Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation

α-lipoic acid has been found to enhance glucose uptake into skeletal muscle in animal models. Studies have also found that the co-ingestion of carbohydrate along with creatine increases muscle creatine uptake by a process related to insulin-stimulated glucose disposal. The purpose of this study was to determine the effect of α-lipoic acid on human skeletal muscle creatine uptake by directly measuring intramuscular concentrations of creatine, phosphocreatine, and ad-enosine triphosphate when creatine monohydrate was co-ingested with α-lipoic acid. Muscle biopsies were acquired from the vastus lateralis m. of 16 male subjects (18–32 y) before and after the experimental intervention. After the initial biopsy, subjects ingested 20 g · d−1 of creatine monohydrate, 20 g · d−1 of creatine monohydrate + 100 g · d−1 of sucrose, or 20 g · d−1 of creatine monohydrate + 100 g · d−1 of sucrose + 1000 mg · d−1 of α-lipoic acid for 5 days. Subjects refrained from exercise and consumed the same balanced diet for 7 days. Body weight increased by 2.1% following the nutritional intervention, with no differences between the groups. There was a significant increase in total creatine concentration following creatine supplementation, with the group ingesting α-lipoic acid showing a significantly greater increase (p < .05) in phosphocreatine (87.6 → 106.2 mmol · kg−1 dry mass [dm]) and total creatine (137.8 → 156.8 mmol · kg−1 dm). These findings indicate that co-ingestion of α-lipoic acid with creatine and a small amount of sucrose can enhance muscle total creatine content as compared to the ingestion of creatine and sucrose or creatine alone.

Download Full-text

Creatine uptake regulates CD8 T cell antitumor immunity

Journal of Experimental Medicine ◽

10.1084/jem.20182044 ◽

2019 ◽

Vol 216 (12) ◽

pp. 2869-2882 ◽

Cited By ~ 5

Author(s):

Stefano Di Biase ◽

Xiaoya Ma ◽

Xi Wang ◽

Jiaji Yu ◽

Yu-Chen Wang ◽

...

Keyword(s):

T Cell ◽

Creatine Supplementation ◽

T Cell Immunity ◽

Mouse Tumor ◽

Creatine Uptake ◽

Cell Immunity ◽

A Cell ◽

Slc6a8 Gene ◽

Cancer Immunotherapies ◽

Metabolic Regulators

T cells demand massive energy to combat cancer; however, the metabolic regulators controlling antitumor T cell immunity have just begun to be unveiled. When studying nutrient usage of tumor-infiltrating immune cells in mice, we detected a sharp increase of the expression of a CrT (Slc6a8) gene, which encodes a surface transporter controlling the uptake of creatine into a cell. Using CrT knockout mice, we showed that creatine uptake deficiency severely impaired antitumor T cell immunity. Supplementing creatine to WT mice significantly suppressed tumor growth in multiple mouse tumor models, and the combination of creatine supplementation with a PD-1/PD-L1 blockade treatment showed synergistic tumor suppression efficacy. We further demonstrated that creatine acts as a “molecular battery” conserving bioenergy to power T cell activities. Therefore, our results have identified creatine as an important metabolic regulator controlling antitumor T cell immunity, underscoring the potential of creatine supplementation to improve T cell–based cancer immunotherapies.

Download Full-text

Chronic Dialysis Patients Are Depleted of Creatine: Review and Rationale for Intradialytic Creatine Supplementation

Nutrients ◽

10.3390/nu13082709 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2709

Author(s):

Yvonne van der Veen ◽

Adrian Post ◽

Daan Kremer ◽

Christa A. Koops ◽

Erik Marsman ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Pilot Study ◽

Kidney Disease ◽

Energy Homeostasis ◽

Creatine Supplementation ◽

Daily Basis ◽

Dietary Recommendations ◽

Double Blind ◽

Creatine Uptake ◽

Related Quality

There is great need for the identification of new, potentially modifiable risk factors for the poor health-related quality of life (HRQoL) and of the excess risk of mortality in dialysis-dependent chronic kidney disease patients. Creatine is an essential contributor to cellular energy homeostasis, yet, on a daily basis, 1.6–1.7% of the total creatine pool is non-enzymatically degraded to creatinine and subsequently lost via urinary excretion, thereby necessitating a continuous supply of new creatine in order to remain in steady-state. Because of an insufficient ability to synthesize creatine, unopposed losses to the dialysis fluid, and insufficient intake due to dietary recommendations that are increasingly steered towards more plant-based diets, hemodialysis patients are prone to creatine deficiency, and may benefit from creatine supplementation. To avoid problems with compliance and fluid balance, and, furthermore, to prevent intradialytic losses of creatine to the dialysate, we aim to investigate the potential of intradialytic creatine supplementation in improving outcomes. Given the known physiological effects of creatine, intradialytic creatine supplementation may help to maintain creatine homeostasis among dialysis-dependent chronic kidney disease patients, and consequently improve muscle status, nutritional status, neurocognitive status, HRQoL. Additionally, we describe the rationale and design for a block-randomized, double-blind, placebo-controlled pilot study. The aim of the pilot study is to explore the creatine uptake in the circulation and tissues following different creatine supplementation dosages.

