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Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5
Hao Shi1, Mayank Verma, Lei Zhang
1Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
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.
Insights
Duchenne muscular dystrophy (DMD) severity is linked to muscle stem cell function. Inhibiting MKP-5 enhances stem cell function, improving muscle regeneration and reducing DMD symptoms in mice.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) is a severe degenerative skeletal muscle disease.
- Muscle stem cell function is critical for DMD severity and is regulated by mitogen-activated protein kinases (MAPKs) and MAPK phosphatases (MKPs).
Purpose of the Study:
- To investigate the role of dual-specificity protein phosphatase DUSP10/MKP-5 in regulating muscle stem cell function in the context of DMD.
- To determine if targeting MKP-5 can ameliorate the dystrophic phenotype.
Main Methods:
- Utilized mouse models, including genetic loss-of-function studies of Mkp5.
- Analyzed muscle stem cell proliferation and differentiation.
- Assessed regenerative myogenesis and the dystrophic phenotype in mdx mice lacking Mkp5.
Main Results:
- MKP-5 negatively regulates muscle stem cell function by controlling JNK and p38 MAPK signaling pathways.
- Genetic deletion of Mkp5 in mice improved muscle regeneration.
- Mice lacking Mkp5 exhibited an attenuated dystrophic muscle phenotype, demonstrating preserved muscle stem cell function even without dystrophin.
Conclusions:
- MKP-5 is a key negative regulator of promyogenic MAPK activity in muscle stem cells.
- Targeting MKP-5 holds potential for therapeutic strategies to enhance muscle stem cell function and treat degenerative skeletal muscle diseases like DMD.
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