Targeting cancer via ribosome biogenesis: the cachexia perspective.

Cancer cachexia afflicts many advanced cancer patients with many progressing to death. While there have been many advancements in understanding the molecular mechanisms that contribute to the development of cancer cachexia, substantial gaps still exist. Chemotherapy drugs often target ribosome biogenesis to slow or blunt tumor cell growth and proliferation. Some of the most frequent side-effects of chemotherapy are loss of skeletal muscle mass, muscular strength and an increase in fatigue. Given that ribosome biogenesis has emerged as a main mechanism regulating muscle hypertrophy, and more recently, also implicated in muscle atrophy, we propose that some chemotherapy drugs can cause further muscle wasting via its effect on skeletal muscle cells. Many chemotherapy drugs, including the most prescribed drugs such as doxorubicin and cisplatin, affect ribosomal DNA transcription, or other pathways related to ribosome biogenesis. Furthermore, middle-aged and older individuals are the most affected population with cancer, and advanced cancer patients often show reduced levels of physical inactivity. Thus, aging and inactivity can themselves affect muscle ribosome biogenesis, which can further worsen the effect of chemotherapy on skeletal muscle ribosome biogenesis and, ultimately, muscle mass and function. We propose that chemotherapy can accelerate the onset or worsen cancer cachexia via its inhibitory effects on skeletal muscle ribosome biogenesis. We end our review by providing recommendations that could be used to ameliorate the negative effects of chemotherapy on skeletal muscle ribosome biogenesis.

Revisiting the roles of protein synthesis during skeletal muscle hypertrophy induced by exercise.

Protein synthesis is deemed the underpinning mechanism enhancing protein balance required for skeletal muscle hypertrophy in response to resistance exercise. The current model of skeletal muscle hypertrophy induced by resistance training states that the acute increase in the rates of protein synthesis after each bout of resistance exercise is the basis for muscle growth. Within this paradigm, each resistance exercise session would add a specific amount of muscle mass; therefore, muscle hypertrophy could be defined as the result of intermittent and short-lived increases in muscle protein synthesis rates following each resistance exercise session. Although a substantial amount of data has accumulated in the last decades regarding the acute changes in protein synthesis (or translational efficiency) following resistance exercise, considerable gaps on the mechanism of muscle growth still exist. Ribosome biogenesis and translational capacity have emerged as important mediators of skeletal muscle hypertrophy. Recent advances in the field have demonstrated that skeletal muscle hypertrophy is associated with markers of translational capacity and long-term changes in protein synthesis under resting conditions. This review will discuss the caveats of the current model of skeletal muscle hypertrophy induced by resistance training while proposing a working model that takes into consideration the novel data generated by independent laboratories utilizing different methodologies. It is argued, herein, that the role of protein synthesis in the current model of muscle hypertrophy warrants revisiting.

Regulation of Ribosome Biogenesis in Skeletal Muscle Hypertrophy.

The ribosome is the enzymatic macromolecular machine responsible for protein synthesis. The rates of protein synthesis are primarily dependent on translational efficiency and capacity. Ribosome biogenesis has emerged as an important regulator of skeletal muscle growth and maintenance by altering the translational capacity of the cell. Here, we provide evidence to support a central role for ribosome biogenesis in skeletal muscle growth during postnatal development and in response to resistance exercise training. Furthermore, we discuss the cellular signaling pathways regulating ribosome biogenesis, discuss how myonuclear accretion affects translational capacity, and explore future areas of investigation within the field.

Volume for Muscle Hypertrophy and Health Outcomes: The Most Effective Variable in Resistance Training.

Resistance training is the most effective method to increase muscle mass. It has also been shown to promote many health benefits. Although it is deemed safe and of clinical relevance for treating and preventing a vast number of diseases, a time-efficient and minimal dose of exercise has been the focus of a great number of research studies. Similarly, an inverted U-shaped relationship between training dose/volume and physiological response has been hypothesized to exist. However, the majority of available evidence supports a clear dose-response relationship between resistance training volume and physiological responses, such as muscle hypertrophy and health outcomes. Additionally, there is a paucity of data to support the inverted U-shaped response. Although it may indeed exist, it appears to be much more plastic than previously thought. The overarching principle argued herein is that volume is the most easily modifiable variable that has the most evidenced-based response with important repercussions, be these muscle hypertrophy or health-related outcomes.

