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

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Nissinen , T A , Degerman , J , Räsänen , M , Poikonen , A R , Koskinen , S , Mervaala , E , Pasternack , A , Ritvos , O , Kivela , R & Hulmi , J J 2016 , ' Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes ' , Scientific Reports , vol. 6 , 32695 . https://doi.org/10.1038/srep32695

Title: Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes
Author: Nissinen, T. A.; Degerman, J.; Räsänen, M.; Poikonen, A. R.; Koskinen, S.; Mervaala, E.; Pasternack, A.; Ritvos, O.; Kivela, R.; Hulmi, J. J.
Contributor: University of Helsinki, Research Programs Unit
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Research Programs Unit
University of Helsinki, Department of Physiology
Date: 2016-09-26
Language: eng
Number of pages: 16
Belongs to series: Scientific Reports
ISSN: 2045-2322
URI: http://hdl.handle.net/10138/168056
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.
Subject: ACUTE DOXORUBICIN CARDIOTOXICITY
SKELETAL-MUSCLE
EXERCISE PROTECTS
CANCER CACHEXIA
MDX MICE
EXPRESSION
MYOSTATIN
RECEPTOR
HEART
CARDIOMYOPATHY
3111 Biomedicine
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