Download Full-text

Creatine Supplementation: A Comparison of Loading and Maintenance Protocols on Creatine Uptake by Human Skeletal Muscle

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.13.1.97 ◽

2003 ◽

Vol 13 (1) ◽

pp. 97-111 ◽

Cited By ~ 22

Author(s):

David Preen ◽

Brian Dawson ◽

Carmel Goodman ◽

John Beilby ◽

Simon Ching

Keyword(s):

Skeletal Muscle ◽

Human Skeletal Muscle ◽

Vastus Lateralis ◽

Effective Means ◽

Creatine Supplementation ◽

Whole Body ◽

Physically Active ◽

Treatment Conditions ◽

Creatine Uptake ◽

The Impact

The purposes of this investigation were first to determine the impact of 3 different creatine (Cr) loading procedures on skeletal muscle total Cr (TCr) accumulation and, second, to evaluate the effectiveness of 2 maintenance regimes on retaining intramuscular TCr stores, in the 6 weeks following a 5-day Cr loading program (20 g · day−1). Eighteen physically active male subjects were divided into 3 equal groups and administered either: (a) Cr (4 X 5 g · day−1 X 5 days), (b) Glucose+Cr (1 g · kg−1 of body mass twice per day), or (c) Cr in conjunction with 60 min of daily muscular (repeated-sprint) exercise. Following the 5-day loading period, subjects were reassigned to 3 maintenance groups and ingested either 0 g · day−1, 2 g · day−1 or 5 g · day−1 of Cr for a period of 6 weeks. Muscle biopsy samples (vastus lateralis) were taken pre- and post-loading as well as post-maintenance and analyzed for skeletal muscle ATP, phosphocreatine (PCr), Cr, and TCr concentrations. Twenty-four hour urine samples were collected for each of the loading days and last 2 maintenance days, and used to determine whole body Cr retention. Post-loading TCr stores were significantly (p < .05) increased in all treatment conditions. The Glucose+Cr condition produced a greater elevation (p < .05) in TCr concentrations (25%) than the Cr Only (16%) or Exercise+Cr (18%) groups. Following the maintenance period, muscle TCr stores were still similar to post-loading values for both the 2 g · day−1 and 5 g · day−1 conditions. Intramuscular TCr values for the 0 g · day−1 condition were significantly lower than the other conditions after the 6-week period. Although not significantly different from pre-loading concentrations, muscle TCr for the 0 g · day−1 group had not fully returned to baseline levels at 6 weeks post-loading. The data suggests that Glucose+Cr (but with a much smaller glucose intake than currently accepted) is potentially the most effective means of elevating TCr accumulation in human skeletal muscle. Furthermore, after 5 days of Cr loading, elevated muscle TCr concentrations can be maintained by the ingestion of small daily Cr doses (2-5 g) for a period of 6 weeks and that TCr concentrations may take longer than currently accepted to return to baseline values after such a Cr loading regime.

Download Full-text

Muscle creatine uptake and creatine transporter expression in response to creatine supplementation and depletion

Journal of Applied Physiology ◽

10.1152/japplphysiol.01171.2002 ◽

2003 ◽

Vol 94 (6) ◽

pp. 2173-2180 ◽

Cited By ~ 13

Author(s):

Jeffrey J. Brault ◽

Kirk A. Abraham ◽

Ronald L. Terjung

Keyword(s):

Skeletal Muscle ◽

Uptake Rate ◽

Creatine Supplementation ◽

Energy Utilization ◽

Fiber Types ◽

Sprague Dawley ◽

Creatine Uptake ◽

Sprague Dawley Rats ◽

Uptake Rates ◽

Cr Uptake

The total creatine pool size [Crtotal; creatine (Cr) + phosphocreatine (PCr)] is crucial for optimal energy utilization in skeletal muscle, especially at the onset of exercise and during intense contractions. The Crtotal likely is controlled by long-term modulation of Cr uptake via the sodium-dependent Cr transporter (CrT). To test this hypothesis, adult male Sprague-Dawley rats were fed 1% Cr, their muscle Crtotal was reduced by ∼85% [1% β-guanidinoproprionic acid (β-GPA)], or their muscle Crtotal was repleted (1% Cr after β-GPA depletion). Cr uptake was assessed by skeletal muscle 14C-Cr accumulation to Cr and PCr by using hindlimb perfusion, and CrT protein content was assessed by Western blot. Cr uptake rate decreased with dietary Cr supplementation in the white gastrocnemius (WG; 45%) only. Depletion of muscle Crtotal to ∼15% of normal increased Cr uptake in the soleus (21%) and red gastrocnemius (22%), corresponding to 70–150% increases in muscle CrT content. In contrast, the inherently lower Cr uptake rate in the WG was unchanged with depletion of muscle Crtotal even though CrT band density was increased by 230%. Thus there was no direct relationship between apparent muscle CrT abundance and Cr uptake rates. However, Cr uptake rates scaled inversely with decreases in muscle Crtotal in the high-oxidative muscle types but not in the WG. This implies that factors controlling Cr uptake are different among fiber types. These observations may help explain the influence of initial muscle Crtotal, time dependency, and variations in muscle Crtotal accumulation during Cr supplementation.

