Blocking of myostatin and activins increase muscle protein synthesis and mTORC1 signaling but decreases capillary density

Blocking of myostatin and activins increases muscle mass but the underlying mechanisms are unknown and whether during muscle growth capillary density is maintained. Soluble activin receptor IIb fused to Fc (ActRIIB/Fc) was produced in house inhibiting myostatin, activin A and activin B signaling in a biological assay. Healthy mice were injected with ActRIIB/Fc either 1x or 2x/wk for 2 weeks. The 2x/wk dosage seemed to increase muscle mass slightly more. In gastrocnemius muscle fiber size increased ~15–20 % whereas the capillary density decreased ~20 %. In muscle homogenate, PGC‐1α and cytochrome C protein decreased 40–50 %. To elucidate mechanisms for these, we next sacrificed mice 1 or 2 days after ActRIIB/Fc or PBS injection. Muscle protein synthesis increased in gastrocnemius ~30 % 2 days after ActRIIB/Fc correlating with increased mTORC1 signaling (increased phosphorylation (p) of rpS6, r=0.8, p<0.01). In contrast, muscle protein ubiquitination and p‐FoxO remained unchanged. Both p‐p38 and p‐Erk 1/2 MAPKs decreased 2 days after ActRIIB/Fc. Of novel proteins possibly associated with TGFβ blocking, REDD1 increased 1–2 days after ActRIIB/Fc. Importance of this finding needs to be studied in the future. In conclusion, blocking of ActRIIB pathway increases muscle protein synthesis and mTORC1 signaling but decreases MAPK signaling after 2 days and decreases muscle capillary density.