Mice lacking MKP-­1 and MKP-­5 Reveal Hierarchical Regulation of Regenerative Myogenesis

Abstract

The relative contribution of the MAP kinase phosphatases (MKPs) in the integration of MAP kinase-dependent signaling during regenerative myogenesis has yet to be fully investigated. MKP-1 and MKP-5 maintain skeletal muscle homeostasis by providing positive and negative effects on regenerative myogenesis, respectively. In order to define the hierarchical contributions of MKP-1 and MKP-5 in the regulation of regenerative myogenesis we genetically ablated both MKPs in mice. MKP-1/MKP 5-deficient double-knockout (MKP1/5- DKO) mice were viable, and upon skeletal muscle injury, were severely impaired in their capacity to regenerate skeletal muscle. Satellite cells were fewer in number in MKP1/5-DKO mice and displayed a reduced proliferative capacity as compared with those derived from wild-type mice. MKP1/5-DKO mice exhibited increased inflammation and the macrophage M1 to M2 transition during the resolution of inflammation was impaired following injury. These results demonstrate that the actions of MKP-1 to positively regulate myogenesis predominate over those of MKP-5, which negatively regulates myogenesis. Hence, MKP-1 and MKP-5 function to maintain skeletal muscle homeostasis through non-overlapping and opposing signaling pathways.

Dual-specificity MAP kinase phosphatases in health and disease

“…More recently, the study of DUSP1 −/− / DUSP10 −/− double knockout (DKO) mice revealed a severe impairment in muscle regeneration. Satellite cells, the precursors of muscle cells, were less proliferative and DKO mice had increased inflammation at sites of injury suggesting that the positive regulation of myogenesis by DUSP1 /MKP-1 is dominant over negative regulation by DUSP10 /MKP-5 [ 80 ]. Despite the fact that they share common substrates in JNK and p38 it is clear that these two MKPs regulate distinct signalling events.…”

Role of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis

“…MKP-5-deficient mice exhibited increased muscle stem cell proliferation and differentiation and consequently improved myogenesis. When a mouse model of Duchenne muscular dystrophy was generated to lack the expression of MKP-5, it was found that dystrophic muscle disease, including the development of fibrosis, was attenuated (19,31,32). These observations suggested the involvement of MKP-5 in skeletal muscle fibrosis.…”

Loss of MKP-5 promotes myofiber survival by activating STAT3/Bcl-2 signaling during regenerative myogenesis

“…MKP-5 is highly expressed in skeletal muscle and is differentially regulated in response to specific stimuli such as cellular injury [ 4 , 13 , 14 ]. Our group has demonstrated that MKP-5 is an essential negative regulator of SC proliferation and differentiation [ 4 , 58 ]. SCs endow skeletal muscle with its highly regenerative capacity, and the process of regeneration in response to injury is orchestrated by synchronizing the activation of various cellular responses [ 59 , 60 ].…”

“…The MAPKs have also been shown to be involved in regulating myofiber survival [ 61 , 62 ]. In skeletal muscle, p38 MAPK and JNK are negatively regulated by MKP-5, which contributes to the maintenance of myofiber homeostasis [ 4 , 58 ]. During muscle regeneration, MKP-5 is downregulated, thereby promoting p38 MAPK/JNK signaling and subsequent repair of damaged muscle [ 4 ].…”