MAP kinase phosphatase-1 deficiency impairs skeletal muscle regeneration and exacerbates muscular dystrophy.
In skeletal muscle, the mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a critical negative regulator of the MAPKs. Since the MAPKs have been reported to be both positive and negative for myogenesis, the physiological role of MKP-1 in skeletal muscle repair and regeneration has remained unclear. Here, we show that MKP-1 plays an essential role in adult regenerative myogenesis. In a cardiotoxin-induced muscle injury model, lack of MKP-1 impaired muscle regeneration. In mdx mice, MKP-1 deficiency reduced body weight, muscle mass, and muscle fiber cross-sectional area. In addition, MKP-1-deficient muscles exhibit exacerbated myopathy accompanied by increased inflammation. Lack of MKP-1 compromised myoblast proliferation and induced precocious differentiation, phenotypes that were rescued by pharmacological inhibition of p38alpha/beta MAPK. MKP-1 coordinates both myoblast proliferation and differentiation. Mechanistically, MyoD bound to the MKP-1 promoter and activated MKP-1 expression in proliferating myoblasts. Later, during myogenesis, MyoD uncoupled from the MKP-1 promoter leading to the down-regulation of MKP-1 and facilitation of promyogenic p38alpha/beta MAPK signaling. Hence, MKP-1 plays a critical role in muscle stem cells and in the immune response to coordinate muscle repair and regeneration.
Shi
Hao
H
Yale University School of Medicine, Department of Pharmacology, 333 Cedar St., New Haven, CT 06520-8066, USA.
Boadu
Emmanuel
E
Mercan
Fatih
F
Le
Annie M
AM
Flach
Rachel J Roth
RJ
Zhang
Lei
L
Tyner
Kristina J
KJ
Olwin
Bradley B
BB
Bennett
Anton M
AM
D000818:Animals; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency* / Q000235:genetics; D007109:Immunity; D051379:Mice; D018101:Mice, Inbred mdx; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000502:physiology*; D009136:Muscular Dystrophies / Q000209:etiology* / Q000503:physiopathology; D017570:MyoD Protein; D032446:Myoblasts / Q000166:cytology; D011401:Promoter Regions, Genetic; D012038:Regeneration; D013234:Stem Cells; D048051:p38 Mitogen-Activated Protein Kinases
D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1