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Cell Reports Mar 2022The factors that promote T cell expansion are not fully known. Creatine is an abundant circulating metabolite that has recently been implicated in T cell function;...
The factors that promote T cell expansion are not fully known. Creatine is an abundant circulating metabolite that has recently been implicated in T cell function; however, its cell-autonomous role in immune-cell function is unknown. Here, we show that creatine supports cell-intrinsic CD8 T cell homeostasis. We further identify creatine kinase B (CKB) as the creatine kinase isoenzyme that supports these T cell properties. Loss of the creatine transporter (Slc6a8) or Ckb results in compromised CD8 T cell expansion in response to infection without influencing adenylate energy charge. Rather, loss of Slc6a8 or Ckb disrupts naive T cell homeostasis and weakens TCR-mediated activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling required for CD8 T cell expansion. These data demonstrate a cell-intrinsic role for creatine transport and creatine transphosphorylation, independent of their effects on global cellular energy charge, in supporting CD8 T cell homeostasis and effector function.
Topics: CD8-Positive T-Lymphocytes; Creatine; Creatine Kinase; Phosphorylation; Signal Transduction
PubMed: 35235777
DOI: 10.1016/j.celrep.2022.110446 -
Nature Chemical Biology Jul 2023Creatine kinases (CKs) provide local ATP production in periods of elevated energetic demand, such as during rapid anabolism and growth. Thus, creatine energetics has...
Creatine kinases (CKs) provide local ATP production in periods of elevated energetic demand, such as during rapid anabolism and growth. Thus, creatine energetics has emerged as a major metabolic liability in many rapidly proliferating cancers. Whether CKs can be targeted therapeutically is unknown because no potent or selective CK inhibitors have been developed. Here we leverage an active site cysteine present in all CK isoforms to develop a selective covalent inhibitor of creatine phosphagen energetics, CKi. Using deep chemoproteomics, we discover that CKi selectively engages the active site cysteine of CKs in cells. A co-crystal structure of CKi with creatine kinase B indicates active site inhibition that prevents bidirectional phosphotransfer. In cells, CKi and its analogs rapidly and selectively deplete creatine phosphate, and drive toxicity selectively in CK-dependent acute myeloid leukemia. Finally, we use CKi to uncover an essential role for CKs in the regulation of proinflammatory cytokine production in macrophages.
Topics: Creatine Kinase; Creatine; Cysteine; Phosphotransferases; Protein Isoforms
PubMed: 36823351
DOI: 10.1038/s41589-023-01273-x -
Amino Acids May 2011The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr).... (Review)
Review
The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluctuations. These studies include tissue-specific expression and subcellular localization of CK isoforms, high-resolution molecular structures and structure-function relationships, transgenic CK abrogation and reverse genetic approaches. Three energy-related physiological principles emerge, namely that the CK/PCr systems functions as (a) an immediately available temporal energy buffer, (b) a spatial energy buffer or intracellular energy transport system (the CK/PCr energy shuttle or circuit) and (c) a metabolic regulator. The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases). Thus, diffusion limitations of ADP and ATP are overcome by PCr/Cr shuttling, as most clearly seen in polar cells such as spermatozoa, retina photoreceptor cells and sensory hair bundles of the inner ear. The CK/PCr system relies on the close exchange of substrates and products between CK isoforms and ATP-generating or -consuming processes. Mitochondrial CK in the mitochondrial outer compartment, for example, is tightly coupled to ATP export via adenine nucleotide transporter or carrier (ANT) and thus ATP-synthesis and respiratory chain activity, releasing PCr into the cytosol. This coupling also reduces formation of reactive oxygen species (ROS) and inhibits mitochondrial permeability transition, an early event in apoptosis. Cr itself may also act as a direct and/or indirect anti-oxidant, while PCr can interact with and protect cellular membranes. Collectively, these factors may well explain the beneficial effects of Cr supplementation. The stimulating effects of Cr for muscle and bone growth and maintenance, and especially in neuroprotection, are now recognized and the first clinical studies are underway. Novel socio-economically relevant applications of Cr supplementation are emerging, e.g. for senior people, intensive care units and dialysis patients, who are notoriously Cr-depleted. Also, Cr will likely be beneficial for the healthy development of premature infants, who after separation from the placenta depend on external Cr. Cr supplementation of pregnant and lactating women, as well as of babies and infants are likely to be of benefit for child development. Last but not least, Cr harbours a global ecological potential as an additive for animal feed, replacing meat- and fish meal for animal (poultry and swine) and fish aqua farming. This may help to alleviate human starvation and at the same time prevent over-fishing of oceans.
Topics: Animals; Creatine; Creatine Kinase; Humans; Phosphocreatine
PubMed: 21448658
DOI: 10.1007/s00726-011-0877-3 -
Respiratory Research Jul 2021Hypoxia is a prominent feature of solid cancer. This research aims to expose the role of mitochondrial creatine kinase 1 (CKMT1) in non-small cell lung cancer (NSCLC)...
BACKGROUND
Hypoxia is a prominent feature of solid cancer. This research aims to expose the role of mitochondrial creatine kinase 1 (CKMT1) in non-small cell lung cancer (NSCLC) progression and hypoxia adaptation.
METHODS
The mRNA and protein expression of CKMT1 in NSCLC tissues were detected by using GEPIA web, immunohistochemistry and qRT-PCR. For hypoxia, cells were exposed to the 1% O atmosphere. The protein levels of HIF-1α and CKMT1 in H1650 and H1299 cells exposed to hypoxia were determined by western blot. The roles of CKMT1 on the proliferation, invasion and hypoxia adaptation of NSCLC cells were measured by CCK8, colony formation and transwell assays. Luciferase activity assay and HIF1 specific inhibitor (LW6) assay indicated the related function of hypoxia and CKMT1.
RESULTS
CKMT1 was highly expressed in NSCLC tissues, and the high level of CKMT1 was significantly correlated with the high pathological grade of NSCLC. Knockdown of CKMT1 inhibited the cell proliferation and invasion of H1650 and H1299 cells, which could be rescued by hypoxia. Hypoxia induced the accumulation of HIF-1α and the expression of CKMT1 in H1650 and H1299 cells. Furthermore, HIF-1 as a transcription factor of CKMT1, could up-regulated the expression of CKMT1 under hypoxia.
CONCLUSIONS
In summary, CKMT1 has the potential as a target for NSCLC hypoxic targeted therapy.
Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Hypoxia; Cell Line, Tumor; Creatine Kinase; Disease Progression; Gene Knockdown Techniques; Humans; Lung Neoplasms
PubMed: 34210337
DOI: 10.1186/s12931-021-01765-1 -
International Journal of Molecular... Jul 2023Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with limited therapeutic options. There is an urgent need for novel biomarkers to be... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease with limited therapeutic options. There is an urgent need for novel biomarkers to be used as surrogates for new therapeutic trials and disease monitoring. In this study, we sought to systematically study creatine kinase isoenzyme MB (CK-MB) in a real-world cohort of ALS patients, assess the diagnostic performance, and evaluate its association with other laboratory and clinical parameters. We reviewed data from 194 consecutive patients that included 130 ALS patients and 64 disease control patients (primary lateral sclerosis [PLS], benign fasciculations syndrome [BFS], Huntington's disease [HD] and Alzheimer's disease [AD]). CK-MB was elevated in the sera of more than half of all patients with ALS. In patients with spinal-onset ALS, CK-MB levels were significantly higher than in patients with other neurodegenerative diseases. Patients with slower rates of functional decline had a significantly higher baseline CK-MB. Furthermore, CK-MB elevations correlated with cardiac troponin T (cTnT) and with revised ALS Functional Rating Scale (ALSFRS-R) bulbar subcategory. We posit that measuring CK-MB in ALS patients in a complimentary fashion could potentially aid in the diagnostic workup of ALS and help discriminate the disease from some ALS mimics and other neurodegenerative diseases. CK-MB levels also may provide valuable prognostic information regarding disease aggressiveness as well as correlations with specific phenotypic presentations.
Topics: Humans; Amyotrophic Lateral Sclerosis; Isoenzymes; Neurodegenerative Diseases; Creatine Kinase, MB Form; Creatine Kinase; Biomarkers
PubMed: 37511443
DOI: 10.3390/ijms241411682 -
Biochimica Et Biophysica Acta Feb 2006Mitochondrial creatine kinase (MtCK), together with cytosolic creatine kinase isoenzymes and the highly diffusible CK reaction product, phosphocreatine, provide a... (Review)
Review
Mitochondrial creatine kinase (MtCK), together with cytosolic creatine kinase isoenzymes and the highly diffusible CK reaction product, phosphocreatine, provide a temporal and spatial energy buffer to maintain cellular energy homeostasis. Mitochondrial proteolipid complexes containing MtCK form microcompartments that are involved in channeling energy in form of phosphocreatine rather than ATP into the cytosol. Under situations of compromised cellular energy state, which are often linked to ischemia, oxidative stress and calcium overload, two characteristics of mitochondrial creatine kinase are particularly relevant: its exquisite susceptibility to oxidative modifications and the compensatory up-regulation of its gene expression, in some cases leading to accumulation of crystalline MtCK inclusion bodies in mitochondria that are the clinical hallmarks for mitochondrial cytopathies. Both of these events may either impair or reinforce, respectively, the functions of mitochondrial MtCK complexes in cellular energy supply and protection of mitochondria form the so-called permeability transition leading to apoptosis or necrosis.
Topics: Animals; Creatine Kinase; Disease; Gene Expression Regulation, Enzymologic; Health; Humans; Mitochondria; Up-Regulation
PubMed: 16236486
DOI: 10.1016/j.bbadis.2005.09.004 -
Clinical Drug Investigation Nov 2022The Low-Dose Colchicine-2 (LoDoCo2) trial showed that 2-4 years exposure to colchicine 0.5 mg once daily reduced the risk of cardiovascular events in patients with... (Clinical Trial)
Clinical Trial
The Effect of Years-Long Exposure to Low-Dose Colchicine on Renal and Liver Function and Blood Creatine Kinase Levels: Safety Insights from the Low-Dose Colchicine 2 (LoDoCo2) Trial.
BACKGROUND AND OBJECTIVE
The Low-Dose Colchicine-2 (LoDoCo2) trial showed that 2-4 years exposure to colchicine 0.5 mg once daily reduced the risk of cardiovascular events in patients with chronic coronary artery disease. The potential effect of years-long exposure to colchicine on renal or liver function and creatine kinase (CK) has not been systematically evaluated and was investigated in this LoDoCo2 substudy.
METHODS
Blood samples drawn from 1776 participants at the close-out visit of the LoDoCo2 trial were used to measure markers of renal function (creatinine, blood urea nitrogen [BUN]), liver function (alanine aminotransferase [ALT], γ-glutamyl transferase [GGT], bilirubin and albumin), and CK. Renal and liver function as well as hyperCKemia (elevated CK) were categorized to the degree of elevation biomarkers as mild, mild/moderate, moderate/severe, and marked elevations.
RESULTS
In total, 1776 participants (mean age 66.5 years, 72% male) contributed to this analysis, with a median exposure to trial medication of 32.7 months. Compared with placebo, colchicine was not associated with changes in creatinine and BUN but was associated with elevations in ALT (30 U/L vs. 26 U/L; p < 0.01) and CK (123 U/L vs. 110 U/L; p < 0.01). Most elevations in ALT and CK were mild in both treatment groups. There were no moderate to marked ALT elevations (> 5-10 × upper limit of normal [ULN]) in both treatment groups, and 6 (0.7%) colchicine-treated vs. 2 (0.2%) placebo-treated participants had moderate to marked CK elevations (> 5-10 × ULN).
CONCLUSION
In chronic coronary artery disease, 2-4 years of exposure to colchicine 0.5 mg once daily was associated with small elevations in ALT and CK, but was not associated with changes in renal function.
TRIAL REGISTRATION
https://www.anzctr.org.au ; ACTRN12614000093684, 24 January 2014.
Topics: Aged; Female; Humans; Male; Biomarkers; Colchicine; Coronary Artery Disease; Creatine Kinase; Creatinine; Kidney; Liver
PubMed: 36208364
DOI: 10.1007/s40261-022-01209-8 -
Function (Oxford, England) 2022Within brown adipose tissue (BAT), the brain isoform of creatine kinase (CKB) has been proposed to regulate the regeneration of ADP and phosphocreatine in a futile...
