Activin A induces skeletal muscle catabolism via p38β mitogen-activated protein kinase

J Cachexia Sarcopenia Muscle. 2017 Apr;8(2):202-212. doi: 10.1002/jcsm.12145. Epub 2016 Sep 16.

Abstract

Background: Activation of type IIB activin receptor (ActRIIB) in skeletal muscle leads to muscle atrophy because of increased muscle protein degradation. However, the intracellular signalling mechanism that mediates ActRIIB-activated muscle catabolism is poorly defined.

Methods: We investigated the role of p38β mitogen-activated protein kinases (MAPK) in mediating ActRIIB ligand activin A-activated muscle catabolic pathways in C2C12 myotubes and in mice with perturbation of this kinase pharmacologically and genetically.

Results: Treatment of C2C12 myotubes with activin A or myostatin rapidly activated p38 MAPK and its effector C/EBPβ within 1 h. Paradoxically, Akt was activated at the same time through a p38 MAPK-independent mechanism. These events were followed by up-regulation of ubiquitin ligases atrogin1 (MAFbx) and UBR2 (E3α-II), as well as increase in LC3-II, a marker of autophagosome formation, leading to myofibrillar protein loss and myotube atrophy. The catabolic effects of activin A were abolished by p38α/β MAPK inhibitor SB202190. Using small interfering RNA-mediated gene knockdown, we found that the catabolic activity of activin A was dependent on p38β MAPK specifically. Importantly, systemic administration of activin A to mice similarly activated the catabolic pathways in vivo, and this effect was blocked by SB202190. Further, activin A failed to activate the catabolic pathways in mice with muscle-specific knockout of p38β MAPK. Interestingly, activin A up-regulated MuRF1 in a p38 MAPK-independent manner, and MuRF1 did not appear responsible for activin A-induced myosin heavy chain loss and muscle atrophy.

Conclusions: ActRIIB-mediated activation of muscle catabolism is dependent on p38β MAPK-activated signalling.

Keywords: ActRIIB; Activin A; Cachexia; Muscle wasting; Myostatin; p38β MAPK.

MeSH terms

  • Activin Receptors, Type II / metabolism*
  • Activins / metabolism*
  • Animals
  • Atrophy / metabolism
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Line
  • Male
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 11 / genetics
  • Mitogen-Activated Protein Kinase 11 / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • RNA, Small Interfering
  • activin A
  • Activins
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 11
  • Activin Receptors, Type II
  • activin receptor type II-B