title: Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins.
abstract: 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 eIF2Bε 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.
authors.affiliation: Department of Biology of Physical Activity, Neuromuscular Research Center, University of Jyväskylä, Jyväskylä, Finland. juha.hulmi@jyu.fi
authors.forename: Juha J
authors.initials: JJ
authors.lastname: Hulmi
authors.forename: Bernardo M
authors.initials: BM
authors.lastname: Oliveira
authors.forename: Mika
authors.initials: M
authors.lastname: Silvennoinen
authors.forename: Willem M H
authors.initials: WM
authors.lastname: Hoogaars
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Ma
authors.forename: Philippe
authors.initials: P
authors.lastname: Pierre
authors.forename: Arja
authors.initials: A
authors.lastname: Pasternack
authors.forename: Heikki
authors.initials: H
authors.lastname: Kainulainen
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors; D000818:Animals; D002196:Capillaries / Q000166:cytology / Q000187:drug effects*; D002452:Cell Count; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000090683:Hippo Signaling Pathway; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D055435:Myostatin / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D055435:Myostatin; D028341:Activins; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases