title: Activin A induces skeletal muscle catabolism via p38β mitogen-activated protein kinase.
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.
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, 77030, USA.|Department of Respiratory Medicine, Yixing Hospital affiliated to Jiangsu University, Yixing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, 77030, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, 77030, USA.
authors.forename: Ka Wai Thomas
authors.initials: KW
authors.lastname: Sin
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, 77030, USA.|Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhelong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, 77030, USA.
authors.forename: Ren-Kuo
authors.initials: RK
authors.lastname: Lin
authors.affiliation: Department of Medicine and Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, 77030, USA.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D028341:Activins / Q000378:metabolism*; D000818:Animals; D001284:Atrophy / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002460:Cell Line; D008297:Male; D018345:Mice, Knockout; D048290:Mitogen-Activated Protein Kinase 11 / Q000235:genetics / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D034741:RNA, Small Interfering; C422405:activin A; D028341:Activins; D051057:Proto-Oncogene Proteins c-akt; D048290:Mitogen-Activated Protein Kinase 11; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B
keywords: ActRIIB; Activin A; Cachexia; Muscle wasting; Myostatin; p38β MAPK