-
Nutrients Mar 2021Despite extensive research on creatine, evidence for use among females is understudied. Creatine characteristics vary between males and females, with females exhibiting... (Review)
Review
Despite extensive research on creatine, evidence for use among females is understudied. Creatine characteristics vary between males and females, with females exhibiting 70-80% lower endogenous creatine stores compared to males. Understanding creatine metabolism pre- and post-menopause yields important implications for creatine supplementation for performance and health among females. Due to the hormone-related changes to creatine kinetics and phosphocreatine resynthesis, supplementation may be particularly important during menses, pregnancy, post-partum, during and post-menopause. Creatine supplementation among pre-menopausal females appears to be effective for improving strength and exercise performance. Post-menopausal females may also experience benefits in skeletal muscle size and function when consuming high doses of creatine (0.3 g·kg·d); and favorable effects on bone when combined with resistance training. Pre-clinical and clinical evidence indicates positive effects from creatine supplementation on mood and cognition, possibly by restoring brain energy levels and homeostasis. Creatine supplementation may be even more effective for females by supporting a pro-energetic environment in the brain. The purpose of this review was to highlight the use of creatine in females across the lifespan with particular emphasis on performance, body composition, mood, and dosing strategies.
Topics: Adult; Affect; Aged; Body Composition; Brain; Creatine; Dietary Supplements; Exercise; Female; Humans; Longevity; Menopause; Middle Aged; Muscle, Skeletal; Phosphocreatine; Resistance Training; Women's Health
PubMed: 33800439
DOI: 10.3390/nu13030877 -
Biomolecules Aug 2019Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and... (Review)
Review
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.
Topics: Animals; Bipolar Disorder; Brain; Clinical Studies as Topic; Creatine; Depressive Disorder, Major; Energy Metabolism; Humans; Nutritional Support; Phosphocreatine
PubMed: 31450809
DOI: 10.3390/biom9090406 -
Journal of the International Society of... 2018Beetroot juice contains high levels of inorganic nitrate (NO) and its intake has proved effective at increasing blood nitric oxide (NO) concentrations. Given the effects... (Review)
Review
Beetroot juice contains high levels of inorganic nitrate (NO) and its intake has proved effective at increasing blood nitric oxide (NO) concentrations. Given the effects of NO in promoting vasodilation and blood flow with beneficial impacts on muscle contraction, several studies have detected an ergogenic effect of beetroot juice supplementation on exercise efforts with high oxidative energy metabolism demands. However, only a scarce yet growing number of investigations have sought to assess the effects of this supplement on performance at high-intensity exercise. Here we review the few studies that have addressed this issue. The databases Dialnet, Elsevier, Medline, Pubmed and Web of Science were searched for articles in English, Portuguese and Spanish published from 2010 to March 31 to 2017 using the keywords: beet or beetroot or nitrate or nitrite and supplement or supplementation or nutrition or "sport nutrition" and exercise or sport or "physical activity" or effort or athlete. Nine articles fulfilling the inclusion criteria were identified. Results indicate that beetroot juice given as a single dose or over a few days may improve performance at intermittent, high-intensity efforts with short rest periods. The improvements observed were attributed to faster phosphocreatine resynthesis which could delay its depletion during repetitive exercise efforts. In addition, beetroot juice supplementation could improve muscle power output via a mechanism involving a faster muscle shortening velocity. The findings of some studies also suggested improved indicators of muscular fatigue, though the mechanism involved in this effect remains unclear.
Topics: Athletic Performance; Beta vulgaris; Dietary Supplements; Energy Metabolism; Fruit and Vegetable Juices; High-Intensity Interval Training; Humans; Nitrates; Nitrites; Phosphocreatine; Sports Nutritional Physiological Phenomena
PubMed: 29311764
DOI: 10.1186/s12970-017-0204-9 -
Heart Failure Reviews Sep 2022Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several... (Review)
Review
Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine supplementation have been investigated in experimental and clinical models, showing controversial findings. The goal of this article is to provide a comprehensive overview on the role of creatine in cardiac energy metabolism, the assessment and clinical value of creatine deficiency in heart failure, and the possible options for the specific metabolic therapy.
