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

Abstract

BackgroundToxicity 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.MethodsThe 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.ResultsThe 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.ConclusionsCardiac 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.

Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses

“…In addition to skeletal muscles, cardiac cachexia and associated pathological changes such as arrhythmias may be linked to survival in cancer cachexia . In our hands, however, the C26 tumour burden resulted in only mild cardiac cachexia and sACVR2B treatment did not affect heart size, similarly as earlier . This differs from the results of Zhou et al who reported significant cardiac atrophy which was fully reversed by sACVR2B.…”

“…Muscle protein synthesis was analysed using surface sensing of translation method as earlier in our laboratory . Briefly, on Day 11 after C26 cell inoculation, mice were anaesthetized and subsequently injected i.p.…”

The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy

“…Such pre‐clinical considerations must be a focus of future studies in PDAC, given that activin receptor inhibition prolongs survival dramatically in combination with chemotherapy . Alternatively, a limitation of this approach could be the lesser protection of cardiac muscle vs. skeletal muscle with activin blockade or the requirement for inhibition of autocrine signalling in other yet unknown organs.…”

Skeletal muscle wasting in chronic heart failure

“…105 Ghrelin, which is primarily produced in the fundus of the stomach, has been used in disease-related anorexia and conditions of muscle loss like sarcopenia and cachexia. 117 However, while neutralizing antibodies such as MYO-029, AMG 74, and LY2495655 or soluble receptor decoys such as ACE-11 and ACE-031 has significant beneficial effects on muscle mass and strength, they also exhibit several side effects including urticarial, aseptic meningitis, diarrhoea, confusion, fatigue, and unintentional muscle contractions. 63 The small Skeletal muscle wasting in chronic heart failure molecule ghrelin-analogue anamorelin also increased muscle mass but had no effect on muscle strength.…”