scholarly journals A Combination of Formoterol and the Histone Deacetylase Inhibitor AR42 has No Effects on Muscle Mass in Tumor-Bearing Rats

2021 ◽  
pp. 1-6
Author(s):  
Silvia Busquets ◽  
Marta Castillejo ◽  
Queralt Jove ◽  
Alina Noguera ◽  
Francisco J. López-Soriano ◽  
...  
Keyword(s):  
Body Weight ◽  
Olive Oil ◽  
Histone Deacetylase ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Body Weight Loss ◽  
Tissue Loss ◽  
Tumor Bearing ◽  
Deacetylase Inhibitor ◽  
Β2 Agonists

Background: Accelerated muscle and adipose tissue loss are two of the main aspects of cancer cachexia. β2-agonists seem to be successful in the treatment of cachexia in experimental animals. The aim if the present investigation was to study the effects on body weight loss in tumor-bearing animals of a combination of formoterol and AR-42, an inhibitor of histone deacetylase (HDAC). Methods: Rats were divided into two groups, namely controls (C) and tumor-bearing (T). TB group was further divided into four subgroups: untreated (saline as a vehicle), treated with Formoterol (F) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with AR-42 (A) (20 mg/kg body weight in olive oil, intragastric (i.g.), only the last 4 days). and double-treated treated (TFA) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and AR-42 (20 mg/kg body weight in olive oil, intragastric (i.g.), only the last 4 days). 7 days after tumor transplantation, muscle weights, grip force and total physical activity were determined in all experimental groups. Results: The presence of the Yoshida AH-130 ascites hepatoma induced severe muscle wasting in rats. Treatment of the tumor-bearing animals with the beta2-agonist formoterol (0,3 mg/kg), resulted in a significant improvement in the cachectic state of the animals. Treatment of the tumor-bearing animals with AR42 did not result in any effects on muscle wasting in the cachectic rats. Furthermore, the combination of formoterol and AR42 showed no additional effects to those observed with just formoterol. Conclusion: The results presented question the previously described effects of AR42 on cancer cachexia, probably due to its effect on tumor growth.

scholarly journals Coix seed oil ameliorates cancer cachexia by counteracting muscle loss and fat lipolysis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Huiquan Liu ◽  
Lu Li ◽  
Jun Zou ◽  
Ting Zhou ◽  
Bangyan Wang ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Food Intake ◽  
Cancer Cachexia ◽  
Seed Oil ◽  
Body Weight Loss ◽  
Tissue Loss ◽  
Epididymal Adipose Tissue ◽  
Tnf Α ◽  
Coix Seed

Abstract Background Cancer cachexia is a cancer-induced multifactorial debilitating syndrome directly accounting for 20% of cancer deaths without effective therapeutic approaches. It is extremely urgent to explore effective anti-cachexia drugs to ameliorate muscle and fat loss in cachexia patients. Methods Lewis lung carcinoma bearing C57BL/6 mice were applied as the animal model to examine the therapeutic effect of Coix seed oil (CSO) on cancer cachexia. The food intake and body weight change were monitored every 3 days throughout the experiment. The IL-6 and TNF-α levels in serum were detected by ELISA assay. Several key proteins involved in muscle wasting and fat lipolysis were tested by Western blot to identify the potential mechanism of CSO. Results Administration of CSO through gavage significantly prevented body weight loss and ameliorated systemic inflammation without affecting food intake and tumor size. The weight and histological morphology of gastrocnemius muscle and epididymal adipose tissue in CSO-treated mice were also improved. In mechanism, we found that CSO decreased the expression of MuRF1 and the ratio of phospho-p65 (Ser536) to p65 in muscle tissue. Meanwhile, cancer-induced activation of HSL and AMPK was also inhibited by CSO administration. Conclusion Coix seed oil exerts an anti-cachexia pharmaceutical effect by counteracting muscle and adipose tissue loss most likely through regulating NF-κB-MuRF1 and AMPK-HSL pathway.

scholarly journals Nonmuscle Tissues Contribution to Cancer Cachexia

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Josep M. Argilés ◽  
Britta Stemmler ◽  
Francisco J. López-Soriano ◽  
Silvia Busquets
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Adipose Tissue ◽  
Muscle Tissue ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Body Weight Loss ◽  
Present Review ◽  
Recent Developments ◽  
The Impact

Cachexia is a syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting, and inflammation, being often associated with anorexia. In spite of the fact that muscle tissue represents more than 40% of body weight and seems to be the main tissue involved in the wasting that occurs during cachexia, recent developments suggest that tissues/organs such as adipose (both brown and white), brain, liver, gut, and heart are directly involved in the cachectic process and may be responsible for muscle wasting. This suggests that cachexia is indeed a multiorgan syndrome. Bearing all this in mind, the aim of the present review is to examine the impact of nonmuscle tissues in cancer cachexia.

