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Abstract Time for post-exercise phosphocreatine-recovery (PCr-R), deemed a robust index of mitochondrial function in vivo, was previously reported to be elevated (signifying impaired ATP production) in veterans with Gulf War illness (GWI). Here we sought to replicate the finding and assess the impact of contravening previous eligibility requirements. The replication sample comprised white males. Cases reported ≥ moderate muscle-weakness to match the organ assessed to an organ affected; controls lacked recent headache or multiple symptoms. The expansion sample added cases without muscle-weakness, controls with recent headache, females, nonwhites. PCr-R, following pedal-depression-exercise, was compared in veterans with GWI versus controls (sample N = 38). In the replication sample, PCr-R results closely matched the prior report: PCr-R veterans with GWI mean(SD) = 47.7(16.5); control mean(SD) = 30.3(9.2), p = 0.017. (Prior-study PCr-R veterans with GWI mean(SD) = 46.1(17.9), control mean(SD) = 29.0(8.7), p = 0.023. Combined replication + prior samples: p = 0.001.) No case–control difference was observed in the expansion sample. In cases, PCr-R related to muscle-weakness: PCr-R = 29.9(7.1), 38.2(8.9), 47.8(15.2) for muscle-weakness rated none/low, intermediate, and high respectively (p for trend = 0.02), validating desirability of matching tissue assessed to tissue affected. In controls, headache/multiple symptoms, sex, and ethnicity each mattered (affecting PCr-R significantly). This study affirms mitochondrial/bioenergetic impairment in veterans with GWI. The importance of careful case/control selection is underscored.

Cardiovascular disease remains one of the most common and influential causes of death worldwide, as the heart plays a key role in the human body. Energetic cardioprotective therapy of the myocardium is an important protective factor, regulating the synthesis and use of energy by myocardial cells, while having a little effect on heart rate, blood pressure, and blood supply. Phosphocreatine plays an important role in the intracellular energy buffering and transport system, ensuring energy transfer from the site of production to the site of use to meet the high and variable demands of the heart. Research shows that phosphocreatine can have a positive effect on patients with coronary heart disease, heart failure, and those who have undergone cardiac surgery. The accumulated information confirms the prospects of using phosphocreatine in clinical practice to improve treatment outcomes in patients with heart diseases.

Background/Objective: Maintaining intracellular adenosine triphosphate (ATP) levels is essential for numerous cellular functions, including energy metabolism, muscle contraction, and nerve impulse transmission. ATP is primarily synthesized in mitochondria through oxidative phosphorylation. It is also generated in the cytosol under anaerobic conditions using phosphocreatine (PCr) as a phosphate donor to adenosine diphosphate. However, the intracellular delivery of exogenous PCr is challenging as it does not readily cross the plasma membrane. This complicates the use of PCr as a therapeutic agent to maintain energy homeostasis or to treat conditions like cerebral creatine deficiency syndrome (CDS), which results from defective creatine transporters. Methods: This study employs the use of fusogenic liposomes to deliver PCr directly into the cytosol, bypassing membrane impermeability issues. We engineered various 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-based fusogenic liposomes, incorporating phospholipids such as 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in combination with phospholipid-aromatic dye components to facilitate membrane fusion and to enhance the delivery of the PCr cargo. Liposomal formulations were co-loaded with membrane-impermeable chromophores and PCr and studied on live cells using confocal microscopy. Conclusions: We demonstrated the successful intracellular delivery of these agents and observed a 23% increase in intracellular ATP levels in cells treated with PCr-loaded liposomes. This increase was not observed with free PCr, confirming the effectiveness of the liposome-based delivery system. Additionally, cell viability assays showed minimal toxicity from the liposomes. Our results indicate that fusogenic liposomes are a promising method for the delivery of PCr (and potentially other cell-impermeable therapeutic agents) to the cellular cytosol. The approach demonstrated here could be advantageous for treating energy-related disorders and improving cellular energy homeostasis.

