Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function

Abstract

Introduction. Doxorubicin (DOX) is widely used as a chemotherapy drug for cancer. However, it is known to affect negatively skeletal muscle mass and function, which can expose to other diseases and decrease survival rate. Presently, there are no accepted drugs for muscle wasting, but myostatin and activin blockers are possible agents. The aim of this study was to investigate the effects of DOX administration alone or combined with blocking of activin receptor signaling on skeletal muscle size, oxidative capacity, mitochondrial function and running performance. Methods. Two identical four-week experiments were conducted in this study. The mice (n = 19 and n = 29 in experiments 1 and 2, respectively) were randomly organized into three groups: 1) controls (Ctrl, n = 6; n = 9), 2) DOX treated group (Dox, n = 6; n = 10) and 3) DOX treated group administered with sACVR2B-Fc (Dox + sACVR2B, n = 7; n = 10). Body composition was determined with DXA imaging and incremental running test was used to examine running capacity. Oxidative capacity was investigated with static biomarkers and mitochondrial function was examined with high resolution respirometry (OROBOROS). Static biomarkers were analyzed with Western immunoblot protein analysis and enzyme assay. PGC-1α gene expression was examined with RT-qPCR method. Results. Skeletal muscle mass decreased significantly in Dox group (p < 0.01), but increased following sACVR2B-Fc administration together with DOX (p < 0.001). Running distance decreased in Dox group compared to Ctrl group (p < 0.01), but did not alter in Dox + sACVR2B group vs. Dox. DOX did not have effect either on oxidative capacity or mitochondrial function. Some static biomarkers changed following sACVR2B-Fc administration. Of those, citrate synthase activity (Krebs cycle enzyme) and porin/VDAC1 protein content increased significantly (p < 0.01) compared to Dox group. The opposite trend was observed in the protein content of respiratory chain subunit (OXPHOS) complexes I (p < 0.001) and V (p < 0.05). However, neither mitochondrial function, other static biomarkers (cytochrome c and total OXPHOS protein contents) nor PGC-1α protein content and isoforms gene expression altered significantly. Conclusion. This study was the first to show decreased maximal running capacity after chemotherapy. This occurred, however without skeletal muscle mitochondrial alterations. sACVR2B-Fc may be a promising strategy to treat chemotherapy induced skeletal muscle loss, without further compromises in running capacity or major mitochondrial alterations.