Myogenesis and muscle regeneration


Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in the protein dystrophin. Dystrophin functions to protect muscle cells from injury and loss of functional dystrophin results in break down and loss of muscle cells. A cellular signal relay system, known as a MAP kinase cascade, regulates the function of muscle stem cells, which serve as a source of new muscle cells. Hao Shi and colleagues identified the protein MKP-5 as a negative regulator of MAP kinase cascades in muscle stem cells. Loss of MKP-5 in a mouse model of DMD enhanced the development of new muscle cells (myogenesis) and helped prevent muscle degeneration. These results identify MKP-5 as an important suppressor of myogenesis and suggest that therapeutics that inhibit MKP-5 could be useful in the treatment of degenerative muscle diseases. In the accompanying image, the gastrocnemius muscle was injured and then monitored for regneration in the presence (left) and absence (right) of MKP-5. The tissue was stained for MYF-5 (pink, a marker of muscle satellite cells), nuclei (blue), BrdU (green, a marker of DNA replication, indicating cell regeneration), and a red tissue stain for contrast.    

Published April 1, 2013, by Jillian Hurst

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Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5
Hao Shi, Mayank Verma, Lei Zhang, Chen Dong, Richard A. Flavell, Anton M. Bennett
Hao Shi, Mayank Verma, Lei Zhang, Chen Dong, Richard A. Flavell, Anton M. Bennett
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Research Article Muscle biology

Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5

Abstract

Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in dystrophin. The degree of functional deterioration in muscle stem cells determines the severity of DMD. The mitogen-activated protein kinases (MAPKs), which are inactivated by MAPK phosphatases (MKPs), represent a central signaling node in the regulation of muscle stem cell function. Here we show that the dual-specificity protein phosphatase DUSP10/MKP-5 negatively regulates muscle stem cell function in mice. MKP-5 controlled JNK to coordinate muscle stem cell proliferation and p38 MAPK to control differentiation. Genetic loss of Mkp5 in mice improved regenerative myogenesis and dystrophin-deficient mdx mice lacking Mkp5 exhibited an attenuated dystrophic muscle phenotype. Hence, enhanced promyogenic MAPK activity preserved muscle stem cell function even in the absence of dystrophin and ultimately curtailed the pathogenesis associated with DMD. These results identify MKP-5 as an essential negative regulator of the promyogenic actions of the MAPKs and suggest that MKP-5 may serve as a target to promote muscle stem cell function in the treatment of degenerative skeletal muscle diseases.

Authors

Hao Shi, Mayank Verma, Lei Zhang, Chen Dong, Richard A. Flavell, Anton M. Bennett

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