Download Full-text

TAMI-25. UPREGULATION OF CREATINE METABOLISM BY MYELOID CELLS RESULTS IN GLIOBLASTOMA PROGRESSION

Neuro-Oncology ◽

10.1093/neuonc/noab196.809 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi203-vi203

Author(s):

Aida Rashidi ◽

Alex Cordero ◽

Brandyn Castro ◽

David Hou ◽

Mark Dapash ◽

...

Keyword(s):

T Cells ◽

De Novo ◽

Myeloid Cells ◽

Creatine Supplementation ◽

Metabolic Phenotype ◽

Hypoxic Stress ◽

Creatine Uptake ◽

Creatine Metabolism

Abstract Malignant brain tumors are uniquely immunosuppressive, with a predominant infiltration of immunosuppressive tumor-associated myeloid cells (TAMCs) and a deficit in T-cells unrivaled to any other tumor. This unique tumor microenvironment (TME) promotes resistance to both conventional and immune therapies for this disease. The underlying mechanisms by which TAMCs promote glioblastoma (GBM) progression are not fully understood. We found that TAMCs specifically upregulate de-novo creatine metabolism within GBM using unbiased genetic and metabolic screening. This metabolic phenotype was confirmed in human GBM patients by comparing peripheral versus tumor-infiltrating myeloid cells. Examination of de-novo creatine generation using Carbon13 arginine flux revealed that TAMCs, but not tumor-infiltrating CD8+ T-cells, can produce creatine. Furthermore, we demonstrate that TAMCs actively secrete de-novo generated creatine into cell cultures. Examination of the single-cell microenvironment of GBM revealed that malignant cells preferentially express the creatine transporter, indicating that TAMC-derived creatine is taken up by GBM. Notably, SLC6A8 is directly upregulated in the context of hypoxia and suggests that creatine uptake is a mechanism to promote survival under hypoxic stress. Indeed, exogenous creatine supplementation promoted both the migration and survival of multiple glioblastoma cell lines in-vitro. Utilizing an established inhibitor of creatine metabolism, β-Guanidinopropionic acid (β -GPA), we found that β -GPA blocks both the migration and survival of glioma cells under hypoxic stress. Lastly, β -GPA also inhibited creatine secretion by TAMCs, showing that creatine blockade can also influence TAMC metabolic phenotype. In the future, we will examine the importance of creatine metabolism on both immune suppression and tumor progression in-vivo. This work provides novel insights into the role of creatine metabolism in GBM and identifies a unique therapeutic avenue for this devastating disease.

Download Full-text

Creatine transporter activity and content in the rat heart supplemented by and depleted of creatine

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00259.2002 ◽

2003 ◽

Vol 284 (2) ◽

pp. E399-E406 ◽

Cited By ~ 31

Author(s):

Ernest Boehm ◽

Sharon Chan ◽

Mina Monfared ◽

Theo Wallimann ◽

Kieran Clarke ◽

...

Keyword(s):

Plasma Membrane ◽

Cardiac Muscle ◽

Rat Heart ◽

Control Diet ◽

Creatine Supplementation ◽

Creatine Transporter ◽

Creatine Uptake ◽

Saturation Kinetics ◽

Creatine Transport ◽

Perfused Hearts

The intracellular creatine concentration is an important bioenergetic parameter in cardiac muscle. Although creatine uptake is known to be via a NaCl-dependent creatine transporter (CrT), its localization and regulation are poorly understood. We investigated CrT kinetics in isolated perfused hearts and, by using cardiomyocytes, measured CrT content at the plasma membrane or in total lysates. Rats were fed control diet or diet supplemented with creatine or the creatine analog β-guanidinopropionic acid (β-GPA). Creatine transport in control hearts followed saturation kinetics with a K m of 70 ± 13 mM and a V max of 3.7 ± 0.07 nmol · min−1 · g wet wt−1. Creatine supplementation significantly decreased the V max of the CrT (2.7 ± 0.17 nmol · min−1 · g wet wt−1). This was matched by an ∼35% decrease in the plasma membrane CrT; the total CrT pool was unchanged. Rats fed β-GPA exhibited a >80% decrease in tissue creatine and increase in β-GPAtotal. The V max of the CrT was increased (6.0 ± 0.25 nmol · min−1 · g wet wt−1) and the K m decreased (39.8 ± 3.0 mM). The plasma membrane CrT increased about fivefold, whereas the total CrT pool remained unchanged. We conclude that, in heart, creatine transport is determined by the content of a plasma membrane isoform of the CrT but not by the total cellular CrT pool.

Download Full-text