Abstract Background This study was conducted to test the hypothesis that phosphocreatine (PCr), administered intravenously and as cardioplegia adjuvant in patients undergoing cardiac surgery with prolonged aortic cross clamping and cardiopulmonary bypass (CPB) time, would decrease troponin I concentration after surgery. Methods In this randomized, double-blind, placebo-controlled pilot study we included 120 patients undergoing double/triple valve repair/replacement under cardiopulmonary bypass in the cardiac surgery department of a tertiary hospital. The treatment group received: intravenous administration of 2 g of PCr after anesthesia induction; 2.5 g of PCr in every 1 L of cardioplegic solution (concentration = 10 mmol/L); intravenous administration of 2 g of PCr immediately after heart recovery following aorta declamping; 4 g of PCr at intensive care unit admission. The control group received an equivolume dose of normosaline. Results The primary endpoint was peak concentration of troponin I after surgery. Secondary endpoints included peak concentration of serum creatinine, need for, and dosage of inotropic support, number of defibrillations after aortic declamping, incidence of arrhythmias, duration of Intensive Care Unit (ICU) stay, length of hospitalization. There was no difference in peak troponin I concentration after surgery (PCr, 10,508 pg/ml [IQR 6,838–19,034]; placebo, 11,328 pg/ml [IQR 7.660–22.894]; p = 0.24). There were also no differences in median peak serum creatinine (PCr, 100 µmol/L [IQR 85.0–117.0]; placebo, 99.5 µmol/L [IQR 90.0–117.0]; p = 0.87), the number of patients on vasopressor/inotropic agents (PCr, 49 [88%]; placebo, 57 [91%]; p = 0.60), the inotropic score on postoperative day 1 (PCr, 4.0 (0–7); placebo, 4.0 (0–10); p = 0.47), mean SOFA score on postoperative day 1 (PCr, 5.25 ± 2.33; placebo, 5,45 ± 2,65; p = 0.83), need for defibrillation after declamping of aorta (PCr, 22 [39%]; placebo, 25 [40%]; p = 0.9),, duration of ICU stay and length of hospitalization as well as 30-day mortality (PCr, 0 (0%); placebo,1 (4.3%); p = 0.4). Conclusion PCr administration to patients undergoing double/triple valve surgery under cardiopulmonary bypass is safe but is not associated with a decrease in troponin I concentration. Phosphocreatine had no beneficial effect on clinical outcomes after surgery. Trial registration The study is registered at ClinicalTrials.gov with the Identifier: NCT02757443. First posted (published): 02/05/2016.

The study assessed vastus lateralis oxygen desaturation kinetics (SmO2) in 32 male cyclists (16 Seniors, 16 Juniors) during a 30 s sprint, examining effects of age and performance. An incremental test was used to determine ventilatory thresholds (VT1, VT2) and maximal oxygen uptake (VO2kg), followed by a sprint test to evaluate anaerobic performance. Cyclists’ performance phenotype was determined as the ratio of power at VT2 to 5 s peak sprint power. Juniors exhibited sprinter-like traits, excelling in all functional tests except for lactate levels post-sprint. SmO2 data showed no age-related or bilateral differences across participants. The combined mean response time (MRT) revealed stronger bilateral goodness of fit (R2 = 0.64) than individual time delay (TD) and time constant (τ). Higher VO2kg at VT2, peak power, and maximal uptake were linked to longer TD, while shorter TD correlated with higher lactate production and increased fatigue. Bilaterally averaged SmO2 kinetics distinguished between sprint and endurance athletes, indicating the potential to reflect the alactic anaerobic system’s capacity and depletion. Age did not affect desaturation rates, but younger cyclists showed greater response amplitude, attributed to a higher initial baseline rather than maximal desaturation at the end of the exercise.

The current study aimed to evidence the strengths and weaknesses of two indirect methods for assessing the anaerobic alactic contribution to a specific CrossFit® workout. Thirty experienced crossfitters performed the Fran workout at maximal intensity, and ventilatory data were collected during the recovery period using a telemetric portable gas analyser to assess the oxygen uptake (VO2) of the off-kinetics fast component (Anarecovery). The kinetics of maximal phosphocreatine splitting (AnaPCr) were determined based on the literature. No differences between the two methods were observed (31.4 ± 4.0 vs. 30.4 ± 4.1 kJ for Anarecovery and AnaPCr, respectively). Despite the existence of some caveats (e.g., errors derived from a delay at the onset of VO2 recovery and the assumption of given values in the concentration of phosphocreatine per kilogram of wet muscle, respectively) in both methods, the data indicate that they yield similar results and allow for estimations of alactic energy contribution from a short-duration and high intensity CrossFit® routine. The current data contributes to CrossFit® workout evaluations and training strategies, helping researchers to evaluate crossfitters more accurately. The advantage of the two methods used in the current study is that they are non-invasive, which differs greatly from muscle biopsies.

The natural variation in estrogen secretion throughout the female menstrual cycle impacts various organs, including estrogen receptor (ER)-expressed skeletal muscle. Many women commonly experience increased fatigue or reduced energy levels in the days leading up to and during menstruation, when blood estrogen levels decline. Yet, it remains unclear whether endogenous 17β-estradiol, a major estrogen component, directly affects the energy metabolism in skeletal muscle due to the intricate and fluctuating nature of female hormones. In this study, we employed 2D 31P FID-MRSI at 7T to investigate phosphoryl metabolites in the soleus muscle of a cohort of young females (average age: 28 ± 6 years, n = 7) during the early follicular (EF) and peri-ovulation (PO) phases, when their blood 17β-estradiol levels differ significantly (EF: 28 ± 18 pg/mL vs. PO: 71 ± 30 pg/mL, p < 0.05), while the levels of other potentially interfering hormones remain relatively invariant. Our findings reveal a reduction in ATP-referenced phosphocreatine (PCr) levels in the EF phase compared to the PO phase for all participants (5.4 ± 4.3%). Furthermore, we observe a linear correlation between muscle PCr levels and blood 17β-estradiol concentrations (r = 0.64, p = 0.014). Conversely, inorganic phosphate Pi and phospholipid metabolite GPC levels remain independent of 17β-estradiol but display a high correlation between the EF and PO phases (p = 0.015 for Pi and p = 0.0008 for GPC). The robust association we have identified between ATP-referenced PCr and 17β-estradiol suggests that 17β-estradiol plays a modulatory role in the energy metabolism of skeletal muscle.

