Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

作者：Hulmi Juha J^*; Oliveira Bernardo M; Silvennoinen Mika; Hoogaars Willem M H; Ma Hongqiang; Pierre Philippe; Pasternack Arja; Kainulainen Heikki; Ritvos Olli

来源：American Journal of Physiology - Endocrinology And Metabolism, 2013, 304(1): E41-E50.

DOI：10.1152/ajpendo.00389.2012

• mammalian target of rapamycin complex 1
• mitogen-activated protein kinase
• myostatin
• muscle hypertrophy
• exercise
• muscle dystrophy
• Hippo

Hulmi JJ, Oliveira BM, Silvennoinen M, Hoogaars WM, Ma H, Pierre P, Pasternack A, Kainulainen H, Ritvos O. Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins. Am J Physiol Endocrinol Metab 304:E41-E50, 2013. First published October 31, 2012; doi:10.1152/ajpendo.00389.2012.-Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1-2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2Be protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, proangiogenic MAPK signaling and VEGF-A protein decreased. Hippo signaling has been characterized recently as a regulator of organ size and an important regulator of myogenesis in vitro. The phosphorylation of YAP (Yes-associated protein), a readout of activated Hippo signaling, increased after short-and longer-term myostatin and activin blocking and in exercised muscle. Moreover, dystrophic mdx mice had elevated phosphorylated and especially total YAP protein content. These results show that the blocking of myostatin and activins induce rapid skeletal muscle growth. This is associated with increased protein synthesis and mTORC1 signaling but decreased capillary density and proangiogenic signaling. It is also shown for the first time that Hippo signaling is activated in skeletal muscle after myostatin blocking and exercise and also in dystrophic muscle. This suggests that Hippo signaling may have a role in skeletal muscle in various circumstances.

• 出版日期2013-1