Exercise Reduces the Resumption of Tumor Growth and Proteolytic Pathways in the Skeletal Muscle of Mice Following Chemotherapy

The pathogenesis of muscle atrophy plays a central role in cancer cachexia, and chemotherapy contributes to this condition. Therefore, the present study aimed to evaluate the effects of endurance exercise on time-dependent muscle atrophy caused by doxorubicin. For this, C57 BL/6 mice were subcutaneously inoculated with Lewis lung carcinoma cells (LLC group). One week after the tumor establishment, a group of these animals initiated the doxorubicin chemotherapy alone (LLC + DOX group) or combined with endurance exercise (LLC + DOX + EXER group). One group of animals was euthanized after the chemotherapy cycle, whereas the remaining animals were euthanized one week after the last administration of doxorubicin. The practice of exercise combined with chemotherapy showed beneficial effects such as a decrease in tumor growth rate after chemotherapy interruption and amelioration of premature death due to doxorubicin toxicity. Moreover, the protein degradation levels in mice undergoing exercise returned to basal levels after chemotherapy; in contrast, the mice treated with doxorubicin alone experienced an increase in the mRNA expression levels of the proteolytic pathways in gastrocnemius muscle (Trim63, Fbxo32, Myostatin, FoxO). Collectively, our results suggest that endurance exercise could be utilized during and after chemotherapy for mitigating muscle atrophy promoted by doxorubicin and avoid the resumption of tumor growth

Formoterol reduces muscle wasting in mice undergoing doxorubicin chemotherapy

BackgroundEven though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease’s evolution and the patient’s quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a β2-adrenoceptor agonist, in managing muscle wasting caused by DOX.Methods and resultsTo evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle.ConclusionsCollectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy

Metformin treatment restored metabolic damage caused by obesity, but induced liver inflammatory response.

A metformina é uma droga utilizada para tratamento da diabetes tipo 2. O PPAR-α tem um papel central no controle imunometabólico. Portanto, o objetivo do estudo foi avaliar os efeitos imunometabólicos da dieta hiperlipídica (HFD), em camundongos C57BL6 (WT) e knockout para PPAR-α, tratados com metformina. Métodos: Os animais foram submetidos a uma HFD por 12 semanas, nos últimos dez dias de dieta os animais foram tratados com metformina. A oxidação de palmitato no músculo esquelético, As citocinas, no fígado, no tecido adiposo retroperitoneal, em hepatócitos e macrófagos intraperitoneais foram analisados. Resultados: O tratamento aumentou a oxidação de palmitado no músculo, promoveu um efeito anti-inflamatório no tecido adiposo e reverteu à inflamação dos macrófagos. No fígado e nos hepatócitos, a metformina causou um efeito inflamatório. Conclusão: A inflamação hepática foi induzida pelo tratamento e o efeito principal foi a um potencial aumento na inflamação nos hepatócitos. Os macrófagos tiveram uma resposta anti-inflamatória, assim como o tecido adiposo.Metformin is a drug used to treatment of type 2 diabetes. PPAR-α plays a central role in immunometabolic control. Therefore, the aim of the study was to evaluate the effects of imumnometabolics of high fat diet (HFD) in C57BL6 mice (WT) and knockout for PPAR-α treated with metformin. Methods: The animals were subjected to a HFD for 12 weeks in the last ten days of diet the animals were treated with metformin. The palmitate oxidation in skeletal muscle, cytokines in the liver, in the retroperitoneal adipose tissue, hepatocytes and intraperitoneal macrophages were analyzed. Results: The treatment increased palmitate oxidation in muscle, it has promoted an anti-inflammatory effect in adipose tissue and macrophages to inflammation reversed. In the liver and hepatocytes, metformin caused an inflammatory effect. Conclusion: The liver inflammation was induced, and treatment was a main effect to a potential increase in inflammation in hepatocytes. Macrophages have an anti-inflammatory response, as well as adipose tissue

Physical exercise as a circadian rhythm synchronizer in cancer.