The purpose of this study was to determine if the sum of estimates of the phosphocreatine contribution and the glycolytic contribution (we refer to this sum as PCr+glycolysis) provides an alternative to oxygen deficit as a way to quantify the anaerobic contribution in running. Thirty university students performed three treadmill tests, each test at one speed individually selected for each participant; one test was terminated after 3 min, one after 7 min, and one at exhaustion (mean ± SD, 10.3 ± 0.4 min). Oxygen deficit was calculated by subtraction of the accumulated oxygen uptake from the total oxygen cost. Phosphocreatine and glycolysis contributions were determined from post-exercise VO2 responses and blood lactate concentrations, respectively. The mean values for PCr+glycolysis was ~3 mL·kg–1 lower (p < .05) than oxygen deficit across three exercise durations, but well correlated (r ≥ .80, p < .05) at each. These results confirm the validity of PCr+glycolysis as an alternative to oxygen deficit to quantify the anaerobic contribution in running exercise.

This narrative review focuses on the studies that estimate the energy systems’ contributions during match simulations of striking (boxing, karate, and taekwondo), grappling (judo), and weapon-based (fencing) Olympic combat sports. The purpose is to provide insights into the metabolism of these athletes. In striking Olympic combat sports, the oxidative contribution varied from 62% (in karate and taekwondo) to 86% (in boxing), the ATP-PCr system contribution varied from 10% (in boxing) to 31% (in taekwondo), and the glycolytic contribution was between 3% (in the third round of taekwondo) and 21% (in karate). In grappling combat sports, only judo was studied, and for a 4 min match, the oxidative contribution was 79%, followed by 14% ATP-PCr system contribution and 7% contribution from the glycolytic system. In fencing, the only weapon-based Olympic combat sport, the oxidative contribution varied from 81% (in the first bout) to 90% (in the second bout), followed by 9% (bout 2) to 12% (bout 1) contribution from the ATP-PCr system, and 0.6% to 7% contribution from the glycolytic system during 3 × 3 min bouts of épée match simulation. Hence, Olympic combat sports are primarily powered by the oxidative system, but the key scoring actions are likely fueled by anaerobic pathways.

Creatine kinase (CK) is an enzyme that produces and uses phosphocreatine to transfer energy to maintain tissue and cellular energy homeostasis, being considered the main controller of cellular energy homeostasis. Its activity in plasma/serum has been commonly used to evaluate tissue damage, since CK is released into the bloodstream during damage. This review summarizes the current knowledge regarding the use of CK activity in fish, focusing on its potential as an indicator of the impairment of energetic homeostasis and tissue damage during stressful situations, such as exposure to contaminants (metals, pesticides, microplastic), hypoxia, thermal stress, and diseases (fungal, parasitic, and bacterial). Based on the data, we can conclude that tissue CK activity can be used as a suitable indicator of the impairment of energetic homeostasis in fish exposed to different aquaculture challenge conditions, while serum/plasma CK activity can be used as the first evidence of possible tissue damage, due to its release into the bloodstream.

Background Numerous studies have demonstrated the efficacy of creatine supplementation for improvements in exercise performance. Few studies, however, have examined the effects of phosphocreatine supplementation on exercise performance. Furthermore, while polyphenols have antioxidant and anti-inflammatory properties, little is known regarding the influence of polyphenol supplementation on muscular strength, power, and endurance. Thus, the purpose of the present study was to compare the effects of 28 days of supplementation with phosphocreatine disodium salts plus blueberry extract (PCDSB), creatine monohydrate (CM), and placebo on measures of muscular strength, power, and endurance. Methods Thirty-three men were randomly assigned to consume either PCDSB, CM, or placebo for 28 days. Peak torque (PT), average power (AP), and percent decline for peak torque (PT%) and average power (AP%) were assessed from a fatigue test consisting of 50 maximal, unilateral, isokinetic leg extensions at 180°·s− 1 before and after the 28 days of supplementation. Individual responses were assessed to examine the proportion of subjects that exceeded a minimal important difference (MID). Results The results demonstrated significant (p 0.05) differences in the proportion of subjects exceeding the MID between the CM and placebo groups or between the CM and PCDSB groups. Conclusions These findings indicated that for the group mean responses, 28 days of supplementation with both PCDSB and CM resulted in increases in PT and AP. The PCDSB, however, may have an advantage over CM when compared to the placebo group for the proportion of individuals that respond favorably to supplementation with meaningful increases in muscular strength.

If mitochondrial energy availability or oxidative metabolism is altered, patients will suffer from insufficient energy supply Phosphocreatine (PCr) not only acts as an energy carrier, but also acts as an antioxidant and defensive agent to maintain the integrity and stability of the membrane, to maintain ATP homeostasis through regulating mitochondrial respiration. Meanwhile, PCr can enhance calcium balance and reduce morphological pathological changes, ultimately, PCr helps to reduce apoptosis. On the other aspect, the activities of ATP synthase and MitCK play a crucial role in the maintenance of cellular energy metabolic function. It is interesting to note, PCr not only rises the activities of ATP synthase as well as MitCK, but also promotes these two enzymatic reactions. Additionally, PCr can also inhibit mitochondrial permeability transition in a concentration-dependent manner, prevent ROS and CytC from spilling into the cytoplasm, thereby inhibit the release of proapoptotic factors caspase-3 and caspase-9, and eventually, effectively prevent LPS-induced apoptosis of cells. Understandably, PCr prevents the apoptosis caused by abnormal mitochondrial energy metabolism and has a protective role in a non-energy manner. Moreover, recent studies have shown that PCr protects cell survival through PI3K/Akt/eNOS, MAPK pathway, and inhibition of Ang II-induced NF-κB activation. Furthermore, PCr antagonizes oxidative stress through the activation of PI3K/Akt/GSK3b intracellular pathway, PI3K/AKT-PGC1α signaling pathway, while through the promotion of SIRT3 expression to maintain normal cell metabolism. Interestingly, PCr results in delaying the time to enter pathological metabolism through the delayed activation of AMPK pathway, which is different from previous studies, now we propose the hypothesis that the “miRNA-JAK2/STAT3 -CypD pathway” may take part in protecting cells from apoptosis, PCr may be further be involved in the dynamic relationship between CypD and STAT3. Furthermore, we believe that PCr and CypD would be the central link to maintain cell survival and maintain cell stability and mitochondrial repair under the mitochondrial dysfunction caused by oxidative stress. This review provides the modern progress knowledge and views on the molecular mechanism and molecular targets of PCr in a non-energy way.

Abstract Background Major depressive disorder (MDD) is a common psychiatric disorder. With systematic antidepressant treatment, 50–75% of patients have a treatment response but require 4–6 weeks to have their symptoms alleviated. Therefore, researchers anticipate the development of novel fast-acting antidepressants. Previous studies have revealed that the decrease of bio-energetic metabolism may contribute to the occurrence of depression, while our team has found adenosine triphosphate (ATP) and phosphocreatine (PCr) to be fast-acting antidepressants in the depressed-animal model. ATP and PCr have already been widely prescribed clinically as energy supplements for cells. This will be the first clinical attempt of the intravenous administration of ATP and PCr combined with orally administered fluoxetine in MDD. Methods This is a single-center, randomized, double-blind, placebo-controlled pilot study. A total of 42 patients will be divided randomly into three groups. Patients will receive an intravenous administration of ATP or PCr or saline twice daily combined with orally administered fluoxetine (20 mg/day) for the first 2 weeks and fluoxetine monotherapy for the following 4 weeks. Follow-up assessment will be completed at week 10. Feasibility outcomes will include percentages of patient eligibility, intention to use medication, willingness to participate, drug adherence, completion of the scheduled assessment, retention, drop-out, etc. Physical examination results, Side Effect Rating Scale, adverse events, results from blood tests, electroencephalogram, and electrocardiograph will be recorded for safety evaluation of the augmentation therapy. The trends of efficacy will be evaluated by the reduction rate of the Hamilton Depression Rating Scale, the mean change of the Clinical Global Impression Scale, and the Patients Health Questionaire-9 items. Discussion In our study, ATP and PCr will be given by intravenous infusion. Thus patients will be hospitalized for the initial 2 weeks for safety concern. Hospitalization will be an impact factor for the recruitment, participation, drop-out, efficacy, results, etc. The evaluation of our feasibility outcomes, study setting, safety of augmentation therapy and possible efficacy trends among groups, will facilitate a full-scale trial design and sample size calculation. Trial registration NCT03138681. Registered on 3 May 2017. First patient: 4 May 2017.

The aim of the present study was to examine the effects of creatine (Cr) supplementation on power output during repeated sprints on a non-motorized treadmill. Sixteen recreationally active males volunteered for this study (age 25.5 ± 4.8 y, height 179 ± 5 cm, body mass 74.8 ± 6.8 kg). All participants received placebo supplementation (75 mg of glucose·kg−1·day−1) for 5 days and then performed a baseline repeated sprints test (6 × 10 s sprints on a non-motorised treadmill). Thereafter, they were randomly assigned into a Cr (75 mg of Cr monohydrate·kg−1·day−1) or placebo supplementation, as above, and the repeated sprints test was repeated. After Cr supplementation, body mass was increased by 0.99 ± 0.83 kg (p = 0.007), peak power output and peak running speed remained unchanged throughout the test in both groups, while the mean power output and mean running speed during the last 5 s of the sprints increased by 4.5% (p = 0.005) and 4.2% to 7.0%, respectively, during the last three sprints (p = 0.005 to 0.001). The reduction in speed within each sprint was also blunted by 16.2% (p = 0.003) following Cr supplementation. Plasma ammonia decreased by 20.1% (p = 0.037) after Cr supplementation, despite the increase in performance. VO2 and blood lactate during the repeated sprints test remained unchanged after supplementation, suggesting no alteration of aerobic or glycolytic contribution to adenosine triphosphate production. In conclusion, Cr supplementation improved the mean power and speed in the second half of a repeated sprint running protocol, despite the increased body mass. This improvement was due to the higher power output and running speed in the last 5 s of each 10 s sprint.

Objective: This study aimed to develop a parent-metabolite joint population pharmacokinetic model to characterize the pharmacokinetic (PK) profile for phosphocreatine (PCr) and its metabolite creatine (Cr) in children with myocarditis and to use this model to study the PK profile of different dosing schemes.Methods: One hundred pediatric patients with myocarditis were enrolled. Blood samples were collected at baseline and approximately 30, 40 or 50, 75, and 180 min after a single dose of phosphocreatine sodium. Plasma PCr and Cr concentrations were determined using an HPLC-MS/MS method. A nonlinear mixed effect model approach was used to build the population pharmacokinetic model. After validation, the model was used for simulations to evaluate the PK profile of different dosing schemes.Results: A total of 997 plasma concentrations (498 for PCr and 499 for Cr) were included in the analysis. A four-compartment chain model (central and peripheral compartments for both PCr and Cr) with the first-order elimination adequately characterized the in vivo process of PCr and Cr. Allometric scaling based on bodyweight was applied to the PK parameters. The covariate analysis identified that the glomerular filtration rate (GFR) was strongly associated with Cr clearance. Bootstrapping and visual predictive checks suggested that a robust and reliable pharmacokinetic model was developed. The simulation results showed that PCr had no accumulation in vivo. With the infusion of PCr, the concentration of Cr increased rapidly.Conclusion: A joint population pharmacokinetic model for PCr and Cr in pediatric patients with myocarditis was successfully developed for the first time.

Abstract Creatine transporter deficiency (CTD) is a metabolic disorder resulting in cognitive, motor, and behavioral deficits. Cyclocreatine (cCr), a creatine analog, has been explored as a therapeutic strategy for the treatment of CTD. We developed a rapid, selective, and accurate HILIC ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) method to simultaneously quantify the intracellular concentrations of cCr, creatine (Cr), creatine‐d3 (Cr‐d3), phosphocyclocreatine (pcCr), and phosphocreatine (pCr). Using HILIC‐UPLC‐MS/MS, we measured cCr and Cr‐d3 uptake and their conversion to the phosphorylated forms in primary human control and CTD fibroblasts. Altogether, the data demonstrate that cCr enters cells and its dominant intracellular form is pcCr in both control and CTD patient cells. Therefore, cCr may replace creatine as a therapeutic strategy for the treatment of CTD.

Abstract Purpose: To observe the efficacy of phosphocreatine pre-administration (PCr-PA) on X-linked inhibitor of apoptosis protein (XIAP), the second mitochondia-derived activator of caspase (Smac) and apoptosis in the ischemic penumbra of rats with focal cerebral ischemia-reperfusion injury (CIRI). Methods: A total of 60 healthy male Sprague Dawley (SD) rats were randomly divided into three groups (n=20): group A (the sham operation group), group B , and group C . After 24 h for reperfusion, the neurological function was evaluated and the tissue was sampled to detect expression of XIAP, Smac and caspase-3 positive cells in the ischemic penumbra so as to observe the apoptosis. Results: Compared with group B, neurological deficit scores, numbers of apoptotic cells, expression of Smac,caspase-9 and the numbers of Caspase-3 positive cells were decreased while expression of XIAP were increased in the ischemic penumbra of group C. Conclusions: Phosphocreatine pre-administration may elicit neuroprotective effects in the brain by increasing expression of X-linked inhibitor of apoptosis protein, reducing expression of second mitochondia-derived activator of caspase, and inhibiting the apoptosis in the ischemic penumbra.

Goal of the review: to review theoretical and practical aspects of using exogenous phosphocreatine in the patients with cardio-vascular disorders in various clinical situations, given that phospho-transporting system disorders are the one of pathogenic elements responsible for reduction of cardiac pumping ability.

Ischemic heart disease is the main cause of death globally. Cardioprotection is the process whereby mechanisms that reduce myocardial damage, and activate protective factors, contribute to the preservation of the heart. Targeting these processes could be a new strategy in the treatment of post-ischemic heart failure (HF). Triiodothyronine (T3) and thyroxine (T4), which have multiple effects on the heart, prevent myocardial damage. This study describes the formulation, and characterization, of chemically modified polymeric nanoparticles incorporating T3, to target the thyroid hormone receptors. Modified T3 was conjugated to polylactide-co-glycolide (PLGA) to facilitate T3 delivery and restrict its nuclear translocation. Modified T3 and PLGA-T3 was characterized with 1H-NMR. The protective role of synthesized phosphocreatine (PCr) encapsulated PLGA-T3 nanoparticles (PLGA-T3/PCr NPs) and PLGA-T3 nanoparticles (PLGA-T3 NPs) in hypoxia-mediated cardiac cell insults was investigated. The results showed that PLGA-T3/PCr NPs represent a potentially new therapeutic agent for the control of tissue damage in cardiac ischemia and resuscitation.

There is an important unmet need to develop interventions that improve outcomes of hypoxic-ischaemic encephalopathy (HIE). Creatine has emerged as a promising neuroprotective agent. Our objective was to systematically evaluate the preclinical animal studies that used creatine for perinatal neuroprotection, and to identify knowledge gaps that need to be addressed before creatine can be considered for pragmatic clinical trials for HIE. Methods: We reviewed preclinical studies up to 20 September 2021 using PubMed, EMBASE and OVID MEDLINE databases. The SYRCLE risk of bias assessment tool was utilized. Results: Seventeen studies were identified. Dietary creatine was the most common administration route. Cerebral creatine loading was age-dependent with near term/term-equivalent studies reporting higher increases in creatine/phosphocreatine compared to adolescent-adult equivalent studies. Most studies did not control for sex, study long-term histological and functional outcomes, or test creatine post-HI. None of the perinatal studies that suggested benefit directly controlled core body temperature (a known confounder) and many did not clearly state controlling for potential study bias. Conclusion: Creatine is a promising neuroprotective intervention for HIE. However, this systematic review reveals key knowledge gaps and improvements to preclinical studies that must be addressed before creatine can be trailed for neuroprotection of the human fetus/neonate.

Creatine monohydrate (CrM) supplementation has been shown to improve body composition and muscle strength when combined with resistance training (RT); however, no study has evaluated the combination of this nutritional strategy with cluster-set resistance training (CS-RT). The purpose of this pilot study was to evaluate the effects of CrM supplementation during a high-protein diet and a CS-RT program on lower-limb fat-free mass (LL-FFM) and muscular strength. Twenty-three resistance-trained men (>2 years of training experience, 26.6 ± 8.1 years, 176.3 ± 6.8 cm, 75.6 ± 8.9 kg) participated in this study. Subjects were randomly allocated to a CS-RT+CrM (n = 8), a CS-RT (n = 8), or a control group (n = 7). The CS-RT+CrM group followed a CrM supplementation protocol with 0.1 g·kg−1·day−1 over eight weeks. Two sessions per week of lower-limb CS-RT were performed. LL-FFM corrected for fat-free adipose tissue (dual-energy X-ray absorptiometry) and muscle strength (back squat 1 repetition maximum (SQ-1RM) and countermovement jump (CMJ)) were measured pre- and post-intervention. Significant improvements were found in whole-body fat mass, fat percentage, LL-fat mass, LL-FFM, and SQ-1RM in the CS-RT+CrM and CS-RT groups; however, larger effect sizes were obtained in the CS-RT+CrM group regarding whole body FFM (0.64 versus 0.16), lower-limb FFM (0.62 versus 0.18), and SQ-1RM (1.23 versus 0.75) when compared to the CS-RT group. CMJ showed a significant improvement in the CS-RT+CrM group with no significant changes in CS-RT or control groups. No significant differences were found between groups. Eight weeks of CrM supplementation plus a high-protein diet during a CS-RT program has a higher clinical meaningfulness on lower-limb body composition and strength-related variables in trained males than CS-RT alone. Further research might study the potential health and therapeutic effects of this nutrition and exercise strategy.

Background. Age-related macular degeneration (AMD) comprises 12.5% and 22% in the structure of ocular incapacitation among persons of working and pension age, respectively. The important role in the pathogenesis of AMD belongs to ocular hemodynamics disorders. The lack of efficacy of a therapy for AMD determines the need to search for new drugs which would improve ocular hemodynamics in the disease. Purpose. To study the effect of phosphocreatine on ocular hemodynamics and the functional state of the macular area in patients with dry age-related macular degeneration. Material and Methods. Twenty-three patients (36 eyes) comprised Study group in which a complex therapy included phosphocreatine as a Neoton drug, in a dose of 1 g diluted in 50 ml of 0.9% sodium chloride, for 8 days. Twenty-five patients (39 eyes), comprising Control group, did not receive phosphocreatine in their treatment. Each patient was performed ultrasonic Doppler examination of the ophthalmic artery and a photostress test. Results. After treatment, the values of Doppler examination and photostress test were improved only in patients of Study group. Maximal and minimal blood flow velocity in the ophthalmic artery increased by 29% and 30%, respectively; vascular resistance index decreased by 14%; and photostress recovery time decreased by 33%. These indices did not change significantly in Control group patients. Conclusions. Inclusion of the phosphocreatine-containing drug in the complex therapy for the patients with dry AMD corrects ocular hemodynamics disorders, improves the functional state of the macular area and improves treatment outcomes.

Creatine is a key player in heart contraction and energy metabolism. Creatine supplementation (throughout the paper, only supplementation with creatine monohydrate will be reviewed, as this is by far the most used and best-known way of supplementing creatine) increases creatine content even in the normal heart, and it is generally safe. In heart failure, creatine and phosphocreatine decrease because of decreased expression of the creatine transporter, and because phosphocreatine degrades to prevent adenosine triphosphate (ATP) exhaustion. This causes decreased contractility reserve of the myocardium and correlates with left ventricular ejection fraction, and it is a predictor of mortality. Thus, there is a strong rationale to supplement with creatine the failing heart. Pending additional trials, creatine supplementation in heart failure may be useful given data showing its effectiveness (1) against specific parameters of heart failure, and (2) against the decrease in muscle strength and endurance of heart failure patients. In heart ischemia, the majority of trials used phosphocreatine, whose mechanism of action is mostly unrelated to changes in the ergogenic creatine-phosphocreatine system. Nevertheless, preliminary data with creatine supplementation are encouraging, and warrant additional studies. Prevention of cardiac toxicity of the chemotherapy compounds anthracyclines is a novel field where creatine supplementation may also be useful. Creatine effectiveness in this case may be because anthracyclines reduce expression of the creatine transporter, and because of the pleiotropic antioxidant properties of creatine. Moreover, creatine may also reduce concomitant muscle damage by anthracyclines.

Abstract. Physiological and biochemical changes proceeding in muscles during physical loads exert systemic influence upon protein biosynthesis. This process is accelerated in presence of free amino acids, sufficient quantities of hormones, creatine, hydrogen ions. High proton concentrations in tissues and longitudinal physical loadings upon human organism suppress the protein biosynthesis, thus leading to decomposition of hormones, immunoglobulins and cell damage. These changes may explain the development of various immunodeficiencies in sportsmen.

Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and wellness. Conventional treatments are not effective for a significant proportion of patients and interventions that are often beneficial for treatment-refractory depression are not widely available. There is, therefore, an immense need to identify novel antidepressant strategies, particularly strategies that target physiological pathways that are distinct from those addressed by conventional treatments. There is growing evidence from human neuroimaging, genetics, epidemiology, and animal studies that disruptions in brain energy production, storage, and utilization are implicated in the development and maintenance of depression. Creatine, a widely available nutritional supplement, has the potential to improve these disruptions in some patients, and early clinical trials indicate that it may have efficacy as an antidepressant agent.

In this review we analyze the recent important and remarkable advancements in studies of compartmentation of adenine nucleotides in muscle cells due to their binding to macromolecular complexes and cellular structures, which results in non-equilibrium steady state of the creatine kinase reaction. We discuss the problems of measuring the energy fluxes between different cellular compartments and their simulation by using different computer models. Energy flux determinations by 18O transfer method have shown that in heart about 80% of energy is carried out of mitochondrial intermembrane space into cytoplasm by phosphocreatine fluxes generated by mitochondrial creatine kinase from adenosine triphosphate (ATP), produced by ATP Synthasome. We have applied the mathematical model of compartmentalized energy transfer for analysis of experimental data on the dependence of oxygen consumption rate on heart workload in isolated working heart reported by Williamson et al. The analysis of these data show that even at the maximal workloads and respiration rates, equal to 174 µmol O2 per min per g dry weight, phosphocreatine flux, and not ATP, carries about 80–85% percent of energy needed out of mitochondria into the cytosol. We analyze also the reasons of failures of several computer models published in the literature to correctly describe the experimental data.

After a brief review of the literature on the effects of creatine supplementation on high-intensity intermittent exercise performance, the main aim of this study was to discuss methodological differences between studies which could explain the discrepancies observed in the literature. The effects of creatine supplementation on high-intensity intermittent exercise performance have been investigated in depth. Although the results of much research demonstrates the effi cacy of this supplement, there is just as much evidence that does not support this ergogenic effect. The explanation for this divergence appears to be multifactorial, although it is always linked to methodological characteristics. Study design (crossover or parallel groups), individual variability of muscular creatine content, chronic high meat intake, sample size, exercise protocol characteristics (body weight dependence and time between series), and gender and age all differ between studies and are potentially the variables responsible, to differing extents, for the discrepancies observed in the literature. Studies involving young males, with parallel group design, adequate statistical power, control of the incorporation of creatine into muscles, food intake assessment and intermittent exercise protocols in which performance is independent of body weight and with rest-recovery intervals of 1 to 6 minutes, usually produce positive results. The many methodological factors which can contribute to divergence on the ergogenic effects of creatine should be considered in futures studies, as well as when prescribing creatine supplementation. Resumo Após breve revisão da literatura existente acerca dos efeitos da suplementação de creatina no rendimento em atividades intermitentes de alta intensidade, o objetivo principal dessa revisão foi discutir diferenças metodológicas dos estudos que possam explicar a divergência encontrada na literatura. Os efeitos da suplementação de creatina no exercício intermitente de alta intensidade são bastante investigados. Embora existam inúmeros achados demonstrando a efi cácia desse suplemento nesse tipo de atividade, outras tantas evidências não suportam tal efeito ergogênico. A explicação para essa divergência parece ser multifatorial, porém sempre ligada às questões metodológicas. O modelo do estudo (crossover ou grupos independentes paralelos), a variabilidade individual no conteúdo muscular de creatina, o alto consumo de carnes, o tamanho da amostra, as características do protocolo de exercício (dependência do peso corporal e tempo de intervalo entre as séries), e diferenças de gênero e idade entre estudos são potenciais variáveis que explicam, em maior ou menor magnitude, a discrepância na literatura. Estudos envolvendo homens jovens, com modelo de grupos paralelos, poder estatístico satisfatório, controle da incorporação de creatina muscular, avaliação do consumo alimentar e protocolos de exercícios intermitentes máximos, cujo rendimento não depende do peso corporal, com intervalos de recuperação entre 1 a 6 minutos, tendem a apresentar resultados positivos. Os diversos fatores metodológicos que podem contribuir para a divergência acerca do tema devem ser considerados quando da realização de futuros estudos, bem como no momento da prescrição desse suplemento.

There is substantial evidence that creatine administration exerts neuroprotective effects both in vitro and in vivo. The precise mechanisms for these neuroprotective effects however are as yet unclear. We investigated whether creatine administration could exert neuroprotective effects in mice deficient in ubiquitous mitochondrial creatine kinase (UbMi-CK). UbMi-CK-deficient mice showed increased sensitivity to 1-methyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopamine depletion and loss of tyrosine hydroxylase (TH) stained neurons. Isolated mitochondria from these mice showed no alterations in calcium retention, oxygen utilization, membrane potential, or swelling in response to a calcium challenge. Creatine administration significantly increased brain concentrations of both creatine and PCr in the UbMi-CK knockout mice. Creatine administration to the UbMi-CK-deficient mice exerted significant neuroprotective effects against MPTP toxicity that were comparable in magnitude to those seen in wild-type mice. These results suggest that the neuroprotective effects of creatine are not mediated by an effect on UbMi-CK to inhibit the mitochondrial permeability transition, and are more likely to be mediated by maintenance of appropriate ATP/ADP and PCr/Cr levels.

Abstract Background Exacerbated oxidative stress is thought to be a mediator of arterial hypertension. It has been postulated that creatine (Cr) could act as an antioxidant agent preventing increased oxidative stress. The aim of this study was to investigate the effects of nine weeks of Cr or placebo supplementation on oxidative stress and cardiovascular parameters in spontaneously hypertensive rats (SHR). Findings Lipid hydroperoxidation, one important oxidative stress marker, remained unchanged in the coronary artery (Cr: 12.6 ± 1.5 vs. Pl: 12.2 ± 1.7 nmol·mg-1; p = 0.87), heart (Cr: 11.5 ± 1.8 vs. Pl: 14.6 ± 1.1 nmol·mg-1; p = 0.15), plasma (Cr: 67.7 ± 9.1 vs. Pl: 56.0 ± 3.2 nmol·mg-1; p = 0.19), plantaris (Cr: 10.0 ± 0.8 vs. Pl: 9.0 ± 0.8 nmol·mg-1; p = 0.40), and EDL muscle (Cr: 14.9 ± 1.4 vs. Pl: 17.2 ± 1.5 nmol·mg-1; p = 0.30). Additionally, Cr supplementation affected neither arterial blood pressure nor heart structure in SHR (p > 0.05). Conclusions Using a well-known experimental model of systemic arterial hypertension, this study did not confirm the possible therapeutic effects of Cr supplementation on oxidative stress and cardiovascular dysfunction associated with arterial hypertension.

Adenosine triphosphate is the present energy currency in the body, and is used in various cellular and indispensable processes for the maintenance of cell homeostasis. The regeneration mechanisms of adenosine triphosphate, from the product of its hydrolysis – adenosine diphosphate – are therefore necessary. Phosphocreatine is known as its quickest form of regeneration, by means of the enzyme creatine kinase. Thus, the primary function of this system is to act as a temporal energy buffer. Nevertheless, over the years, several other functions were attributed to phosphocreatine. This occurs as various isoforms of creatine kinase isoforms have been identified with a distinct subcellular location and functionally coupled with the sites that generate and use energy, in the mitochondria and cytosol, respectively. The present study discussed the central and complex role that the phosphocreatine system performs in energy homeostasis in muscle cells, as well as its alterations in pathological conditions.