Doping survey in the youth school games in brazil / Levantamento de doping nos jogos escolares da juventude no brasil / Levantamiento de doping en los juegos escolares de la juventud en brasil

ABSTRACT Introduction: Doping control is an important means for preventing the use of illegal substances and methods in sports. Objective: This study investigated the self-reported use of illegal substances among young Brazilian students in the Youth School Games, the main sporting event among school-aged athletes in Brazil with almost 2 million students during all the phases. Methods: Cross-sectional study with athletes of the Youth School Games 2006 aged 14-17 years. The subjects were randomly selected and completed an anonymous questionnaire about substances use. Chi-square test was used for comparison of proportions between different variables on self-reported use of substances. Univariate and multivariate analyzes and logistic regression were performed. Results: Among the 402 athletes (aged 14-17) who volunteered to participate, the results showed high prevalence of alcohol (35.8%), nutritional supplements (39.1%), and tobacco (5.4%). Regarding illegal drugs and doping, 1.7% reported the use of stimulants, 2.2% illicit drugs, 0.5% anabolic steroids, and 1.7% hormones and other similar substances. Moreover, a different use of stimulants was found (especially Judo and Table tennis), medications (especially Judo and Chess) and dietary supplements (especially Swimming and Judo, with over 50% reported use). Conclusion: The present study suggests that the use of substances among young athletes is similar to the results found among adult Olympic athletes as per International Olympic Committee and World Anti-Doping Agency, especially regarding the use of dietary supplements, anabolic steroids, and stimulants according to data collected by other studies. We consider that the findings of the present work indicate the need for specific efforts to monitor, prevent, and control use of substances among school athletes in big events and competitions, such as this research on doping in the Youth School Games.

RESUMO Introdução: O controle de dopagem é um meio importante para a prevenção do uso de substâncias e métodos ilegais no esporte. Objetivo: Este estudo investigou o uso autorrelatado de substâncias ilícitas entre jovens estudantes brasileiros nos Jogos Escolares da Juventude, o principal evento esportivo entre atletas em idade escolar do Brasil, com quase dois milhões de estudantes durante todas as fases. Métodos: Estudo transversal com atletas dos Jogos Escolares da Juventude de 2006 com idades entre 14 e 17 anos. Os sujeitos foram selecionados randomicamente e preencheram um questionário anônimo sobre o uso de substâncias. Foi utilizado teste do qui-quadrado para comparação de proporções entre as diferentes variáveis sobre o uso autorrelatado de substâncias. Foram realizadas análises univariada e multivariada e regressão logística. Resultados: Entre os 402 atletas (idade 14-17 anos) que tiveram participação voluntária, os resultados mostraram alta prevalência de álcool (35,8%), suplementos nutricionais (39,1%) e fumo (5,4%). Com relação às drogas ilegais e ao doping, 1,7% relataram o uso de estimulantes, 2,2% de drogas ilícitas, 0,5% de esteroides anabolizantes e 1,7% de hormônios e outras substâncias similares. Além disso, foi encontrado um uso diferente de estimulantes (especialmente judô e tênis de mesa), medicamentos (especialmente judô e xadrez) e suplementos dietéticos (especialmente natação e judô, com mais de 50% de uso relatado). Conclusão: O presente estudo sugere que o uso de substâncias entre jovens atletas é semelhante aos resultados encontrados entre os atletas adultos de acordo com o Comitê Olímpico Internacional e a Agência Mundial Antidoping, especialmente no que diz respeito ao uso de suplementos alimentares, esteroides anabolizantes e estimulantes, segundo os dados coletados por outros estudos. Consideramos que os resultados do presente trabalho indicam a necessidade de esforços específicos para monitor, prevenir e controlar o uso de substâncias entre atletas escolares em grandes eventos e competições, tais como esta pesquisa sobre dopagem nos Jogos Escolares da Juventude.