scholarly journals Pancreatic cancer induces muscle wasting by promoting the release of pancreatic adenocarcinoma upregulated factor

2021 ◽  
Author(s):  
Wonbeak Yoo ◽  
Hyunji Choi ◽  
Young Hoon Son ◽  
Jaemin Lee ◽  
Seongyea Jo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Weight Loss ◽  
Body Weight ◽  
Pancreatic Adenocarcinoma ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Group Analysis ◽  
Body Weight Loss ◽  
C2c12 Myotubes ◽  
Pancreatic Cancer Cells

AbstractCancer cachexia is a highly debilitating condition characterized by weight loss and muscle wasting that contributes significantly to the morbidity and mortality of pancreatic cancer. The factors that induce cachexia in pancreatic cancer are largely unknown. We previously showed that pancreatic adenocarcinoma upregulated factor (PAUF) secreted by pancreatic cancer cells is responsible for tumor growth and metastasis. Here, we analyzed the relation between pancreatic cancer-derived PAUF and cancer cachexia in mice and its clinical significance. Body weight loss and muscle weight loss were significantly higher in mice with Panc-1/PAUF tumors than in those with Panc-1/Mock tumors. Direct administration of rPAUF to muscle recapitulated tumor-induced atrophy, and a PAUF-neutralizing antibody abrogated tumor-induced muscle wasting in Panc-1/PAUF tumor-bearing mice. C2C12 myotubes treated with rPAUF exhibited rapid inactivation of Akt-Foxo3a signaling, resulting in Atrogin1/MAFbx upregulation, myosin heavy chain loss, and muscle atrophy. The neutrophil-to-lymphocyte ratio and body weight loss were significantly higher in pancreatic cancer patients with high PAUF expression than in those with low PAUF expression. Analysis of different pancreatic cancer datasets showed that PAUF expression was significantly higher in the pancreatic cancer group than in the nontumor group. Analysis of The Cancer Genome Atlas data found associations between high PAUF expression or a high DNA copy number and poor overall survival. Our data identified tumor-secreted circulating PAUF as a key factor of cachexia, causing muscle wasting in mice. Neutralizing PAUF may be a useful therapeutic strategy for the treatment of pancreatic cancer-induced cachexia.

scholarly journals Skeletal Muscle Fibrosis in Pancreatic Cancer Patients with Respect to Survival

2018 ◽  
Vol 2 (3) ◽  
Author(s):  
Sarah M Judge ◽  
Rachel L Nosacka ◽  
Daniel Delitto ◽  
Michael H Gerber ◽  
Miles E Cameron ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Body Weight ◽  
Cellular Response ◽  
Cancer Cachexia ◽  
Cancer Control ◽  
Body Weight Loss ◽  
Collagen Content ◽  
Calcium Deposition ◽  
Control Subjects

Abstract Background Cancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), which has one of the highest rates of cachexia. Methods Morphological analyses were performed on rectus abdominis muscle biopsies obtained from resectable PDAC patients undergoing tumor resection surgery (N = 20) and from weight-stable non-cancer control subjects undergoing benign abdominal surgery (N = 16). PDAC patients with a body weight loss of greater than 5% during the previous 6 months were considered cachectic (N = 15). Statistical tests were two sided. Results Skeletal muscle from cachectic PDAC patients had increased collagen content compared with non-cancer control subjects (1.43% vs 9.66%, P = .0004, Dunn test). Across all PDAC patients, collagen content positively correlated with body weight loss (P = .0016, r = 0.672), was increased in patients with lymph node metastasis (P = .007, Mann-Whitney U test), and was associated with survival on univariate (HR = 1.08, 95% confidence interval [CI] = 1.02 to 1.04, P = .008) and multivariable analyses (HR = 1.08, 95% CI = 1.00 to 1.17, P = .038). Cachectic PDAC patients also displayed increased lipid deposition (2.63% vs 5.72%, P = .042), infiltration of CD68+ macrophages (63.6 cells/mm2 vs 233.8 cells/mm2, P = .0238), calcium deposition (0.21% vs 2.51%, P = .030), and evidence of deficient cellular quality control mechanisms (Mann-Whitney U test). Transcriptional profiling of all patients supported these findings by identifying gene clusters related to wounding, inflammation, and cellular response to TGF-β upregulated in cachectic PDAC patients compared with non-cancer control subjects. Conclusions To our knowledge, this work is the first to demonstrate increased collagen content in cachectic PDAC patients that is associated with poor survival.

scholarly journals Pioglitazone Treatment Increases Survival and Prevents Body Weight Loss in Tumor–Bearing Animals: Possible Anti-Cachectic Effect

