Moderate-intensity aerobic exercise training improves CD8+ tumor-infiltrating lymphocytes effector function by reducing mitochondrial loss.

Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function, which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function, thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia, TIL infiltration and effector function, and mitochondrial content, morphology and function were evaluated. AET reduced tumor growth, improved survival, and decreased tumor hypoxia. An increased CD8+ TIL infiltration, IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively, AET decreases tumor growth partially by increasing CD8+ TIL effector function through an improvement in their mitochondrial content and function.

Heme: The Lord of the Iron Ring.

Heme is an iron-protoporphyrin complex with an essential physiologic function for all cells, especially for those in which heme is a key prosthetic group of proteins such as hemoglobin, myoglobin, and cytochromes of the mitochondria. However, it is also known that heme can participate in pro-oxidant and pro-inflammatory responses, leading to cytotoxicity in various tissues and organs such as the kidney, brain, heart, liver, and in immune cells. Indeed, heme, released as a result of tissue damage, can stimulate local and remote inflammatory reactions. These can initiate innate immune responses that, if left uncontrolled, can compound primary injuries and promote organ failure. In contrast, a cadre of heme receptors are arrayed on the plasma membrane that is designed either for heme import into the cell, or for the purpose of activating specific signaling pathways. Thus, free heme can serve either as a deleterious molecule, or one that can traffic and initiate highly specific cellular responses that are teleologically important for survival. Herein, we review heme metabolism and signaling pathways, including heme synthesis, degradation, and scavenging. We will focus on trauma and inflammatory diseases, including traumatic brain injury, trauma-related sepsis, cancer, and cardiovascular diseases where current work suggests that heme may be most important.

The influence of a supervised group exercise intervention combined with active lifestyle recommendations on breast cancer survivors' health, physical functioning, and quality of life indices: study protocol for a randomized and controlled trial.

BACKGROUND: Most cancer patients, under active treatment or not, are sedentary, despite increasing scientific and clinical understanding of the benefits of exercise and physical activity, such as improving quality of life, limiting disease symptoms, decreasing cancer recurrence, and increasing overall survival. Studies have shown that both supervised exercise and unsupervised physical activity programs have low adherence and limited long-term benefits among cancer survivors. Therefore, interventions focused on increasing physical activity levels have clinical and psychological relevance. The present study will examine the feasibility and efficacy of an intervention that combines supervised group exercise with active lifestyle recommendations, analyzing its clinical, psychological, physiological, functional, and immunological effects in breast cancer survivors. METHODS: Women aged 35-75 years who have completed chemotherapy, radiotherapy, and surgery for breast cancer will be recruited from the Cancer Institute of the State of Sao Paulo (ICESP) and take part in a 16-week, parallel-group, randomized, and controlled trial. They will receive a booklet with recommendations for achieving a physically active lifestyle by increasing overall daily movement and undertaking at least 150 min/week of structured exercise. Then, they will be randomized into two groups: the supervised group will take part in two canoeing group exercise sessions every week, and the unsupervised group will increase their overall physical activity level by any means, such as active commuting, daily activities, or home-based exercise. Primary outcome includes aerobic capacity. Secondary outcomes are physical activity, physical functioning, self-reported quality of life, fatigue, presence of lymphedema, body composition, immune function, adherence to physical activity guidelines, and perceptions of self-image. DISCUSSION: Results should contribute to advance knowledge on the impact of a supervised group exercise intervention to improve aspects related to health, physical functioning, and quality of life in female breast cancer survivors. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials Number: RBR-3fw9xf. Retrospectively Registered on 27 December 2018. Items from the World Health Organization Trial Registration Data Set can be accessed on http://www.ensaiosclinicos.gov.br/rg/RBR-3fw9xf/ .

Treinamento aeróbio de natação aumenta a atividade de enzimas antioxidantes e o conteúdo de glicogênio no musculoesquelético de ratos / Aerobic swimming training increases the actitivy of antioxidant enzymes and the glycogen content in the skeletal muscle of rats