Alterações do ritmo circadiano estão relacionadas ao desenvolvimento e crescimento do câncer e os mecanismos moleculares subjacentes a este efeito ainda precisam ser mais estudados. No entanto, sabe-se que o exercício físico pode sincronizar o ritmo circadiano, atuando na modulação do sistema psiconeuroimunoendócrino. O desenvolvimento do tumor, por sua vez, promove alterações no equilíbrio desse sistema resultando em perturbação do ritmo circadiano. Um programa regular de exercício físico pode ser uma intervenção útil e de baixo custo como estratégia para melhorar a qualidade de vida de pacientes e sobreviventes do câncer. Assim, o objetivo do presente estudo foi avaliar se os mecanismos envolvidos na inibição do crescimento tumoral pelo treinamento físico podem estar associados com o papel cronomarcador do exercício físico. Métodos: Foram utilizados camundongos da linhagem C57BL/6J divididos em 4 grupos: controle (CTL); Tumor (LLC); Tumor + Treino no mesmo horário do dia (LLC+T(ZT2)); Tumor + Treino em horários alternados (LLC+T(ZTAlt)). Os animais foram submetidos ao treinamento aeróbio no terceiro dia após a inoculação do tumor. Foram realizadas 14 sessões de treino, compreendendo 5 sessões na primeira e 5 sessões na segunda semana e 4 sessões na terceira semana (60 minutos a 60% da velocidade máxima). Os animais foram eutanasiados com 21 dias após inocular o tumor, a cada 4 horas do dia, até completar 24 horas (ZT0, ZT4, ZT8, ZT12, ZT16 e ZT20). No músculo esquelético gastrocnêmio foram feitas as análises da expressão gênica dos clock genes (Clock, Bmal1, Per1, Per2, Per3 Cry1, Cry2, REV ERB &#945, Ror &#945 e Ror &#946), Ampk, Atrogina-1, Murf1 e GAPDH. A determinação das concentrações de TNF- &#945 , IL-1 &#946 , MCP-1, IFN-, VEGF, IL-10 e IL-4 foram realizadas no músculo gastrocnêmio e no tumor. Resultados: O treino reduziu o peso total quando comparado com o grupo LCC. Apenas o grupo LLC+T(ZTAlt) teve redução no peso quando comparado com o grupo CTL. O peso do tumor foi menor no grupo LLC+T(ZTAlt) quando comparado com o grupo LLC. Os músculos EDL e sóleo apresentaram maior peso no grupo LLC+T(ZT2) quando comparado com o grupo LLC. O exercício em diferentes horários reduziu a concentração de glicose quando comparado com o grupo LLC (ZT8). O treinamento físico praticado em horários alternados foi capaz de aumentar a expressão no gene Per1(ZT4) quando comparado com os grupos sedentários. O grupo LLC+T(ZT2) teve aumento da expressão de Per2 quando comparado com o grupo CTL no ZT0 e ZT4, já o grupo LLC+T(ZTAlt) apresentou aumento do Per2 quando comparado com o grupo CTL e LLC apenas no ZT4. Na análise feita no gene Per3, o grupo LLC+T(ZTAlt) apresentou maior expressão no ZT4 quando comparado com os grupos CTL e LLC. A expressão gênica da AMPK foi aumentada no período claro e a Atrogina-1 reduzida, ambos no grupo LLC+T(ZT2). Atrogina-1 estava aumentada no grupo LLC+T(ZTAlt) no ZT20 quando comparado com o grupo CTL. Ainda no músculo gastrocnêmio, a concentração proteica do TNF- foi maior no grupo LLC(ZT16) quando comparado com os grupos CTL e LLC+T(ZTAlt). Já o VEGF estava aumentado no grupo LLC quando comparado com o grupo LLC+T(ZTAlt). A IL-10 (ZT16) estava aumentada no grupo LCC quando comparado com os grupos CTL e LLC+T(ZT2 e ZTAlt). No mesmo ZT o grupo LLC+T(ZTAlt) apresentou menor concentração da IL-10 quando comparado com o grupo CTL e LLC+T(ZT2). A IL-4 apresentou aumento da concentração no ZT16 no grupo LLC+T(ZT2) quando comparado com os grupos CTL e LLC+T(ZTAlt). No tumor, TNF- &#945 mostrou efeito do exercício físico em horários alternados, com aumento no grupo LCC+T(ZTAlt) no ZT16 quando comparado com o grupo LLC+T(ZT2). A IL-10 e IL-4 também foram mais expressas no grupo LLC+T(ZTAlt)(ZT4). Conclusão: O exercício físico mostrou ser um grande modulador do relógio circadiano no músculo esquelético, promovendo efeitos protetores ao músculo, além de atenuar o crescimento tumoral.Background: Changes in circadian rhythm are related to cancer development and growth, however the molecular mechanisms underlying this effect need to be further studied. It is known that physical exercise can synchronize the circadian rhythm, since it acts in the modulation of the psychoneuroimmunoendocrine system. The development of the tumor, in turn, promotes changes in the balance of this system resulting in a disturbance