MAP kinase phosphatase‐1 deficiency impairs skeletal muscle regeneration and exacerbates muscular dystrophy

Abstract

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.

p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair

“…Satellite cell-intrinsic MKP-1 loss neither affected activation of p38 (a critical regulatory pathway in satellite cell behavior) or myogenesis in any of the models, whereas dysregulated cytokine production in macrophages lacking MKP-1 / altered satellite cell functions in a paracrine manner. Interestingly, previous studies had anticipated a relevant function for MKP-1 in myogenesis (Bennett and Tonks, 1997;Wu et al, 2006;Roth et al, 2009;Shi et al, 2010). The distinct findings concerning myogenesis could be explained by the different experimental models used, supporting the need for a future evaluation of MKP-1 function using muscle-specific deletion approaches.…”

“…gain-and loss-of-function studies in vitro and in vivo (Bennett and Tonks, 1997;Wu et al, 2006;Roth et al, 2009;Shi et al, 2010). Similarly, increases in TNF, IL-6 (interleukin-6), and IL-10 (interleukin-10) expression dependent on p38 activation, concomitant with enhanced induced NO synthase-NO and reduced arginase synthesis, have been proposed to underlie the exacerbated response to endotoxin challenge in mice genetically deficient in MKP-1 (Chi et al, 2006;Hammer et al, 2006;Wu et al, 2006;Zhao et al, 2006).…”

Mitogen-Activated Protein Kinases and Mitogen-Activated Protein Kinase Phosphatases in Regenerative Myogenesis and Muscular Dystrophy

“…Although a wide body of evidence supports the pro-myogenic role of p38 MAPK, several reports also imply the involvement of p38 MAPK in muscle cell proliferation. The concomitant activation of p38 MAPKα/ and satellite cells imply that p38 MAPK may also be involved in satellite cell activation, since blockade of p38 MAPK by pharmacological inhibitors of p38 MAPK prevents both satellite cell proliferation and differentiation (Jones et al, 2005;Shi et al, 2010). A recent study using p38 -deficient mice revealed that muscles lacking this isoform of p38 MAPK contain 50% less satellite cells, and these cells exhibit reduced proliferation (Gillespie et al, 2009) implying that this p38 MAPK isoform may also be an important regulator of satellite cell deposition and proliferation.…”

“…Hence, MKP-1 plays both positive and negative roles in myogenesis in a temporal manner by selectively regulating one or more MAPKs (Figure 1). MKP-1 appears to be directly coupled to the myogenic transcriptional machinery as studies have shown that MKP-1 is a target for upregulation by MyoD (Shi et al, 2010). Within the proximal promoter of MKP-1 there resides an E-box binding site that serves to mediate MKP-1 activation by MyoD (Shi et al, 2010).…”

MAPK Pathway in Skeletal Muscle Diseases

“…MKP-1 is a nuclear phosphatase that dephosphrylates p38 MAPK, JNK, and ERK1/2 not only in skeletal muscle but also in the immune, metabolic, and nervous system as well [9,[31][32][33][34]. In the cardiotoxin-induced skeletal muscle regeneration, knockout of MKP-1 impaired the recovery of the damaged muscle likely through the effect of p38 MAPK pathways on muscle stem cell function [33], since the precocious differentiation of muscle stem cells caused by enhanced p38 MAPK may slow down the injured muscle from returning to a normal musculature [33]. Interestingly, when another MKP family member MKP-5 was knocked out, muscle regeneration following damage was greatly improved [35].…”