INTRODUÇÃO: São escassos os estudos os quais verificaram os efeitos do exercício físico sobre os biomarcadores de estresse oxidativo e sua relação com o glicogênio muscular. OBJETIVO: O presente estudo verificou o efeito do treinamento aeróbio de natação (TAN) sobre os biomarcadores de estresse oxidativo, conteúdo de glicogênio e crescimento celular no músculo esquelético de ratos. MÉTODOS: Dezoito ratos Wistar macho (60 dias) foram divididos em dois grupos: Grupo Sedentário (SG; n = 10): ratos sedentários; e Grupo Treinado (TG; n = 8): ratos submetidos ao TAN (5,0 % do peso corporal), 1h/dia, 5X/semana, durante oito semanas. A atividade das enzimas antioxidantes (AEA) superóxido dismutase (SOD; U/ml), catalase (CAT; µmol/min/100 mg) e glutationa peroxidase (GPx; nmol/min/100 mg), bem como a concentração das substâncias que reagem ao ácido tiobarbitúrico (TBARs; nmolMDA/mg proteína) foram determinadas no músculo gastrocnêmio direito. Os conteúdos de glicogênio (mg/100 mg), proteína (g/100 g) e DNA (g/100 g) foram mensurados no músculo gastrocnêmio esquerdo. RESULTADOS: A AEA foi maior no TG (CAT: 0,87 ± 0,04; SOD: 6,49 ± 0,045; GPX: 6,49 ± 0,52) quando comparados com SG (CAT: 0,52 ± 0,03; SOD: 4,1 ± 0,37; GPx: 2,94 ± 0,56). Os níveis de TBARs foram menores em TG (TG: 2,35 ± 0,41; SG: 8,90 ± 0,47). O conteúdo de glicogênio muscular (SG: 0,108 ± 0,013; TG: 0,320 ± 0,012) e a razão proteína/DNA (SG: 24,94 ± 3,25; TG: 41,68 ± 4,02) foram maiores no TG. CONCLUSÃO: Em conjunto, estes dados confirmam que o TAN melhorou a defesa antioxidante, a qual pode estar associada ao aumento do conteúdo de glicogênio no músculo esquelético dos animais.

INTRODUCTION: Studies which verified the effects of physical exercise on oxidative stress biomarkers and its relation to muscle glycogen are lack. OBJECTIVE: The present study verified the effects of aerobic swimming training (AST) on biomarkers of oxidative stress, glycogen content and cell growth in the skeletal muscle of rats. METHODS: Eighteen male Wistar rats (60 days) were divided into two groups: Sedentary Group (SG; n = 10): sedentary rats; and Trained Group (TG; n = 8): rats subjected to AST (5.0% of body weight), 1h/day, 5x/week, during 8 weeks. The activity of antioxidant enzymes (AOE) superoxide dismutase (SOD; U/ml), catalase (CAT; µmol/min/100mg), glutathione peroxidase (GPx; nmol/min/100mg), and substances that react with thiobarbituric acid levels (TBARs; nmolMDA/mg protein) were determined in the right gastrocnemius muscle. Glycogen (mg/100mg), protein (g/100g), and DNA (g/100g) contents were evaluated in the left gastrocnemius muscle. Data were analyzed by Student t-test (p < 0.05). RESULTS: AOE activity was higher in the TG group (CAT: 0.87 ± 0.04; SOD: 6.49 ± 0.45; GPX: 6.49 ± 0.52) when compared to SG group (CAT: 0.52 ± 0.03; SOD: 4.10 ± 0.37; GPx: 2.87 ± 0.35). TBARs levels was lower in TG (TG: 2.35 ± 0.45; SG: 8.90 ± 0.47). Gastrocnemius glycogen content (SG: 0.108 ± 0.013; TG: 0.320 ± 0.012) and protein/DNA ratio (SG: 24.94 ± 3.25; TG: 41.68 ± 4.02) were higher in TG group. CONCLUSION: Altogether, these data provide evidence that AST improved antioxidant defense, which may be associated to higher glycogen content of skeletal muscle of the animals.

Efeitos dos treinamentos físicos aeróbicos e resistido sobre a atrofia muscular esquelética na insuficiência cardíaca / Effects of aerobic and resistance exercise training on skeletal muscle atrophy induced by heart failure

A insuficiência cardíaca é uma síndrome que envolve múltiplos sistemas e mecanismos compensatórios neuro-hormonais, acompanhada de altos índices de morbidade e mortalidade, caracterizadas por sintomas clínicos como fadiga, dispnéia e intolerância aos esforços físicos. Além do comprometimento cardíaco, observam-se importantes alterações periféricas, como a atrofia muscular esquelética, a qual contribui para o mau prognóstico e para o aumento da mortalidade dos pacientes. Estudos têm demonstrado que essa atrofia muscular pode ser causada por um desbalanço entre vias de síntese e degradação protéica, pricipalmente pelo aumento da ativação do sistema proteolítico ubiquitina-proteassoma e pela diminuição da ativação da via IGF-1/Akt. O treinamento físico, estratégia não farmacológica no tratamento da insuficiência cardíaca, tem se mostrado capaz de atenuar ou reverter o quadro de miopatia esquelética encontrado nessa síndrome. Portanto, foi objetivo da presente revisão discutir em maiores detalhes a atrofia muscular esquelética observada na insuficiência cardíaca e os efeitos dos treinamentos físicos aeróbicos e resistido sobre esta condição. Embora o treinamento físico aeróbico, de moderada ou alta intensidade, não seja conhecido por promover aumento da massa muscular esquelética, alguns estudos demonstram que este tipo de treinamento promove adaptações importantes na regulação da massa muscular na insuficiência cardíaca, prevenindo a atrofia e, consequentemente, contribuindo para a melhora da tolerância ao esforço físico. Por outro lado, o treinamento físico resistido parece ser mais eficaz em atenuar ou reverter a atrofia muscular esquelética presente na insuficiência cardíaca.