of the circadian rhythm. Thus a regular exercise program can be a useful and a low-cost intervention as a strategy to improve the quality of life of cancer patients and survivors. Therefore, our objective was to evaluate whether the mechanisms involved in the inhibition of tumor growth by physical training can be correlated with the chronological role of physical exercise. Methods: C57BL / 6J mice were used, divided into 4 groups: control (CTL); Tumor (LLC); Tumor + Training at the same time of day (LLC + TZT2); Tumor + Training at alternate times (LLC + TZTAlt). The animals were submitted to aerobic training on the third day after tumor inoculation. 14 training sessions were carried out comprising 5 sessions / week (40 to 60 minutes at 60% of maximum speed). The animals were euthanized 21 days after inoculating the tumor, every 4 hours of the day, until completing 24 hours (ZT0, ZT4, ZT8, ZT12, ZT16 and ZT20). In the gastrocnemius muscle, analyzes of the gene expression of the clock genes were performed (Clock, Bmal1, Per1, Per2, Per3, Cry1, Cry2, REV-ERB &#945, Ror &#945 and Ror &#946 ), Ampk, Atrogin-1, Murf1 and GAPDH. The determination of the concentration of TNF- &#945 , IL-1 &#946 , MCP-1, IFN-, VEGF, IL-10 and IL-4 were performed in the gastrocnemius muscle and in the tumor. Results: The training reduced the total weight when compared with the LCC group, and only the LLC + T(ZTAlt) had a reduction in weight when compared with the CTL group. The tumor weight was lower in the LLC+T(ZTAlt) group when compared to the LLC group. The EDL and soleus muscles presented greater weight in the ZT2 group when compared to the LLC group. Exercise at different times also reduced glucose concentration when compared to the LLC group (ZT8). The physical training practiced at alternated times was able to increase the expression in the Per1 gene (ZT4) when compared with sedentary groups. The group that trained in ZT2 had an increase in Per2 expression when compared with the CTL group in ZT0 and ZT4, whereas the group with alternate training showed an increase in Per2 when compared with the CTL and LLC group only in ZT4. On the Per3 gene, the LLC+T (ZTAlt) group showed a higher expression in ZT4 when compared with the CTL and LLC groups. The gene expression of AMPK was increased in the light period and Atrogin-1 reduced, both in the LLC+T(ZT2) group. Atrogin-1 was increased in the LLC+T(ZTAlt) group in the ZT20 when compared to the CTL group. Also in the gastrocnemius muscle, the protein expression of TNF- was higher in the LLC group (ZT16) when compared with the CTL and LLC+T(ZTAlt). VEGF was increased in the LLC group when compared to the LLC+T(ZTAlt). IL-10(ZT16) was increased in the LCC group when compared to the CTL and LLC+T groups (ZT2 and Alt). In the same ZT, the LLC+T(ZTAlt) group showed a lower expression of IL-10 when compared to the CTL and LLC + T(ZT2) group. IL-4 showed an increase in ZT16 expression in the LLC +T(ZT2) group when compared with the CTL and LLC+T(ZTAlt) groups. In the tumor, TNF- &#945 was affected by exercise, being increased in the group that trained at alternate times (ZT16) when compared with the LLC+T(ZT2). And IL-10 and IL-4 were also more expressed in alternate exercise (ZT4). Conclusion: Physical exercise proved to be a major modulator of the circadian clock in skeletal muscle, promoting protective effects to the muscle, in addition to attenuating tumor growth

Post-COVID-19 condition: systemic inflammation and low functional exercise capacity

IntroductionPost-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported.MethodsIn this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6–12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group (n = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment.ResultsSRPF presented lower IL-4 concentration compared with Control (q = 0.0018) and with SR (q = 0.030), and lower IFN-α2 serum content compared with Control (q = 0.007). In addition, SRPF presented higher MIP-1β serum concentration compared with SR (q = 0.029). SR presented lower CCL11 (q = 0.012 and q = 0.001, respectively) and MCP-1 levels (q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control (q = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF (q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group (q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes