). This suggests that cardiac output responses affect O₂ stores utilization and hence τ(VO₂) : thus τ(VO₂) is not necessarily a good estimate of τ(mVO₂).
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Role of creatine phosphate as a myoprotective agent during coronary artery bypass graft in elderly patients.
Guo-han, C, Jian-hua, G, Xuan, H, Jinyi, W, Rong, L, Zhong-min, L
Coronary artery disease. 2013;(1):48-53
Abstract
OBJECTIVE To evaluate the myocardial protective effect of exogenous creatine phosphate added to a cardioplegic solution for elderly patients undergoing a coronary artery bypass graft (CABG) in China. METHODS Twenty-four patients (age>65 years) who underwent CABG were randomly divided into a control group (n=12) and an experimental group (n=12). The concentrations of malonyldehyde and superoxide dismutase in the blood were measured before aortic clamping and at 0, 30, 60, and 120 min after the release of aortic clamping. Creatine phosphokinase (CK), creatine phosphokinase-MB (CK-MB), lactate dehydrogenase, and cardiac troponin T were measured before aortic clamping and at 2, 24, and 48 h after the release of aortic clamping. Myocardial ultrastructures were examined under an electron microscope. RESULTS The concentrations of malonyldehyde in both groups increased after the release of aortic clamping (at 0, 30, 60, and 120 min), but were higher in the control group compared with the experimental group (P<0.01). The concentrations of superoxide dismutase in both groups were decreased after the release of aortic clamping and were higher in the experimental group compared with the control group (P<0.01) at 0, 30, 60, and 120 min after the release of aortic clamping. The values of CK, CK-MB, lactate dehydrogenase, and cardiac troponin T at 2, 24, and 48 h after the release of the aortic clamping were lower in the experimental group than in the control group (P<0.01). Electron microscopy showed that the mitochondria in the experimental group were histologically better than those in the control group. CONCLUSION Exogenous creatine phosphate added to the cardioplegia solution can provide energy to myocardial cells and can relieve ischemia/reperfusion-related injury in elderly patients during CABG in China.
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A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects.
Holloway, CJ, Cochlin, LE, Emmanuel, Y, Murray, A, Codreanu, I, Edwards, LM, Szmigielski, C, Tyler, DJ, Knight, NS, Saxby, BK, et al
The American journal of clinical nutrition. 2011;(4):748-55
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Abstract
BACKGROUND High-fat, low-carbohydrate diets are widely used for weight reduction, but they may also have detrimental effects via increased circulating free fatty acid concentrations. OBJECTIVE We tested whether raising plasma free fatty acids by using a high-fat, low-carbohydrate diet results in alterations in heart and brain in healthy subjects. DESIGN Men (n = 16) aged 22 ± 1 y (mean ± SE) were randomly assigned to 5 d of a high-fat, low-carbohydrate diet containing 75 ± 1% of calorie intake through fat consumption or to an isocaloric standard diet providing 23 ± 1% of calorie intake as fat. In a crossover design, subjects undertook the alternate diet after a 2-wk washout period, with results compared after the diet periods. Cardiac (31)P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, and computerized cognitive tests were used to assess cardiac phosphocreatine (PCr)/ATP, cardiac function, and cognitive function, respectively. RESULTS Compared with the standard diet, subjects who consumed the high-fat, low-carbohydrate diet had 44% higher plasma free fatty acids (P < 0.05), 9% lower cardiac PCr/ATP (P < 0.01), and no change in cardiac function. Cognitive tests showed impaired attention (P < 0.01), speed (P < 0.001), and mood (P < 0.01) after the high-fat, low-carbohydrate diet. CONCLUSION Raising plasma free fatty acids decreased myocardial PCr/ATP and reduced cognition, which suggests that a high-fat diet is detrimental to heart and brain in healthy subjects.
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[Effects of phosphocreatine on plasma brain natriuretic peptide level in elderly patients with chronic congestive heart failure].
Du, XH, Liang, FY, Zhao, XW
Nan fang yi ke da xue xue bao = Journal of Southern Medical University. 2009;(1):154-5, 159
Abstract
OBJECTIVE To investigate the therapeutic effects of phosphocreatine in elderly patients with chronic congestive heart failure (CHF) and its effects on plasma brain natriuretic peptide (BNP). METHODS Forty elderly patients with chronic CHF were randomly divided into two groups to receive basic treatment (control group) and additional phosphocreatine treatment (treatment group) with a treatment course of 8 weeks. The patients were evaluated for improvement in New York Heart Association (NYHA) functional class, symptoms, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) and the levels of BNP before and after treatment. RESULTS After 8 weeks of treatment, the overall efficacy rate was significantly higher in treatment group than in the control group, and LVESD, LVEDD, LVEF and BNP level of the treatment group were significantly lowered in comparison with those of the control group (P<0.05). CONCLUSION Phosphocreatine in addition to the basic treatment can reduce the BNP level and improve the cardiac systolic and diastolic function in elderly patients with chronic CHF.
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Effect of thirty days of creatine supplementation with phosphate salts on anaerobic working capacity and body weight in men.
Eckerson, JM, Bull, AA, Moore, GA
Journal of strength and conditioning research. 2008;(3):826-32
Abstract
The purpose of this study was to determine the effect of 30 days of single-dose creatine supplementation with phosphate salts (CPS) on body weight (BW) and anaerobic working capacity (AWC) in men. Using a double-blind design, 32 men randomly received 1 serving of either CPS (5 g Cr + 4 g phosphate) (n = 17) or 20 g of dextrose as placebo (PL) (n = 15) for 30 days. AWC determined from the Critical Power Test and BW were measured at baseline, 10 days, 20 days, 30 days, and 10 days post-supplementation. Results (2 x 5 ANOVA) showed no significant differences between groups for AWC at any time point; however, BW was significantly increased at 10 days in the CPS group (1.0 kg) vs. PL (0.0 kg), and remained elevated for the duration of the study. These findings suggest that a single 5 g x d(-1) dose of CPS for 30 days increases BW but is not effective for increasing AWC in men.
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Effect of creatine phosphate supplementation on anaerobic working capacity and body weight after two and six days of loading in men and women.
Eckerson, JM, Stout, JR, Moore, GA, Stone, NJ, Iwan, KA, Gebauer, AN, Ginsberg, R
Journal of strength and conditioning research. 2005;(4):756-63
Abstract
The purpose of this study was to determine the effects of 2 and 6 days of creatine phosphate loading on anaerobic working capacity (AWC) and body weight (BW) in men and women. Sixty-one men (n = 31) and women (n = 30) randomly received 1 of 3 treatments (4 x 5 g.d(-1) x 6 days) using a double blind design: (a) 18 g dextrose as placebo (PL); (b) 5.0 g Cr + 20 g dextrose (Cr); or (c) 5.0 g Cr + 18 g dextrose + 4 g of sodium and potassium phosphates (CrP). AWC was determined at baseline and following 2 and 6 days of supplementation using the Critical Power Test. BW increased significantly over time, and the mean value for the men was significantly greater compared to that for women, but there were no interactions (p > 0.05). There were gender-specific responses for AWC expressed in both absolute values (kJ) and relative to BW (kJ. kg(-1)), with the women demonstrating no significant interactions. For the men, CrP loading significantly increased AWC following 2 days (23.8%) and 6 days (49.8%) of supplementation vs. PL (kJ and kJ.kg(-1)). Cr supplementation increased AWC 13-15% in both genders compared to PL (1.1%- 3.0% decline); although this result was not statistically significant, it may have some practical significance.