title: Mice lacking MKP-1 and MKP-5 Reveal Hierarchical Regulation of Regenerative Myogenesis.
abstract: The relative contribution of the MAP kinase phosphatases (MKPs) in the integration of MAP kinase-dependent signaling during regenerative myogenesis has yet to be fully investigated. MKP-1 and MKP-5 maintain skeletal muscle homeostasis by providing positive and negative effects on regenerative myogenesis, respectively. In order to define the hierarchical contributions of MKP-1 and MKP-5 in the regulation of regenerative myogenesis we genetically ablated both MKPs in mice. MKP-1/MKP 5-deficient double-knockout (MKP1/5- DKO) mice were viable, and upon skeletal muscle injury, were severely impaired in their capacity to regenerate skeletal muscle. Satellite cells were fewer in number in MKP1/5-DKO mice and displayed a reduced proliferative capacity as compared with those derived from wild-type mice. MKP1/5-DKO mice exhibited increased inflammation and the macrophage M1 to M2 transition during the resolution of inflammation was impaired following injury. These results demonstrate that the actions of MKP-1 to positively regulate myogenesis predominate over those of MKP-5, which negatively regulates myogenesis. Hence, MKP-1 and MKP-5 function to maintain skeletal muscle homeostasis through non-overlapping and opposing signaling pathways.
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Pharmacology.
authors.forename: Florian
authors.initials: F
authors.lastname: Gatzke
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Molle
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
authors.forename: Han Bin
authors.initials: HB
authors.lastname: Lee
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
authors.forename: Emma T
authors.initials: ET
authors.lastname: Helm
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
authors.forename: Jessie J
authors.initials: JJ
authors.lastname: Oldham
authors.affiliation: Department of Pharmacology.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Gerrard
authors.affiliation: Department of Pharmacology; Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
keywords: MAP kinase phosphatases; Macrophage function; Mitogen-activated protein kinase; Regenerative myogenesis; Signal transduction pathways