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0122660 ◽  
Author(s):  
Mércia Beluzi ◽  
Sidney B. Peres ◽  
Felipe S. Henriques ◽  
Rogério A. L. Sertié ◽  
Felipe O. Franco ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Body Weight Loss ◽  
Tumor Bearing ◽  
Pioglitazone Treatment

Muscle wasting associated with endotoxemia in the rat: Modification by the β2-adrenoceptor agonist clenbuterol

1989 ◽  
Vol 9 (5) ◽  
pp. 615-621 ◽  
Author(s):  
J. J. Choo ◽  
M. A. Horan ◽  
R. A. Little ◽  
N. J. Rothwell
Keyword(s):  
Body Weight ◽  
Gastrocnemius Muscle ◽  
Muscle Wasting ◽  
Single Injection ◽  
Body Weight Gain ◽  
Body Weight Loss ◽  
Separate Experiment ◽  
Febrile Response ◽  
Adrenoceptor Agonist ◽  
Adrenoceptor Agonists

A single injection of endotoxin (1 mg/kg, sc) in rats caused significant fever, body weight loss and reduction in gastrocnemius muscle mass, none of which was mimicked by pair-feeding. Infusion of endotoxin via osmotic minipump over five days caused transient fever and suppression of growth. Recovery of body weight was significantly enhanced by the administration of the β2-adrenoceptor agonist clenbuterol (added to the diet at 4 mg/kg). In a separate experiment, injections of endotoxin (day 0 and day 2) caused significant reductions in body weight gain (42%), mass (9%) and protein content (13%) of gastrocnemius muscle over 3 days. Addition of clenbuterol to the diet reversed all of these effects but did not alter food intake or the febrile response to endotoxin. Clenbuterol caused large (20%) increases in the ratio of RNA to protein in muscle indicating that it may have stimulated protein synthesis. β2-adrenoceptor agonists may therefore be of value in preventing or inhibiting muscle atrophy associated with infection or injury.

scholarly journals Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting

2020 ◽  
Vol 295 (51) ◽  
pp. 17441-17459
Author(s):  
Hawley E. Kunz ◽  
Jessica M. Dorschner ◽  
Taylor E. Berent ◽  
Thomas Meyer ◽  
Xuewei Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Mass ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mitochondrial Protein ◽  
Coupling Efficiency ◽  
C2c12 Myotubes ◽  
Tumor Bearing

Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week–old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.

scholarly journals Formoterol decreases muscle wasting as well as inflammation in the rat model of rheumatoid arthritis

2016 ◽  
Vol 310 (11) ◽  
pp. E925-E937 ◽  
Author(s):  
Ana Belén Gómez-SanMiguel ◽  
Carolina Gomez-Moreira ◽  
María Paz Nieto-Bona ◽  
Carmen Fernández-Galaz ◽  
Maria Ángeles Villanúa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Body Weight ◽  
Muscle Wasting ◽  
Body Weight Loss ◽  
Intradermal Injection ◽  
Cross Sectional ◽  
Akt Phosphorylation ◽  
Male Wistar Rats ◽  
And Control ◽  
Igfbp 3

Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. β2-adrenergic receptor agonists are powerful anabolic agents that trigger skeletal muscle hypertrophy and have been proposed as a promising treatment for muscle wasting in human patients. The aim of this work was to determine whether formoterol, a selective β2-adrenoreceptor agonist, is able to ameliorate muscle wasting in arthritic rats. Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant. Control and arthritic rats were injected daily with 50 μg/kg sc formoterol or saline for 12 days. Body weight change, food intake, and arthritis index were analyzed. After euthanasia, in the gastrocnemius mRNA was analyzed by PCR, and proteins were analyzed by Western blotting. Arthritis decreased gastrocnemius weight, cross-sectional area, and myofiber size, whereas formoterol increased those variables in both arthritic and control rats. Formoterol decreased the external signs of arthritis as well as NF-κB(p65) activation, TNFα, and COX-2 levels in the gastrocnemius of arthritic and control rats. Those effects of formoterol were associated with a decreased expression of myostatin, atrogin-1, and MuRF1 and in LC3b lipidation. Arthritis increased the expression of MyoD, myogenin, IGF-I, and IGFBP-3 and -5 in the gastrocnemius. In control and in arthritic rats, treatment with formoterol increased Akt phosphorylation and myogenin levels, whereas it decreased IGFBP-3 expression in the gastrocnemius. These data suggest that formoterol has an anti-inflammatory effect and decreases muscle wasting in arthritic rats through increasing Akt activity and myogenin and decreasing myostatin, the p-NF-κB(p65)/TNF pathway, and IGFBP-3.

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