Topics: Adenosine Triphosphate; Creatine; Energy Metabolism; Heart Failure; Humans; Mitochondria, Heart; Myocardium; Phosphocreatine
PubMed: 34618287
DOI: 10.1007/s10741-021-10173-y -
Frontiers in Bioscience (Scholar... Jan 2011Magnetic resonance spectroscopy (MRS) is an established technique for the non-invasive assessment of myocardial metabolism. MRS is ideal for the evaluation of heart... (Review)
Review
Magnetic resonance spectroscopy (MRS) is an established technique for the non-invasive assessment of myocardial metabolism. MRS is ideal for the evaluation of heart failure, as it allows quantification of the primary energy source for all myocardial cellular functions (ATP), the energy reserve phosphocreatine (PCr), and the creatine kinase reaction, which maintains cellular energy equilibrium. PCr forms the primary ATP buffer in the cell via the creatine kinase (CK) reaction and is involved in transporting the chemical energy from the ATP-producing mitochondria to the ATP-consuming contractile proteins. Using 31phosphorus (31P) MRS, a low cardiac PCr/ATP has consistently been found in patients with heart failure, supporting the hypothesis that the failing heart is energy starved. The use of 1H MRS has allowed the detection of total creatine, which when combined with 31P MRS, provides an in depth examination of the creatine kinase reaction. MRS signals from 31P, 1H, 23Na and 13C, including novel hyperpolarization techniques, have provided considerable insight into the understanding of energy metabolism in the healthy and diseased heart.
Topics: Creatine Kinase; Energy Metabolism; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus Isotopes; Protons; Rubidium Radioisotopes; Sodium Isotopes
PubMed: 21196379
DOI: 10.2741/s154 -
Journal of Magnetic Resonance (San... Apr 2020Creatine is an important metabolite involved in muscle contraction. Administration of exogenous creatine (Cr) or phosphocreatine (PCr) has been used for improving...
Creatine is an important metabolite involved in muscle contraction. Administration of exogenous creatine (Cr) or phosphocreatine (PCr) has been used for improving exercise performance and protecting the heart during surgery including during valve replacements, coronary artery bypass grafting and repair of congenital heart defects. In this work we investigate whether it is possible to use chemical exchange saturation transfer (CEST) MRI to monitor uptake and clearance of exogenous creatine and phosphocreatine following supplementation. We were furthermore interested in determining the limiting conditions for distinguishing between creatine (1.9 ppm) and phosphocreatine (2.6 ppm) signals at ultra-high fields (21 T) and determine their concentrations could be reliably obtained using Bloch equation fits of the experimental CEST spectra. We have tested these items by performing CEST MRI of hind limb muscle and kidneys at 11.7 T and 21.1 T both before and after intravenous administration of PCr. We observed up to 4% increase in contrast in the kidneys at 2.6 ppm which peaked ~30 min after administration and a relative ratio of 1.3 in PCr:Cr signal. Overall, these results demonstrate the feasibility of independent monitoring of PCr and Cr concentration changes using CEST MRI.
Topics: Animals; Creatine; Hindlimb; Humans; Image Processing, Computer-Assisted; Kidney; Magnetic Resonance Imaging; Mice; Muscle, Skeletal; Phantoms, Imaging; Phosphocreatine
PubMed: 32179431
DOI: 10.1016/j.jmr.2020.106703 -
Biomedicine & Pharmacotherapy =... Sep 2021If mitochondrial energy availability or oxidative metabolism is altered, patients will suffer from insufficient energy supply Phosphocreatine (PCr) not only acts as an... (Review)
Review
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.
Topics: Animals; Cell Survival; Energy Metabolism; Humans; Oxidative Stress; Phosphocreatine; Signal Transduction
PubMed: 34174505
DOI: 10.1016/j.biopha.2021.111839 -
Brain : a Journal of Neurology Jan 2024The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically...
The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects. Sixty participants (35 patients with Parkinson's disease and 25 healthy controls) underwent 31P-MRS for quantification of energy-rich metabolites [ATP, inorganic phosphate (Pi) and phosphocreatine] in putamen and midbrain. In parallel, skin biopsies were obtained from all research participants to establish fibroblast cell lines for subsequent quantification of total intracellular ATP and mitochondrial membrane potential (MMP) as well as mitochondrial and lysosomal morphology, using high content live cell imaging. Lower MMP correlated with higher intracellular ATP (r = -0.55, P = 0.0016), higher mitochondrial counts (r = -0.72, P < 0.0001) and higher lysosomal counts (r = -0.62, P = 0.0002) in Parkinson's disease patient-derived fibroblasts only, consistent with impaired mitophagy and mitochondrial uncoupling. 31P-MRS-derived posterior putaminal Pi/ATP ratio variance was considerably greater in Parkinson's disease than in healthy controls (F-tests, P = 0.0036). Furthermore, elevated 31P-MRS-derived putaminal, but not midbrain Pi/ATP ratios (indicative of impaired oxidative phosphorylation) correlated with both greater mitochondrial (r = 0.37, P = 0.0319) and lysosomal counts (r = 0.48, P = 0.0044) as well as lower MMP in both short (r = -0.52, P = 0.0016) and long (r = -0.47, P = 0.0052) mitochondria in Parkinson's disease. Higher 31P-MRS midbrain phosphocreatine correlated with greater risk of rapid disease progression (r = 0.47, P = 0.0384). Our data suggest that impaired oxidative phosphorylation in the striatal dopaminergic nerve terminals exceeds mitochondrial dysfunction in the midbrain of patients with early Parkinson's disease. Our data further support the hypothesis of a prominent link between impaired mitophagy and impaired striatal energy homeostasis as a key event in early Parkinson's disease.
