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Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle.

ABSTRACT: BACKGROUND:Toxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown. METHODS:The effects of DOX treatment with or without pre-treatment with soluble ACVR2B-Fc (sACVR2B-Fc) were investigated. The mice were randomly assigned into one of the three groups: (1) vehicle (PBS)-treated controls, (2) DOX-treated mice (DOX), and (3) DOX-treated mice administered with sACVR2B-Fc during the experiment (DOX + sACVR2B-Fc). DOX was administered with a cumulative dose of 24 mg/kg during 2 weeks to investigate cachexia outcome in the heart and skeletal muscle. To understand similarities and differences between skeletal and cardiac muscles in their responses to chemotherapy, the tissues were collected 20 h after a single DOX (15 mg/kg) injection and analysed with genome-wide transcriptomics and mRNA and protein analyses. The combination group was pre-treated with sACVR2B-Fc 48 h before DOX administration. Major findings were also studied in mice receiving only sACVR2B-Fc. RESULTS:The DOX treatment induced similar (~10%) wasting in skeletal muscle and the heart. However, transcriptional changes in response to DOX were much greater in skeletal muscle. Pathway analysis and unbiased transcription factor analysis showed that p53-p21-REDD1 is the main common pathway activated by DOX in both skeletal and cardiac muscles. These changes were attenuated by blocking ACVR2B ligands especially in skeletal muscle. Tceal7 (3-fold to 5-fold increase), transferrin receptor (1.5-fold increase), and Ccl21 (0.6-fold to 0.9-fold decrease) were identified as novel genes responsive to blocking ACVR2B ligands. Overall, at the transcriptome level, ACVR2B ligand blocking had only minor influence in the heart while it had marked effects in skeletal muscle. The same was also true for the effects on tissue wasting. This may be explained in part by about 18-fold higher gene expression of myostatin in skeletal muscle compared with the heart. CONCLUSIONS:Cardiac and skeletal muscles display similar atrophy after DOX treatment, but the mechanisms for this may differ between the tissues. The present results suggest that p53-p21-REDD1 signalling is the main common DOX-activated pathway in these tissues and that blocking activin receptor ligands attenuates this response, especially in skeletal muscle supporting the overall stronger effects of this treatment in skeletal muscles.

SUBMITTER: Hulmi JJ

PROVIDER: S-EPMC5879968 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle.

Hulmi Juha J JJ Nissinen Tuuli A TA Räsänen Markus M Degerman Joni J Lautaoja Juulia H JH Hemanthakumar Karthik Amudhala KA Backman Janne T JT Ritvos Olli O Silvennoinen Mika M Kivelä Riikka R

Journal of cachexia, sarcopenia and muscle 20171211 2

<h4>Background</h4>Toxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown.<h4>Methods</h4>The effects of DOX treatment with ...[more]

PMID: 29230965

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Project description:BackgroundCachexia, highly prevalent in patients with non-small cell lung cancer (NSCLC), impairs quality of life and is associated with reduced tolerance and responsiveness to cancer therapy and decreased survival. MicroRNAs (miRNAs) are small non-coding RNAs that play a central role in post-transcriptional gene regulation. Changes in intramuscular levels of miRNAs have been implicated in muscle wasting conditions. Here, we aimed to identify miRNAs that are differentially expressed in skeletal muscle of cachectic lung cancer patients to increase our understanding of cachexia and to allow us to probe their potential as therapeutic targets.MethodsA total of 754 unique miRNAs were profiled and analysed in vastus lateralis muscle biopsies of newly diagnosed treatment-naïve NSCLC patients with cachexia (n = 8) and age-matched and sex-matched healthy controls (n = 8). miRNA expression analysis was performed using a TaqMan MicroRNA Array. In silico network analysis was performed on all significant differentially expressed miRNAs. Differential expression of the top-ranked miRNAs was confirmed using reverse transcription-quantitative real-time PCR in an extended group (n = 48) consisting of NSCLC patients with (n = 15) and without cachexia (n = 11) and healthy controls (n = 22). Finally, these miRNAs were subjected to univariate and multivariate Cox proportional hazard analysis using overall survival and treatment-induced toxicity data obtained during the follow-up of this group of patients.ResultsWe identified 28 significant differentially expressed miRNAs, of which five miRNAs were up-regulated and 23 were down-regulated. In silico miRNA-target prediction analysis showed 158 functional gene targets, and pathway analysis identified 22 pathways related to the degenerative or regenerative processes of muscle tissue. Subsequently, the expression of six top-ranked miRNAs was measured in muscle biopsies of the entire patient group. Five miRNAs were detectable with reverse transcription-quantitative real-time PCR analysis, and their altered expression (expressed as fold change, FC) was confirmed in muscle of cachectic NSCLC patients compared with healthy control subjects: miR-424-5p (FC = 4.5), miR-424-3p (FC = 12), miR-450a-5p (FC = 8.6), miR-144-5p (FC = 0.59), and miR-451a (FC = 0.57). In non-cachectic NSCLC patients, only miR-424-3p was significantly increased (FC = 5.6) compared with control. Although the statistical support was not sufficient to imply these miRNAs as individual predictors of overall survival or treatment-induced toxicity, when combined in multivariate analysis, miR-450-5p and miR-451a resulted in a significant stratification between short-term and long-term survival.ConclusionsWe identified differentially expressed miRNAs putatively involved in lung cancer cachexia. These findings call for further studies to investigate the causality of these miRNAs in muscle atrophy and the mechanisms underlying their differential expression in lung cancer cachexia.