RESUMEN Introducción: El control de dopaje es un medio importante para la prevención del uso de sustancias y métodos ilegales en el deporte. Objetivo: Este estudio investigó el uso autoinformado de sustancias ilegales entre jóvenes estudiantes brasileños en los Juegos Escolares de la Juventud, el principal evento deportivo entre atletas en edad escolar de Brasil, con casi dos millones de estudiantes durante todas las fases. Métodos: Estudio transversal con atletas de los Juegos Escolares de la Juventud de 2006 con edades entre 14 y 17 años. Los sujetos fueron seleccionados aleatoriamente y llenaron un cuestionario anónimo sobre el uso de sustancias. Se utilizó la prueba del chi-cuadrado para la comparación de las proporciones entre las diferentes variables sobre el uso autoinformado de sustancias. Se realizaron análisis univariado y multivariado y regresión logística. Resultados: Entre los 402 atletas (edad 14-17 años) que tuvieron participación voluntaria, los resultados mostraron alta prevalencia de alcohol (35,8%), suplementos nutricionales (39,1%) y tabaco (5,4%). En cuanto a las drogas ilegales y al dopaje, el 1,7% relató el uso de estimulantes, el 2,2% de drogas ilícitas, el 0,5% de esteroides anabolizantes y el 1,7% de hormonas y otras sustancias similares. Además, se encontró un uso diferente de estimulantes (especialmente judo y tenis de mesa), medicamentos (especialmente judo y ajedrez) y suplementos dietéticos (especialmente natación y judo, con más del 50% de uso reportado). Conclusión: El presente estudio sugiere que el uso de sustancias entre los jóvenes atletas es similar a los resultados encontrados entre los atletas adultos de acuerdo con el Comité Olímpico Internacional y la Agencia Mundial Antidopaje, especialmente en lo que se refiere al uso de suplementos alimenticios, esteroides anabolizantes y estimulantes según los datos recogidos por otros estudios. Consideramos que los resultados del presente trabajo indican la necesidad de esfuerzos específicos para monitoreo, prevención y control del uso de sustancias entre atletas escolares en grandes eventos y competiciones, tales como esta investigación sobre dopaje en los Juegos Escolares de la Juventud.

Considerations on mTOR regulation at serine 2448: implications for muscle metabolism studies.

The mammalian target of rapamycin (mTOR) complex exerts a pivotal role in protein anabolism and cell growth. Despite its importance, few studies adequately address the complexity of phosphorylation of the mTOR protein itself to enable conclusions to be drawn on the extent of kinase activation following this event. In particular, a large number of studies in the skeletal muscle biology field have measured Serine 2448 (Ser2448) phosphorylation as a proxy of mTOR kinase activity. However, the evidence to be described is that Ser2448 is not a measure of mTOR kinase activity nor is a target of AKT activity and instead has inhibitory effects on the kinase that is targeted by the downstream effector p70S6K in a negative feedback loop mechanism, which is evident when revisiting muscle research studies. It is proposed that this residue modification acts as a fine-tuning mechanism that has been gained during vertebrate evolution. In conclusion, it is recommended that Ser2448 is an inadequate measure and that preferential analysis of mTORC1 activation should focus on the downstream and effector proteins, including p70S6K and 4E-BP1, along mTOR protein partners that bind to mTOR protein to form the active complexes 1 and 2.

Cosmetic doping--when anabolic-androgenic steroids are not enough.

Doping is considered to be a major sports problem. This article describes a new threat and challenge to the sport of bodybuilding; the nonmedical use of a chemical in order to mimic muscle hypertrophy. Although muscle fillers are not new, being used for cosmetic purposes in medicine for a long time, the illegal use of muscle fillers has been increasing during the last few years and decades. The history of cosmetic doping, with particular attention to the Brazilian case, is discussed. Limitations are noted and future needed research is suggested.

Is carbohydrate needed to further stimulate muscle protein synthesis/hypertrophy following resistance exercise?

