Creatine promotes cancer metastasis through activation of Smad2/3.

As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.

Beneficial Impact of Semicarbazide-Sensitive Amine Oxidase Inhibition on the Potential Cytotoxicity of Creatine Supplementation in Type 2 Diabetes Mellitus.

Creatine supplementation of the population with type 2 diabetes mellitus (T2DM) combined with an exercise program is known to be a possible therapy adjuvant with hypoglycemic effects. However, excessive administration of creatine leads to the production of methylamine which is deaminated by the enzyme semicarbazide-sensitive amine oxidase (SSAO) and as a result, cytotoxic compounds are produced. SSAO activity and reaction products are increased in the serum of T2DM patients. Creatine supplementation by diabetics will further augment the activity of SSAO. The current review aims to find a feasible way to ameliorate T2DM for patients who exercise and desire to consume creatine. Several natural agents present in food which are involved in the regulation of SSAO activity directly or indirectly are reviewed. Particularly, zinc-α2-glycoprotein (ZAG), zinc (Zn), copper (Cu), histamine/histidine, caffeine, iron (Fe), and vitamin D are discussed. Inhibiting SSAO activity by natural agents might reduce the potential adverse effects of creatine metabolism in population of T2DM.

Creatine supplementation impairs airway inflammation in an experimental model of asthma involving P2 × 7 receptor.

Creatine (Cr) is a substrate for adenosine triphosphate synthesis, and it is the most used dietary supplement among professional and recreative athletes and sportsmen. Creatine supplementation may increase allergic airway response, but the cellular and molecular mechanisms are unknown. We used murine model of OVA-induced chronic asthma and showed that Cr supplementation increased total proteins, ATP level, lymphocytes, macrophages, and IL-5 levels in BALF, as well as IL-5 in the supernatant of re-stimulated mediastinal lymph nodes. IL-5 and IL-13 expression by epithelial cells and by peribronchial leukocytes were increased by Cr. Cr augmented the expression of P2 × 7 receptor by peribronchial leukocytes and by epithelial cells, and increased the accumulation of eosinophils in peribronchial space and of collagen fibers in airway wall. In human cells, while Cr induced a release of ATP, IL-6, and IL-8 from BEAS-2B cells, whole blood cells, such as eosinophils, and CD4+ T cells, P2 × 7 receptor inhibitor (A740003) reduced such effects, as denoted by reduced levels of ATP, IL-6, and IL-8. Therefore, Cr supplementation worsened asthma pathology due to activation of airway epithelial cells and peribronchial leukocytes, involving purinergic signaling.

Study of renal and hepatic toxicity in rats supplemented with creatine.

PURPOSE: To evaluate the renal and hepatic function, through biochemical analysis after 14 days of creatine supplementation in physically inactive rats. METHODS: Twenty four male, adult, Wistar rats were used which were kept in individual metabolic cages and were distributed into four groups, and received the following treatments by gavage:1) CONTROL: distilled water; 2)Creatine 0.5g/Kg/day; 3) Creatine 1g/Kg/day; 4) Creatine 2g/Kg/day. Their urinary outputs as well as food and water intake were daily measured. At the end of the experiment, the animals were euthanized and serum samples were stored for biochemical analysis. RESULTS: Creatine supplementation at the doses given produced no significant changes in plasma levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin, total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, glucose, creatinine, urea, and creatinine clearance, compared to control group (p> 0.05) Similarly, water and food intake, as well as urinary output, did not show significant changes among the four groups studied. CONCLUSION: At the doses used, oral creatine supplementation did not result in renal and/or hepatic toxicity.

Study of renal and hepatic toxicity in rats supplemented with creatine

PURPOSE: To evaluate the renal and hepatic function, through biochemical analysis after 14 days of creatine supplementation in physically inactive rats. METHODS: Twenty four male, adult, Wistar rats were used which were kept in individual metabolic cages and were distributed into four groups, and received the following treatments by gavage:1) Control: distilled water; 2)Creatine 0.5g/Kg/day; 3) Creatine 1g/Kg/day; 4) Creatine 2g/Kg/day. Their urinary outputs as well as food and water intake were daily measured. At the end of the experiment, the animals were euthanized and serum samples were stored for biochemical analysis. RESULTS: Creatine supplementation at the doses given produced no significant changes in plasma levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin, total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, glucose, creatinine, urea, and creatinine clearance, compared to control group (p> 0.05) Similarly, water and food intake, as well as urinary output, did not show significant changes among the four groups studied. CONCLUSION: At the doses used, oral creatine supplementation did not result in renal and/or hepatic toxicity. .