Project description:Muscle wasting in cancer cachexia can be alleviated by blocking activin receptor type 2 (ACVR2) ligands through changes in protein synthesis/degradation. These changes in cellular and protein metabolism may alter protein homeostasis. First, we elucidated the acute (1-2 days) and 2-week effects of blocking ACVR2 ligands by soluble activin receptor 2B (sACVR2B-Fc) on unfolded protein response (UPR), heat shock proteins (HSPs) and redox balance in a healthy mouse skeletal muscle. Second, we examined UPR, autophagy and redox balance with or without sACVR2B-Fc administration in muscle and liver of C26 tumor-bearing mice. The indicators of UPR and HSPs were not altered 1-2 days after a single sACVR2B-Fc administration in healthy muscles, but protein carbonyls increased (p < 0.05). Two weeks of sACVR2B-Fc administration increased muscle size, which was accompanied by increased UPR markers: GRP78 (p < 0.05), phosphorylated eIF2? (p < 0.01) and HSP47 (p < 0.01). Additionally, protein carbonyls and reduced form of glutathione increased (GSH) (p < 0.05). On the other hand, C26 cancer cachexia manifested decreased UPR markers (p-eIF2?, HSP47, p-JNK; p < 0.05) and antioxidant GSH (p < 0.001) in muscle, whereas the ratio of oxidized to reduced glutathione increased (GSSG/GSH; p < 0.001). Administration of sACVR2B-Fc prevented the decline in GSH and increased some of the UPR indicators in tumor-bearing mice. Additionally, autophagy markers LC3II/I (p < 0.05), Beclin-1 (p < 0.01), and P62 (p < 0.05) increased in the skeletal muscle of tumor-bearing mice. Finally, indicators of UPR, PERK, p-eIF2? and GRP78, increased (p < 0.05), whereas ATF4 was strongly decreased (p < 0.01) in the liver of tumor-bearing mice while sACVR2B-Fc had no effect. Muscle GSH and many of the altered UPR indicators correlated with tumor mass, fat mass and body mass loss. In conclusion, experimental cancer cachexia is accompanied by distinct and tissue-specific changes in proteostasis. Muscle hypertrophy induced by blocking ACVR2B ligands may be accompanied by the induction of UPR and increased protein carbonyls but blocking ACVR2B ligands may upregulate antioxidant protection.

Project description:BackgroundCachexia is a complex metabolic disorder and muscle atrophy syndrome, impacting 80% patients with advanced cancers. Malignant glioma is considered to be one of the deadliest human cancers, accounting for about 60% of all primary brain tumors. However, cachexia symptoms induced by glioma have received little attention. This work aims to explore skeletal muscle atrophy in orthotopic glioma murine models.MethodsBALB/c nude mice were orthotopicly implanted with normal glial (HEB) and glioma (WHO II CHG5 and WHO IV U87) cells. Cachexia symptoms of mice were depicted by phenotypic, histopathologic, physiological, and biochemical analyses. Muscle atrophy-related proteins were examined by western blot, and the involved signaling pathways were analyzed. NMR-based metabolomic analysis was applied to profile metabolic derangements in the skeletal muscle, including multivariate statistical analysis, characteristic metabolite identification, and metabolic pathway analysis.ResultsCompared with controls, mice implanted with glioma cells exhibit typical cachexia symptoms, indicating a high correlation with the malignant grades of glioma. U87 mice develop cachexia much earlier and more severe than CHG5 mice. The glioma-bearing mice showed significantly decreased skeletal muscle mass and strength, which were associated with suppressed AKT, activated AMPK, FOXO, Atrogin1, and LC3. Interestingly, expressions of MuRF1, MyoD1, and eIF3f were not significantly changed. Consistently, metabolomic analyses elucidate pronounced metabolic derangements in cachectic gastrocnemius relative to controls. Glucose, glycerol, and 3-hydroxybutyrate were remarkably downregulated, whereas glutamate, arginine, leucine, and isoleucine were upregulated in cachectic gastrocnemius. Furthermore, U87 mice showed more characteristic metabolites and more disturbed metabolic pathways including glucose and lipid metabolism, protein catabolism, anabolism, and citric acid cycle anaplerotic.ConclusionsThis study demonstrates for the first time that the orthotopic glioma murine model developed here exhibits high fidelity of cachexia manifestations in two malignant grades of glioma. Signaling pathway analysis in combination with metabolomic analysis provides significant insights into the complex pathophysiology of glioma cachexia and expands understanding of the molecular mechanisms underlying muscle atrophy.

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Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle.

Publications

Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle.

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