Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance (original) (raw)
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Muscle myostatin signalling is enhanced in experimental cancer cachexia
European Journal of Clinical Investigation, 2008
Myostatin belongs to the transforming growth factor-β superfamily and negatively regulates skeletal muscle mass. Its deletion induces muscle overgrowth, while, on the contrary, its overexpression or systemic administration cause muscle atrophy. The present study was aimed at investigating whether muscle depletion as occurring in an experimental model of cancer cachexia, the rat bearing the Yoshida AH-130 hepatoma, is associated with modulations of myostatin signalling and whether the cytokine tumour necrosis factor-α may be relevant in this regard.
International journal of cancer. Journal international du cancer, 2015
Formoterol is a highly potent β2 -adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/Activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of the present investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2 -agonist formoterol in the cachectic Lewis lung carcinoma model (LLC). The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumour-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake both in control and tumour-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumour. In addition, it significantly reduced the numbe...
Myostatin Gene Inactivation Prevents Skeletal Muscle Wasting in Cancer
Cancer Research, 2014
Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in Apc Min/þ mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagyrelated genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in Apc Min/þ mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease. Cancer Res; 74(24); 7344-56. Ó2014 AACR.
Molecular cancer therapeutics, 2015
Skeletal muscle wasting occurs in a great majority of cancer patients with advanced disease and is associated with a poor prognosis and decreased survival. Myostatin functions as a negative regulator of skeletal muscle mass and has recently become a therapeutic target for reducing the loss of skeletal muscle and strength associated with clinical myopathies. We generated neutralizing antibodies to myostatin in order to test their potential use as therapeutic agents to attenuate the skeletal muscle wasting due to cancer. We show that our neutralizing anti-myostatin antibodies significantly increase body weight, skeletal muscle mass and strength in non-tumor bearing mice with a concomitant increase in mean myofiber area. The administration of these neutralizing antibodies in two preclinical models of cancer induced muscle wasting (C26 colon adenocarcinoma and PC3 prostate carcinoma) resulted in a significant attenuation of the loss of muscle mass and strength with no effect on tumor gr...
Changes in Myostatin Signaling in Non-Weight-Losing Cancer Patients
Annals of Surgical Oncology, 2012
Background. Myostatin is a negative regulator of skeletal muscle mass. We recently demonstrated that myostatin expression is upregulated in an experimental model of cancer cachexia, suggesting that modulations of this pathway might play a pathogenic role in cancer-related muscle wasting. The present study was designed to investigate whether myostatin signaling is modulated in the muscle of non-weight-losing (nWL) patients with lung and gastric cancer. Methods. Myostatin signaling was studied in muscle biopsies obtained during surgical procedure from nWL patients affected by gastric (n = 16) or lung (n = 17) cancer. Western blotting was applied to test both the total expression of myostatin and the expression of phosphorylated form of GSK-3beta and Smad2/3.
Role of Activin A and Myostatin in Human Cancer Cachexia
Journal of Clinical Endocrinology & Metabolism
Cachexia is a multifactorial syndrome, characterized by the loss of skeletal muscle mass and not fully reversible by nutritional support. Recent animal observations suggest that production of Activin A (ActA) and Myostatin (Mstn) by some tumors might contribute to cancer cachexia. Objective: Our goal was to investigate the role of ActA and Mstn in the development of the human cancer cachexia. Design/Setting: The ACTICA study is a cross-sectional study, which prospectively enrolled patients from a tertiary-care center between January 2012 and March 2014. Subjects/Outcome Measures: One hundred fifty two patients with colorectal or lung cancer had clinical, nutritional and functional assessment. Body composition was measured by CT-scan, anthropometry, and bioimpedance. Plasma concentrations of ActA, Mstn, and Follistatin were determined. Results: Cachexia was associated with reduced lean and fat mass (p Ͻ .01 and p Ͻ .001), reduced physical function, lower quality of life, and increased symptoms (QLQC30; p Ͻ .001). Anorexia (SNAQ score Ͻ 14) was more common in cachectic patients (CC) than in noncachectic patients (CNC) (p Ͻ .001). ActA concentrations in CC patients were higher than in CNC patients (ϩ40%; p Ͻ .001) and were correlated positively with weight loss (R ϭ 0.323; p Ͻ .001) and negatively with the SNAQ score (R ϭ Ϫ0.225; p Ͻ .01). In contrast, Mstn concentrations were decreased in CC patients compared to CNC patients (Ϫ35%; p Ͻ .001). Conclusions: These results demonstrate an association between circulating concentrations of ActA and the presence of the anorexia/cachexia syndrome in cancer patients. Given the known muscle atrophic effects of ActA, our study suggests that increased circulating concentrations of ActA may contribute to the development of cachexia in cancer patients.
Journal of Cellular Physiology, 2014
Cachexia is a relevant comorbid condition of chronic diseases including cancer. Inflammation, oxidative stress, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen activated protein kinases (MAPK) are involved in the pathophysiology of cancer cachexia. Currently available treatment is limited and data demonstrating effectiveness in in vivo models are lacking. Our objectives were to explore in respiratory and limb muscles of lung cancer (LC) cachectic mice whether proteasome, NF-κB, and MAPK inhibitors improve muscle mass and function loss through several molecular mechanisms. Body and muscle weights, limb muscle force, protein degradation and the ubiquitin-proteasome system, signaling pathways, oxidative stress and inflammation, autophagy, contractile and functional proteins, myostatin and myogenin, and muscle structure were evaluated in the diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing cachectic mice (BALB/c), with and without concomitant treatment with NF-κB (sulfasalazine), MAPK (U0126), and proteasome (bortezomib) inhibitors. Compared to control animals, in both respiratory and limb muscles of LC cachectic mice: muscle proteolysis, ubiquitinated proteins, autophagy, myostatin, protein oxidation, FoxO-1, NF-κB and MAPK signaling pathways, and muscle abnormalities were increased, while myosin, creatine kinase, myogenin, and slow-and fast-twitch muscle fiber size were decreased. Pharmacological inhibition of NF-κB and MAPK, but not the proteasome system, induced in cancer cachectic animals, a substantial restoration of muscle mass and force through a decrease in muscle protein oxidation and catabolism, myostatin, and autophagy, together with a greater content of myogenin, and contractile and functional proteins. Attenuation of MAPK and NF-κB signaling pathway effects on muscles is beneficial in cancer-induced cachexia.
The Skeletal Muscle as an Active Player Against Cancer Cachexia
Frontiers in Physiology, 2019
The management of cancer patients is frequently complicated by the occurrence of cachexia. This is a complex syndrome that markedly impacts on quality of life as well as on tolerance and response to anticancer treatments. Loss of body weight, wasting of both adipose tissue and skeletal muscle and reduced survival rates are among the main features of cachexia. Skeletal muscle wasting has been shown to depend, mainly at least, on the induction of protein degradation rates above physiological levels. Such hypercatabolic pattern is driven by overactivation of different intracellular proteolytic systems, among which those dependent on ubiquitin-proteasome and autophagy. Selective rather than bulk degradation of altered proteins and organelles was also proposed to occur. Within the picture described above, the muscle is frequently considered a sort of bystander tissue where external stimuli, directly or indirectly, can poise protein metabolism toward a catabolic setting. By contrast, several observations suggest that the muscle reacts to the wasting drive imposed by cancer growth by activating different compensatory strategies that include anabolic capacity, the activation of autophagy and myogenesis. Even if muscle response is eventually ill-fated, its occurrence supports the idea that in the presence of appropriate treatments the development of cancer-induced wasting might not be an ineluctable event in tumor hosts.
Current Cancer Drug Targets, 2009
Muscle wasting, as occurring in cancer cachexia, is primarily characterized by protein hypercatabolism and increased expression of ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1. Myostatin, a member of the TGF superfamily, negatively regulates skeletal muscle mass and we showed that increased myostatin signaling occurs in experimental cancer cachexia. On the other hand, enhanced expression of follistatin, an antagonist of myostatin, by inhibitors of histone deacetylases, such as valproic acid or trichostatin-A, has been shown to increase myogenesis and myofiber size in mdx mice. For this reason, in the present study we evaluated whether valproic acid or trichostatin-A can restore muscle mass in C26 tumor-bearing mice.
Myokines as Possible Therapeutic Targets in Cancer Cachexia
Journal of Immunology Research, 2018
Cachexia is an extremely serious syndrome which occurs in most patients with different cancers, and it is characterized by systemic inflammation, a negative protein and energy balance, and involuntary loss of body mass. This syndrome has a dramatic impact on the patient’s quality of life, and it is also associated with a low response to chemotherapy leading to a decrease in survival. Despite this, cachexia is still underestimated and often untreated. New research is needed in this area to understand this complex phenomenon and ultimately find treatment methods and therapeutic targets. The skeletal muscle can act as an endocrine organ. Signaling between muscles and other systems is done through myokines, cytokines, and proteins produced and released by myocytes. In this review, we would like to draw attention to some of the most important myokines that could have potential as biomarkers and therapeutic targets: myostatin, irisin, myonectin, decorin, fibroblast growth factor 21, inter...