Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes.

T A Nissinen,S Koskinen,J Degerman,A R Poikonen,R Kivelä,A Pasternack,O Ritvos,M Räsänen,J J Hulmi,E Mervaala

doi:10.1038/srep32695

Abstract

Doxorubicin is a widely used and effective chemotherapy drug. However, cardiac and skeletal muscle toxicity of doxorubicin limits its use. Inhibiting myostatin/activin signalling can prevent muscle atrophy, but its effects in chemotherapy-induced muscle wasting are unknown. In the present study we investigated the effects of doxorubicin administration alone or combined with activin receptor ligand pathway blockade by soluble activin receptor IIB (sACVR2B-Fc). Doxorubicin administration decreased body mass, muscle size and bone mineral density/content in mice. However, these effects were prevented by sACVR2B-Fc administration. Unlike in many other wasting situations, doxorubicin induced muscle atrophy without markedly increasing typical atrogenes or protein degradation pathways. Instead, doxorubicin decreased muscle protein synthesis which was completely restored by sACVR2B-Fc. Doxorubicin administration also resulted in impaired running performance without effects on skeletal muscle mitochondrial capacity/function or capillary density. Running performance and mitochondrial function were unaltered by sACVR2B-Fc administration. Tumour experiment using Lewis lung carcinoma cells demonstrated that sACVR2B-Fc decreased the cachectic effects of chemotherapy without affecting tumour growth. These results demonstrate that blocking ACVR2B signalling may be a promising strategy to counteract chemotherapy-induced muscle wasting without damage to skeletal muscle oxidative capacity or cancer treatment.

Highlights

Cancer-related cachexia has been suggested to account for up to 20–30% of all cancer deaths[1]
The weight loss was most dramatic during the second week of doxorubicin administration and the reduced body weight was sustained after the cessation of doxorubicin administration (Fig. 1a)
This was accompanied by a significant reduction in tissue masses of tibialis anterior (TA) and gastrocnemius muscles and epididymal fat pads determined upon euthanasia (Fig. 1b–e and Supplementary Fig. S1a–d)

Summary

Introduction

Cancer-related cachexia has been suggested to account for up to 20–30% of all cancer deaths[1]. An often used strategy to prevent muscle loss in animal models is to block these ACVRIIB ligands by administration of a soluble ligand binding domain of ACVR2B fused to the Fc region of IgG (sACVR2B-Fc) This strategy has been shown to increase muscle mass effectively in mice[17,18,19]. Blocking ACVR2B ligands can depending on the context, have adverse effects[22,23,24] It is not known whether sACVR2B-Fc administration could prevent doxorubicin-induced muscle atrophy without negatively altering muscle oxidative capacity. In the present study we investigated the effects of systemic doxorubicin administration alone or combined with sACVR2B-Fc treatment on skeletal muscle size and function and the underlying molecular mechanisms. SACVR2B-Fc administration did not affect tumour growth or the effect of doxorubicin on tumour growth

Methods

Results

Conclusion