Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes.
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.
Department of Biology of Physical Activity, Neuromuscular Research Center, University of Jyväskylä, Jyväskylä, Finland.
T A
TA
Nissinen
Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland.
J
J
Degerman
Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland.
M
M
Räsänen
Department of Biology of Physical Activity, Neuromuscular Research Center, University of Jyväskylä, Jyväskylä, Finland.
A R
AR
Poikonen
LIKES Research Center for Sport and Health Sciences, Jyväskylä, Finland.
S
S
Koskinen
Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
E
E
Mervaala
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland.
A
A
Pasternack
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland.|Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
O
O
Ritvos
Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland.
R
R
Kivelä
Department of Biology of Physical Activity, Neuromuscular Research Center, University of Jyväskylä, Jyväskylä, Finland.|Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
J J
JJ
Hulmi
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