Topics: Humans; Parkinson Disease; Phosphocreatine; Mitochondria; Corpus Striatum; Adenosine Triphosphate
PubMed: 38059801
DOI: 10.1093/brain/awad364 -
Methods in Molecular Biology (Clifton,... 2022Thermogenic adipose tissue plays a vital function in regulating whole-body energy expenditure and nutrient homeostasis due to its capacity to dissipate chemical energy...
Thermogenic adipose tissue plays a vital function in regulating whole-body energy expenditure and nutrient homeostasis due to its capacity to dissipate chemical energy as heat, in a process called non-shivering thermogenesis. A reduction of creatine levels in adipocytes impairs thermogenic capacity and promotes diet-induced obesityKazak et al, Cell 163, 643-55, 2015; Kazak et al, Cell Metab 26, 660-671.e3, 2017; Kazak et al, Nat Metab 1, 360-370, 2019). Mechanistically, thermogenic respiration can be promoted by the liberation of an excess quantity of ADP that is dependent on addition of creatine. A model of a two-enzyme system, which we term the Futile Creatine Cycle, has been posited to support this thermogenic action of creatine. Futile creatine cycling can be monitored in purified mitochondrial preparations wherein creatine-dependent liberation of ADP is monitored through the measurement of oxygen consumption under ADP-limiting conditions. The current model proposes that, in thermogenic fat cells, mitochondria-targeted creatine kinase B (CKB) uses mitochondrial-derived ATP to phosphorylate creatine (Rahbani JF, Nature 590, 480-485, 2021). The creatine kinase reaction generates phosphocreatine and ADP, and ADP stimulates respiration. Next, a pool of mitochondrial phosphocreatine is directly hydrolyzed by a phosphatase, to regenerate creatine. The liberated creatine can then engage mitochondrial CKB to trigger another round of this cycle to support ADP-dependent respiration. In this model, the coordinated action of creatine phosphorylation and phosphocreatine hydrolysis triggers a futile cycle that produces a molar excess of mitochondrial ADP to promote thermogenic respiration (Rahbani JF, Nature 590, 480-485, 2021; Kazak and Cohen, Nat Rev Endocrinol 16, 421-436, 2020). Here, we provide a detailed method to perform respiratory measurements on isolated mitochondria and calculate the stoichiometry of creatine-dependent ADP liberation. This method provides a direct measure of the futile creatine cycle.
Topics: Creatine; Energy Metabolism; Phosphocreatine; Substrate Cycling; Thermogenesis
PubMed: 35167096
DOI: 10.1007/978-1-0716-2087-8_10 -
NMR in Biomedicine Jun 2023Chemical exchange saturation transfer (CEST) MRI has become a promising technique to assay target proteins and metabolites through their exchangeable protons,... (Review)
Review
Chemical exchange saturation transfer (CEST) MRI has become a promising technique to assay target proteins and metabolites through their exchangeable protons, noninvasively. The ubiquity of creatine (Cr) and phosphocreatine (PCr) due to their pivotal roles in energy homeostasis through the creatine phosphate pathway has made them prime targets for CEST in the diagnosis and monitoring of disease pathologies, particularly in tissues heavily dependent on the maintenance of rich energy reserves. Guanidinium CEST from protein arginine residues (i.e. arginine CEST) can also provide information about the protein profile in tissue. However, numerous obfuscating factors stand as obstacles to the specificity of arginine, Cr, and PCr imaging through CEST, such as semisolid magnetization transfer, fast chemical exchanges such as primary amines, and the effects of nuclear Overhauser enhancement from aromatic and amide protons. In this review, the specific exchange properties of protein arginine residues, Cr, and PCr, along with their validation, are discussed, including the considerations necessary to target and tune their signal effects through CEST imaging. Additionally, strategies that have been employed to enhance the specificity of these exchanges in CEST imaging are described, along with how they have opened up possible applications of protein arginine residues, Cr and PCr CEST imaging in the study and diagnosis of pathology. A clear understanding of the capabilities and caveats of using CEST to image these vital metabolites and mitigation strategies is crucial to expanding the possibilities of this promising technology.
Topics: Creatine; Phosphocreatine; Protons; Arginine; Magnetic Resonance Imaging
PubMed: 34978371
DOI: 10.1002/nbm.4671