Formoterol reduces muscle wasting in mice undergoing doxorubicin chemotherapy.

Background: Even 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 ß2-adrenoceptor agonist, in managing muscle wasting caused by DOX. Methods and results: To 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. Conclusions: Collectively, 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.

Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism.

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation- and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.

Doxorubicin modulated clock genes and cytokines in macrophages extracted from tumor-bearing mice.

Circadian rhythm is essential for cellular regulation of physiological, metabolic, and immune functions. Perturbations of circadian rhythms have been correlated with increased susceptibility to cancer and poor prognosis in the cancer treatment. Our aim is to investigate the role of doxorubicin (DOX) treatment on clock genes expression and inflammation in intraperitoneal macrophages and the antitumoral response. METHODS: Macrophages were extracted from intraperitoneal cavity of mice without or with Lewis lung carcinoma (LLC) and treated with DOX totaling four groups (CTL, LLC, LLC+DOX and DOX) and analyzes of clock genes in six time points (ZT02, ZT06, ZT10, ZT14, ZT18 AND ZT22). Intraperitoneal macrophages cell culture was stimulated with LPS and DOX and clock genes and inflammatory profile were analyzed. In tumor were analyzed macrophages markers. RESULTS: The expression of F4/80 (ZT22) and CD11c (ZT06) tumor tissue was significantly differed between LLC and LCC+DOX groups. In the intraperitoneal macrophages, DOX increased Clock (ZT10), Rev-Erbα (ZT18 and ZT22) and Per2 expressions (ZT18); in the LLC+DOX group was increased Bmal1 (ZT10), Per2 (ZT18) and NF-kB (ZT22) expressions; IL-6 expression increased in the LCC group (ZT02). In intraperitoneal macrophages cell culture stimulated with DOX and LPS after 24 h decreased Clock and Per1. DOX causes depression after 6 and 24 h in TNF-α content and Per2 gene expression after 24 h IL-1ß expression was reduced also. CONCLUSION: DOX treatment in vivo disrupted cytokine and clock genes expression in intraperitoneal macrophages suppressing immune response. Moreover, macrophages cultured with DOX had decreased expression of LPS-stimulated inflammatory cytokines.

Short-term treatment with metformin reduces hepatic lipid accumulation but induces liver inflammation in obese mice.

The study aimed to evaluate the metabolic and inflammatory effects of short-term treatments (10 days) with metformin (MET) on the NAFLD caused by a high-fat diet (HFD) in C57BL/6 mice. After the treatment, histological liver slices were obtained, hepatocytes and macrophages were extracted and cultured with phosphate buffered saline, LPS (2.5 µg/mL) and MET (1 µM) for 24 h. Cytokine levels were determined by ELISA. NAFLD caused by the HFD was partially reduced by MET. The lipid accumulation induced by the HFD was not associated with liver inflammation; however, MET seemed to promote pro-inflammatory effects in liver, since it increased hepatic concentration of IL-1ß, TNF-α, IL-6, MCP-1 and IFN-γ. Similarly, MET increased the concentration of IL-1ß, IL-6 in hepatocyte cultures. However, in macrophages culture, MET lowered levels of IL-1ß, IL-6 and TNF-α stimulated by LPS. Overall, MET reduced liver NAFLD but promoted hepatocyte increase in pro-inflammatory cytokines, thus, leading to liver inflammation.

Aerobic Exercise Modulates the Free Fatty Acids and Inflammatory Response During Obesity and Cancer Cachexia.

White adipose tissue (WAT) is no longer considered a tissue whose main function is the storage of TAG. Since the discovery of leptin in 1994, several studies have elucidated the important role of WAT as an endocrine organ, the source of the adipokines. The low-grade inflammation observed in obese and cancer cachexia patients is explained, at least partially, by the exacerbated release of proinflammatory adipokines. Despite of the recent progress in the characterization of the various adipokines and lipokines produced by WAT, little is known about the mechanisms regulating the secretion of these molecules in different physiological and pathological circumstances. Chronic exercise is a nonpharmacological therapy employed in several chronic diseases and shows an anti-inflammatory effect through the regulation of the cytokine network. In this review, we address the potential mechanisms by which the aerobic physical exercise modulate the production and release of inflammatory adipokines, as well as the inflammation-lipolysis axis in WAT, with special focus in the therapeutic role of exercise in obesity-associated insulin resistance and cancer cachexia.

Macrophage Polarization: Implications on Metabolic Diseases and the Role of Exercise.

Macrophages are cells of the innate immune response that trigger inflammation resolution. The phenotype of "classically activated macrophages" (M1) has anti-tumoricidal and anti-bactericidal activities. On the other hand, "alternatively activated macrophages" (M2) are involved in tissue remodeling and immunomodulatory functions. The change in the polarization of macrophages varies according to the diversity of cytokines present in the microenvironment or by the stimuli of an antigen. It involves such factors as interferon-regulatory factors, peroxisome proliferator-activated receptors (PPARs), hypoxia-inducible factors (HIFs), and signal transducers and activators of transcription (STATs). Switching the phenotype of macrophages can help attenuate the development of an inflammatory disease. Exercise can promote alterations in the number of innate immune cells and stimulates phagocytic function. Chronic exercise seems to inhibit macrophage infiltration into adipose tissue by attenuating the expression of F4/80 mRNA. Furthermore, exercise may also increase the expression of M2 markers and reduce TNF-α and TLR4 mRNA expression, which activates the inflammatory pathway of NF-κB. Chronic exercise reduces ß2-adrenergic receptors in monocytes and macrophages by modulating TLR4 signaling as well as suppressing IL-12 production, a stimulator of interferon Y. In this review, we discuss macrophage polarization in metabolic diseases and how exercise can modulate macrophage plasticity.

Exercise training as treatment in cancer cachexia.

Cachexia is a wasting syndrome that may accompany a plethora of diseases, including cancer, chronic obstructive pulmonary disease, aids, and rheumatoid arthritis. It is associated with central and systemic increases of pro-inflammatory factors, and with decreased quality of life, response to pharmacological treatment, and survival. At the moment, there is no single therapy able to reverse cachexia many symptoms, which include disruption of intermediary metabolism, endocrine dysfunction, compromised hypothalamic appetite control, and impaired immune function, among other. Growing evidence, nevertheless, shows that chronic exercise, employed as a tool to counteract systemic inflammation, may represent a low-cost, safe alternative for the prevention/attenuation of cancer cachexia. Despite the well-documented capacity of chronic exercise to counteract sustained disease-related inflammation, few studies address the effect of exercise training in cancer cachexia. The aim of the present review was hence to discuss the results of cachexia treatment with endurance training. As opposed to resistance exercise, endurance exercise may be performed devoid of equipment, is well tolerated by patients, and an anti-inflammatory effect may be observed even at low-intensity. The decrease in inflammatory status induced by endurance protocols is paralleled by recovery of various metabolic pathways. The mechanisms underlying the response to the treatment are considered.