Efeitos da suplementação oral com creatina sobre o metabolismo e a morfologia hepática em ratos / Effects of creatine oral supplementation on the hepatic metabolism and morphology of rats

A creatina é uma amina nitrogenada e tem sido utilizada principalmente por atletas e praticantes de atividade física que desejam aumentar a massa muscular e o desempenho físico. Entretanto seu uso não está somente relacionado à prática esportiva, pois inúmeros trabalhos apresentam efeitos benéficos na prática médica. Alguns estudos demonstraram que a suplementação oral com creatina resulta em aumento da sua biodisponibilidade plasmática e também de seus estoques em inúmeros órgãos. Entretanto, estudos sobre possíveis efeitos tóxicos da suplementação com creatina são escassos. Portanto, o objetivo deste trabalho foi avaliar os possíveis efeitos tóxicos da suplementação oral com creatina sobre a função e morfologia hepáticas em ratos após 14 dias de suplementação oral com creatina na dose de 0.5 g/kg/dia. A função hepática foi avaliada através de testes bioquímicos e a estrutura hepática foi avaliada através da massa hepática relativa e da análise histológica. Os resultados demonstraram que 14 dias de suplementação com creatina não alteraram a função hepática quando comparado os grupos controle e suplementado: AST (39.5 x 44.4 U/L), ALT (18.6 x 30.8 U/L), ALP (38.5 x 31.4 U/L), GGT (134.8 x 143.8 U/L), proteínas totais (5.1 x 5.5 g/dl), triglicérides (141.0 x 141.0 mg/dl), colesterol total (130.1 x 126.2 mg/dl), colesterol LDL (36.1 x 36.1 mg/dl), colesterol HDL (65.6 x 62.4 mg/dl), colesterol VLDL (25.0 x 28.0 mg/dl), e também estrutura hepática, exceto nos níveis plasmáticos de albumina (3.0 x 3.5 mg/dl - p<0.02). Nossos resultados demonstraram claramente que, ao menos na dose utilizada, a suplementação oral com creatina não induziu a nenhum tipo de efeito tóxico sobre o fígado.

Creatine is a nitrogenated amine and it has been used mainly by athletes and physical activity practitioners who wish to increase muscle mass and performance. However its use is not just related to sports practice, once several studies have shown beneficial effects on medical practice. Some studies have demonstrated that oral creatine supplementation increases its plasmatic bioavailability and also its concentration in several organs. However, studies about the possible toxic effects followed by creatine supplementation are scarce. Therefore, the aim of this work was to evaluate the hepatic structure and function in rats after 14 days of oral creatine supplementation at dose of 0.5g/kg/day. The hepatic function was evaluated through biochemical assays and the hepatic structure was analyzed through the relative hepatic mass and histological analysis. The results showed that 14 days of creatine supplementation did not alter the hepatic function and structure when compared with the control and supplemented groups, AST (39.5 x 44.4 U/L), ALT (18.6 x 30.8 U/L), ALP (38.5 x 31.4 U/L), GGT (134.8 x 143.8 U/L), total proteins (5.1 x 5.5 g/dl), triglycerides (141.0 x 141.0 mg/dl), total cholesterol (130.1 x 126.2 mg/dl), LDL cholesterol (36.1 x 36.1 mg/dl), HDL cholesterol (65.6 x 62.4 mg/dl), VLDL cholesterol (25.0 x 28.0 mg/dl), and also the hepatic structure, except for the albumin plasmatic levels (3.0 x 3.5 mg/dl - p<0.02). Our results clearly demonstrated that, at least at the used dosage, oral creatine supplementation did not induce any toxic effect on the liver.

Histological assessment of intermediate- and long-term creatine monohydrate supplementation in mice and rats.

Creatine monohydrate (CrM) supplementation appears to be relatively safe based on data from short-term and intermediate-term human studies and results from several therapeutic trials. The purpose of the current study was to characterize pathological changes after intermediate-term and long-term CrM supplementation in mice [healthy control and SOD1 (G93A) transgenic] and rats (prednisolone and nonprednisolone treated). Histological assessment (18-20 organs/tissues) was performed on G93A mice after 159 days, and in Sprague-Dawley rats after 365 days, of CrM supplementation (2% wt/wt) compared with control feed. Liver histology was also evaluated in CD-1 mice after 300 days of low-dose CrM supplementation (0.025 and 0.05 g x kg-1x day-1) and in Sprague-Dawley rats after 52 days of CrM supplementation (2% wt/wt) with and without prednisolone. Areas of hepatitis were observed in the livers of the CrM-supplemented G93A mice (P < 0.05), with no significant inflammatory lesions in any of the other 18-20 tissues/organs that were evaluated. The CD-1 mice also showed significant hepatic inflammatory lesions (P < 0.05), yet there was no negative effect of CrM on liver histology in the Sprague-Dawley rats after intermediate-term or long-term supplementation nor was inflammation seen in any other tissues/organs (P = not significant). Dietary CrM supplementation can induce inflammatory changes in the liver of mice, but not rats. The observed inflammatory changes in the murine liver must be considered in the evaluation of hepatic metabolism in CrM-supplemented mice. Species differences must be considered in the evaluation of toxicological and physiological studies.