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Aims: This work investigated the effects of creatine supplementation on different pathways related to the pathogenesis of non-alcoholic fatty liver disease and alcoholic liver disease., Main Methods: To induce alcoholic liver disease, male Swiss mice were divided into three groups: control, ethanol and ethanol supplemented with creatine. To induce non-alcoholic fatty liver disease, mice were divided into three groups: control, high-fat diet and high-fat diet supplemented with creatine. Each group consisted of eight animals. In both cases, creatine monohydrate was added to the diets (1 %; weight/vol)., Key Findings: Creatine supplementation prevented high-fat diet-induced non-alcoholic fatty liver disease progression, demonstrated by attenuated liver fat accumulation and liver damage. On the other hand, when combined with ethanol, creatine supplementation up-regulated key genes related to ethanol metabolism, oxidative stress, inflammation and lipid synthesis, and exacerbated ethanol-induced liver steatosis and damage, demonstrated by increased liver fat accumulation and histopathological score, as well as elevated oxidative damage markers and inflammatory mediators., Significance: Our results clearly demonstrated creatine supplementation exerts different outcomes in relation to non-alcoholic fatty liver disease and alcoholic liver disease, namely it protects against high-fat diet-induced non-alcoholic fatty liver disease but exacerbates ethanol-induced alcoholic liver disease. The exacerbating effects of the creatine and ethanol combination appear to be related to oxidative stress and inflammation-mediated up-regulation of ethanol metabolism., Competing Interests: Declaration of competing interest None of the authors have a potential conflict of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: This study aimed to investigate if titanium dioxide (TiO 2 ) joint administration is a useful pre-clinical model to study sarcopenia-related chronic arthritis, and if exercise is a useful therapeutic approach against the pathogenesis of TiO 2 -induced arthritis and sarcopenia in mice., Main Methods: Two experiments were conducted. Firstly, 36 female Swiss mice were randomly divided into a control group (n = 12) and two groups who received intra-articular TiO 2 injections of 0.3-mg (n = 12) and 3-mg (n = 12), respectively. Mice were euthanized 4 and 8 weeks after TiO 2 injections. Based on data of the first experiment, mice were exposed to four groups: control (C, n = 10), exercised (Ex, n = 10), injected with 3-mg of TiO 2 (TiO 2 , n = 10), and injected with 3-mg of TiO 2 and exercised (TiO 2  + Ex, n = 10) for a total of 8-weeks., Key Findings: Eight-week of 3 mg of TiO 2 joint administration promoted characteristics of chronic inflammation such as elevated histopathological score, inflammation, edema and pain. Hallmarks of sarcopenia were also observed such as muscle atrophy and loss of strength. Furthermore, voluntary exercise running reduced TiO 2 -induced chronic inflammation and pain, attenuating chronic arthritis-related muscle atrophy, strength loss and impairment of locomotion capacity. In addition, exercise was also able to prevent TiO 2 -induced collagen degradation, an important marker of functional and structural integrity loss of cartilage and chronic arthritis disease progression., Significance: TiO 2 joint administration mimed titanium prosthesis release-induced joint chronic arthritis and sarcopenia-related chronic arthritis, disturbances that were attenuated by voluntary exercise., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to determine the role of mammalian target of rapamycin (mTORC1) activation and catabolic markers in resistance training's (RT) antiatrophy effect during cachexia-induced muscle loss., Methods: Myofiber atrophy was induced by injecting Walker 256 tumor cells into rats exposed or not exposed to the RT protocol of ladder climbing. The role of RT-induced anabolic stimulation was investigated in tumor-bearing rats with the mTORC1 inhibitor rapamycin, and cross-sectional areas of skeletal muscle were evaluated to identify atrophy or hypertrophy. Components of the mTORC1 and ubiquitin-proteasome pathways were assessed by real-time polymerase chain reaction or immunoblotting., Results: Although RT prevented myofiber atrophy and impaired the strength of tumor-bearing rats, in healthy rats, it promoted activated mTORC1, as demonstrated by p70S6K's increased phosphorylation and myofiber's enlarged cross-sectional area. However, RT promoted no changes in the ratio of p70S6K to phospho-p70S6K protein expression while prevented myofiber atrophy in tumor-bearing rats. Beyond that, treatment with rapamycin did not preclude RT's preventive effect on myofiber atrophy in tumor-bearing rats. Thus, RT's ability to prevent cancer-induced myofiber atrophy seems to be independent of mTORC1's and p70S6K's activation. Indeed, RT's preventive effect on cancer-induced myofiber atrophy was associated with its capacity to attenuate elevated tumor necrosis factor α and interleukin 6 as well as to prevent oxidative damage in muscles and an elevated abundance of atrogin-1., Conclusions: By inducing attenuated myofiber atrophy independent of mTORC1's signaling activation, RT prevents muscle atrophy during cancer by reducing inflammation, oxidative damage, and atrogin-1 expression., (Copyright © 2021 by the American College of Sports Medicine.)

Objectives: This study aimed to analyze the effect of creatine (Cr) supplementation on tumor microenvironment, evaluating the parameters of tumor aggressiveness., Methods: Sixteen male Wistar rats were randomly assigned to 2 groups (n = 8/group): Tumor-bearing (T) and tumor-bearing supplemented with Cr (TCr). Cr supplementation was provided in drinking water for a total of 21 d. After 11 d of Cr supplementation (TCr group) or water (T group), Walker-256 tumor cells were inoculated subcutaneously in the right flank of all rats, which kept receiving Cr supplementation (TCr group) or water (T group) for 10 more days. The total period of the experiment was 21 d., Results: Tumor weight corresponded with approximately 3.5% ± 0.9% of animal body weight in the T group. Cr supplementation did not accelerate tumor growth or increase tumor size. The histopathological analysis demonstrated the presence of nuclear pleomorphisms and atypical nuclei, with the presence of low-differentiated tumor cells, in both groups. Cr supplementation did not alter apoptosis and cell proliferation markers, nor tumor capsule thickness and viable tumor area., Conclusions: Cr supplementation in Walker-256 tumor-bearing rats did not induce significant changes in tumor development, and did not interfere with the parameters of tumor aggressiveness, such as the level of cell differentiation and proliferation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate the effects of creatine supplementation on muscle wasting in Walker-256 tumor-bearing rats., Methods: Wistar rats were randomly assigned into three groups (n = 10/group): control (C), tumor bearing (T), and tumor bearing supplemented with creatine (TCr). Creatine was provided in drinking water for a total of 21 days. After 11 days of supplementation, tumor cells were implanted subcutaneously into T and TCr groups. The animals' weight, food and water intake were evaluated along the experimental protocol. After 10 days of tumor implantation (21 total), animals were euthanized for inflammatory state and skeletal muscle cross-sectional area measurements. Skeletal muscle components of ubiquitin-proteasome pathways were also evaluated using real-time PCR and immunoblotting., Results: The results showed that creatine supplementation protected tumor-bearing rats against body weight loss and skeletal muscle atrophy. Creatine intake promoted lower levels of plasma TNF-α and IL-6 and smaller spleen morphology changes such as reduced size of white pulp and lymphoid follicle compared to tumor-bearing rats. In addition, creatine prevented increased levels of skeletal muscle Atrogin-1 and MuRF-1, key regulators of muscle atrophy., Conclusion: Creatine supplementation prevents skeletal muscle atrophy by attenuating tumor-induced pro-inflammatory environment, a condition that minimizes Atrogin-1 and MuRF-1-dependent proteolysis.

Aims: The main aim of this study was to investigate the moderate versus high-load resistance training on muscle strength, hypertrophy and protein synthesis signaling in rats., Methods: Twenty rats were randomly allocated into three groups as follow: control group (C, n = 6), high-load training (HL, n = 7) and moderate-load training (ML, n = 7). A ladder climb exercise was used to mimic resistance exercise. ML resistance training consisted of a moderate load, allowing performance at higher volume of load inherent to higher number of repetitions (8-16 climbing). HL resistance training consisted of progressively increase training load, with low volume of load (4-8 climbing). C group remained with physical activity restricted to their cage space. This experiment was conducted over a six-weeks period. Forty-eight hours after the last resistance training session the animals were euthanized for tissue collection., Results: Both HL and ML regimens promoted similar increases in muscle strength, elevated protein synthesis signaling demonstrated by increased skeletal muscle total/phosphorylated P-70S6K ratio and similar increases in plantaris and FHL muscle hypertrophy, all compared to control. All these similarities were demonstrated even though testosterone/cortisol ratio was higher in HL group compared to ML and control. ML regimen caused higher total training volume and soleus muscle hypertrophy, which was not demonstrated in HL group., Conclusion: In conclusion, results suggest that both HL and ML induce muscle hypertrophy and increase on strength in a similar way. ML moreover seems to favor slow fiber hypertrophy due the higher training volume., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to investigate the effects of creatine supplementation on early stages of ethanol-induced hepatic damage., Methods: Male Swiss mice were divided into three groups (n = 12/group): control (C), ethanol (E), and ethanol supplemented with creatine (EC). The control group received a diet containing 15.8% of total calories from proteins, 46.3% from carbohydrates, and 37.9% from lipids. The ethanol and ethanol and creatine groups received diets containing 15.8% of total calories from proteins, 16.2% from carbohydrates, and 34.5% from lipids; the remaining calories were obtained from the addition of 5% of 95% ethanol. Creatine (1%; weight/vol) was added to the diet of EC mice. After 14 and 28 d, six animals from each group were sacrificed, generating subdivisions in each group: C14 and C28, E14 and E28, EC14 and EC28. After sacrifice, the liver was removed, weighed, and prepared for histologic, biochemical, and molecular analysis, and blood was collected., Results: Ethanol intake induced mild cell degeneration, liver damage, oxidative lesions, and inflammation. Surprisingly, ethanol intake combined with creatine exacerbated cell degeneration and fat accumulation, hepatic expression of genes related to ethanol metabolism, oxidative stress and inflammation, and promoted oxidative stress and elevated plasma alanine aminotransferase (P < 0.05)., Conclusion: Creatine supplementation associated with ethanol is able to interfere in the alcohol metabolism and oxidative stress and to exacerbate ethanol-induced hepatic damage. These new findings are opposite to those observed in several studies where protective effects of creatine in a wide variety of injury models, including non-alcoholic fatty liver disease, were described., (Copyright © 2019 Elsevier Inc. All rights reserved.)