Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle
Hulmi, J., Nissinen, T., Räsänen, M., Degerman, J., Lautaoja, J., Hemanthakumar, K. A., Backman, J. T., Ritvos, O., Silvennoinen, M., & Kivelä, R. (2018). Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle, 9(2), 417-432. https://doi.org/10.1002/jcsm.12265
Julkaistu sarjassa
Journal of Cachexia, Sarcopenia and MuscleTekijät
Päivämäärä
2018Tekijänoikeudet
© 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License.
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.
...
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This work was supported by the Academy of Finland (grant nos. 275922 and 297245) and Jenny and Antti Wihuri Foundation.Lisenssi
Ellei muuten mainita, aineiston lisenssi on © 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License.
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