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.

Regulation of the chondrogenic phenotype in culture.

In recent years, there has been a great deal of interest in the development of regenerative approaches to produce hyaline cartilage ex vivo that can be utilized for the repair or replacement of damaged or diseased tissue. It is clinically imperative that cartilage engineered in vitro mimics the molecular composition and organization of and exhibits biomechanical properties similar to persistent hyaline cartilage in vivo. Experimentally, much of our current knowledge pertaining to the regulation of cartilage formation, or chondrogenesis, has been acquired in vitro utilizing high-density cultures of undifferentiated chondroprogenitor cells stimulated to differentiate into chondrocytes. In this review, we describe the extracellular matrix molecules, nuclear transcription factors, cytoplasmic protein kinases, cytoskeletal components, and plasma membrane receptors that characterize cells undergoing chondrogenesis in vitro and regulate the progression of these cells through the chondrogenic differentiation program. We also provide an extensive list of growth factors and other extracellular signaling molecules, as well as chromatin remodeling proteins such as histone deacetylases, known to regulate chondrogenic differentiation in culture. In addition, we selectively highlight experiments that demonstrate how an understanding of normal hyaline cartilage formation can lead to the development of novel cartilage tissue engineering strategies. Finally, we present directions for future studies that may yield information applicable to the in vitro generation of hyaline cartilage that more closely resembles native tissue.

MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice.

Oxidative myofibers, also known as slow-twitch myofibers, help maintain the metabolic health of mammals, and it has been proposed that decreased numbers correlate with increased risk of obesity. The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) plays a central role in maintaining levels of oxidative myofibers in skeletal muscle. Indeed, loss of PGC-1alpha expression has been linked to a reduction in the proportion of oxidative myofibers in the skeletal muscle of obese mice. MAPK phosphatase-1 (MKP-1) is encoded by mkp-1, a stress-responsive immediate-early gene that dephosphorylates MAPKs in the nucleus. Previously we showed that mice deficient in MKP-1 have enhanced energy expenditure and are resistant to diet-induced obesity. Here we show in mice that excess dietary fat induced MKP-1 overexpression in skeletal muscle, and that this resulted in reduced p38 MAPK-mediated phosphorylation of PGC-1alpha on sites that promoted its stability. Consistent with this, MKP-1-deficient mice expressed higher levels of PGC-1alpha in skeletal muscle than did wild-type mice and were refractory to the loss of oxidative myofibers when fed a high-fat diet. Collectively, these data demonstrate an essential role for MKP-1 as a regulator of the myofiber composition of skeletal muscle and suggest a potential role for MKP-1 in metabolic syndrome.