Heart failure is a complex syndrome involving multiple systems and neurohumoral compensatory mechanisms accompanied by high morbidity and mortality, and it is characterized by clinical signs such as fatigue, dyspneia, and exercise intolerance. Although heart failure is a syndrome of cardiac origin, it promotes changes in other tissues, such as skeletal muscle, where modifications of muscle phenotype and the loss of skeletal muscle mass observed in heart failure contribute to poor prognosis and increased mortality of patients. Studies have show that skeletal muscle atrophy is caused by an imbalance between the process of protein synthesis and degradation, mainly due to increased activation of ubiquitin-proteasome proteolytic system and decreased activation of IGF-1/Akt pathway. Exercise training, a non-pharmacological strategy to treat heart failure, has been shown to attenuate or reverse the skeletal myopathy in this syndrome. this review aimed to discuss in details the muscular atrophy observed in heart failure and the effects of aerobic and resistance exercise training on skeletal muscle atrophy induced by this conditions. Although aerobic exercise training, at moderate or high intensity, is not known for promoting skeletal muscle hypertrophy, some studies show that this type of exercise training promotes major changes in skeletal muscle mass in heart failure, preventing atrophy and consequently contributing to improved exercise tolerance. On the other hand, resistance exercise training appears to be more effective in attenuating or reversing the skeletal muscle atrophy in heart failure. However, the benefits promoted by aerobic exercise training in many aspects of heart failure are more established in the literature and should be considered in the treatment of this syndrome in association with resistance exercise training, in order to obtain better results.

Does Branched-Chain Amino Acids Supplementation Modulate Skeletal Muscle Remodeling through Inflammation Modulation? Possible Mechanisms of Action.

Skeletal muscle protein turnover is modulated by intracellular signaling pathways involved in protein synthesis, degradation, and inflammation. The proinflammatory status of muscle cells, observed in pathological conditions such as cancer, aging, and sepsis, can directly modulate protein translation initiation and muscle proteolysis, contributing to negative protein turnover. In this context, branched-chain amino acids (BCAAs), especially leucine, have been described as a strong nutritional stimulus able to enhance protein translation initiation and attenuate proteolysis. Furthermore, under inflammatory conditions, BCAA can be transaminated to glutamate in order to increase glutamine synthesis, which is a substrate highly consumed by inflammatory cells such as macrophages. The present paper describes the role of inflammation on muscle remodeling and the possible metabolic and cellular effects of BCAA supplementation in the modulation of inflammatory status of skeletal muscle and the consequences on protein synthesis and degradation.

Músculo esquelético, insuficiência cardíaca crônica e o papel do exercício / Skeletal muscle, chronic heart failure and the role of the exercise

Pacientes com Insuficiência Cardíaca Crônica (ICC) apresentam alterações metabólicas, hemodinâmicas e do músculo-esquelético as quais diminuem a expectativa de vida e são atribuídas a inúmeros fatores. O foco dessa revisão foi abordar as questões relacionadas às alterações fisiológicas, metabólicas, morfológicas e moleculares que afetam o sistema muscular desses pacientes. Posteriormente, foram discutidos os benefícios do exercício físico sobre essa síndrome assim como as intervenções farmacológicas que estão em investigação para o tratamento da mesma. Algumas alterações musculares já estão bem descritas na literatura. Dentre elas se destacam a maior predominância de fibrasdo tipo II, menor atividade enzimática oxidativa, atrofia muscular e elevada concentrações de citocinas, as quais afetam a integridade muscular. Assim, são necessários estudos futuros que envolvam os mecanismos celulares e moleculares do músculo-esquelético com o intuito de criar estratégias de prevenção e tratamento para os pacientes com ICC.

Patients with chronic heart failure (CHF) show metabolic, hemodynamic and skeletal muscle alterations, which decrease the life expectancy. These alterations are attributed to several factors. The focus of this review was to approach the questions related to physiological, metabolic, morphological and molecular alterations which affect the muscular system of these patients. Later, it was discussed the benefits of physical exercise to this syndrome as well as the pharmacological interventions, which are in investigation aiming the treatment of the same. Some muscle alterations are already described on theliterature. For example, the more predominance of type II fibers, lower oxidative enzymatic activity, muscle atrophy and elevated concentration of cytokines that affect the muscle integrity. Thus, further studies involving cellular and molecular mechanisms of skeletal muscle in order to create strategies for prevention and treatment for patients with CHF are required.