It is now well established that protein supplementation after resistance exercise promotes increased muscle protein synthesis, which ultimately results in greater net muscle accretion, relative to exercise alone or exercise with supplementary carbohydrate ingestion. However, it is not known whether combining carbohydrate with protein produces a greater anabolic response than protein alone. Recent recommendations have been made that the composition of the ideal supplement post-exercise would be a combination of a protein source with a high glycemic index carbohydrate. This is based on the hypothesis that insulin promotes protein synthesis, thus maximising insulin secretion will maximally potentiate this action. However, it is still controversial as to whether raising insulin level, within the physiological range, has any effect to further stimulate muscle protein synthesis. The present commentary will review the evidence underpinning the recommendation to consume carbohydrates in addition to a protein supplementation after resistance exercise for the specific purpose of increasing muscle mass. The paucity of data will be discussed, thus our conclusions are that further studies are necessary prior to any conclusions that enable evidence-based recommendations to be made.

Ursolic acid directly promotes protein accretion in myotubes but does not affect myoblast proliferation.

Ursolic acid (UA) has been recently proposed as a potential candidate for the treatment of muscle wasting conditions because of its protein sparring/anabolic effects. Despite this finding, it is unknown whether this response is the consequence of a direct effect on the muscle fibre or if it is mediated by neural or other systemic factors. In the present study, we sought to determine if UA has direct effects in skeletal muscle cells, whether it can increase myoblast proliferation and whether UA can become myotoxic at higher doses. Our results demonstrate that UA directly promoted protein accretion in cultured myotubes but did not modulate myoblast proliferation. At higher doses, UA compromised cell viability in both myoblasts and myotubes. We conclude that the anabolic properties of UA seen in vivo and in vitro are likely a direct effect on the muscle cell, but at higher doses, the benefits decline in favour of a myotoxic outcome.

Cysteamine prevents inhibition of adenylate kinase caused by cystine in rat brain cortex.

Cystinosis is a systemic genetic disease caused by a lysosomal transport deficiency accumulating cystine in the lysosomes of almost all tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are still obscures. Adenylate kinase, along with creatine kinase, is responsible for the enzymatic phosphotransfer network, crucial for energy homeostasis. Taking into account that cystine is known to inhibit creatine kinase activity, the two enzymes have thiol groups, and the strong interaction between the two activities, our main objective was to investigate the effect of cystine on adenylate kinase activity in the brain cortex of Wistar rats. For the in vivo studies, the animals were injected twice a day with 1.6 micromol/g body weight of cystine dimethylester and/or 0.46 micromol/g body weight of cysteamine from the 25th to the 29th postpartum day and sacrificed after 12 h. Cystine inhibited the enzyme activity in vitro in a concentration dependent way, whereas cysteamine prevented the inhibition. Adenylate kinase activity was found diminished in the brain cortex of rats loaded with cystine dimethylester and co-administration of cysteamine prevented the diminution of the enzyme activity. Considering that adenylate kinase together with creatine kinase is crucial for energy homeostasis, the release of cystine from lysosomes with consequent enzymes inhibition could impair energy homeostasis, contributing to tissue damage in patients with cystinosis.

Cysteamine prevents inhibition of adenylate kinase caused by cystine in rat brain cortex.

Cystinosis is a systemic genetic disease caused by a lysosomal transport deficiency accumulating cystine in the lysosomes of almost all tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are still obscures. Adenylate kinase, along with creatine kinase, is responsible for the enzymatic phosphotransfer network, crucial for energy homeostasis. Taking into account that cystine is known to inhibit creatine kinase activity, the two enzymes have thiol groups, and the strong interaction between the two activities, our main objective was to investigate the effect of cystine on adenylate kinase activity in the brain cortex of Wistar rats. For the in vivo studies, the animals were injected twice a day with 1.6 micromol/g body weight of cystine dimethylester and/or 0.46 micromol/g body weight of cysteamine from the 25th to the 29th postpartum day and sacrificed after 12 h. Cystine inhibited the enzyme activity in vitro in a concentration dependent way, whereas cysteamine prevented the inhibition. Adenylate kinase activity was found diminished in the brain cortex of rats loaded with cystine dimethylester and co-administration of cysteamine prevented the diminution of the enzyme activity. Considering that adenylate kinase together with creatine kinase is crucial for energy homeostasis, the release of cystine from lysosomes with consequent enzymes inhibition could impair energy homeostasis, contributing to tissue damage in patients with cystinosis.