Within brown adipose tissue (BAT), the brain isoform of creatine kinase (CKB) has been proposed to regulate the regeneration of ADP and phosphocreatine in a futile creatine cycle (FCC) that stimulates energy expenditure. However, the presence of FCC, and the specific creatine kinase isoforms regulating this theoretical model within white adipose tissue (WAT), remains to be fully elucidated. In the present study, creatine did not stimulate respiration in cultured adipocytes, isolated mitochondria or mouse permeabilized WAT. Additionally, while creatine kinase ubiquitous-type, mitochondrial (CKMT1) mRNA and protein were detected in human WAT, shRNA-mediated reductions in did not decrease submaximal respiration in cultured adipocytes, and ablation of CKMT1 in mice did not alter energy expenditure, mitochondrial responses to pharmacological β-adrenergic activation (CL 316, 243) or exacerbate the detrimental metabolic effects of consuming a high-fat diet. Taken together, these findings solidify CKMT1 as dispensable in the regulation of energy expenditure, and unlike in BAT, they do not support the presence of FCC within WAT.
Topics: Animals; Humans; Mice; Adipose Tissue, Beige; Adipose Tissue, White; Creatine; Creatine Kinase; Energy Metabolism; Mitochondria
PubMed: 37954502
DOI: 10.1093/function/zqac037 -
European Journal of Sport Science Oct 2018Physiological or performance tests are routinely utilised to assess athletes' recovery. At present, the ideal tool to assess recovery remains unknown. Therefore, the aim... (Meta-Analysis)
Meta-Analysis Review
Physiological or performance tests are routinely utilised to assess athletes' recovery. At present, the ideal tool to assess recovery remains unknown. Therefore, the aim of this systematic review was to examine the change in creatine kinase (CK) and neuromuscular function as measured via a countermovement jump (CMJ) following a match in the contact codes of football. A comprehensive search of databases was undertaken with RevMan (V 5.3) used for statistical analysis. Our results demonstrated that CK pre- versus post-match (standardised mean difference (SMD) = 0.90, 95% CI = 0.50 to 1.31, p < .0001), CK pre- versus 24 h post-match (SMD = 1.50, 95% CI = 1.12 to 1.88, p < .00001), and CK pre- versus 48 h post-match all increased significantly (SMD = 0.90, 95% CI = 0.50 to 1.31, p < .0001), while CMJ peak power (PP) pre- versus post-match (SMD = -0.59, 95% CI = -1.12 to -0.06, p = .03), and pre- versus 24 h post-match (SMD = -0.80, 95% CI = -1.31 to -0.28, p = .002) decreased significantly. There was a significant relationship between the change in CK and the change in CMJ PP from immediately pre to immediately post (r = -0.924, p = .025), and between CMJ immediately following a match and 24 h CK change (r = -0.983, p = .017). In conclusion, CK levels increase and performance in the CMJ decreases following a match of a contact code of football. The identification of this relationship may allow coaching staff to implement a standalone measure of recovery.
Topics: Athletes; Athletic Performance; Creatine Kinase; Football; Humans; Muscle Fatigue
PubMed: 29870313
DOI: 10.1080/17461391.2018.1480661 -
Biochemistry. Biokhimiia Oct 2001This review describes properties of mitochondrial creatine kinase from heart and skeletal muscle studied in the author's group at the Department of Biochemistry of... (Review)
Review
This review describes properties of mitochondrial creatine kinase from heart and skeletal muscle studied in the author's group at the Department of Biochemistry of Moscow State University. The results are compared to the data in the literature. The author's point of view on the physiological role of mitochondrial creatine kinase is presented.
Topics: Animals; Cattle; Creatine Kinase; Creatine Kinase, Mitochondrial Form; Hydrogen-Ion Concentration; Intracellular Membranes; Isoelectric Point; Isoenzymes; Kinetics; Membrane Proteins; Mitochondria; Muscle, Skeletal; Myocardium; Protein Structure, Quaternary; Substrate Specificity
PubMed: 11736631
DOI: 10.1023/a:1012428812780