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Skelet Muscle. 2017 Oct 18;7(1):21. doi: 10.1186/s13395-017-0137-7.

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

Author information

1
Department of Pharmacology, Yale University, New Haven, CT, 06520, USA.
2
Department of Pharmacology, Yale University, New Haven, CT, 06520, USA. anton.bennett@yale.edu.
3
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University, New Haven, CT, 06520, USA. anton.bennett@yale.edu.

Abstract

BACKGROUND:

The mitogen-activated protein kinases (MAPKs) have been shown to be involved in regulating myofiber survival. In skeletal muscle, p38 MAPK and JNK are negatively regulated by MAPK phosphatase-5 (MKP-5). During muscle regeneration, MKP-5 is downregulated, thereby promoting p38 MAPK/JNK signaling, and subsequent repair of damaged muscle. Mice lacking MKP-5 expression exhibit enhanced regenerative myogenesis. However, the effect of MKP-5 on myofiber survival during regeneration is unclear.

METHODS:

To investigate whether MKP-5 is involved in myofiber survival, skeletal muscle injury was induced by cardiotoxin injection, and the effects on apoptosis were assessed by TUNEL assay in wild type and MKP-5-deficient mice. The contribution of MKP-5 to apoptotic signaling and its link to this pathway through mitochondrial function were determined in regenerating skeletal muscle of MKP-5-deficient mice.

RESULTS:

We found that loss of MKP-5 in skeletal muscle resulted in improved myofiber survival. In response to skeletal muscle injury, loss of MKP-5 decreased activation of the mitochondrial apoptotic pathway involving the signal transducer and activator of transcription 3 (STAT3) and increased expression of the anti-apoptotic transcription factor Bcl-2. Skeletal muscle of MKP-5-deficient mice also exhibited an improved anti-oxidant capacity as a result of increased expression of catalase further contributing to myofiber survival by attenuating oxidative damage.

CONCLUSIONS:

Taken together, these findings suggest that MKP-5 coordinates skeletal muscle regeneration by regulating mitochondria-mediated apoptosis. MKP-5 negatively regulates apoptotic signaling, and during regeneration, MKP-5 downregulation contributes to the restoration of myofiber survival. Finally, these results suggest that MKP-5 inhibition may serve as an important therapeutic target for the preservation of skeletal muscle survival in degenerative muscle diseases.

KEYWORDS:

Bcl-2; MAP kinase; MKP-5; Mitochondria; Myonuclear apoptosis; Reactive oxygen species; Regeneration; STAT3

PMID:
29047406
PMCID:
PMC5648478
DOI:
10.1186/s13395-017-0137-7
[Indexed for MEDLINE]
Free PMC Article

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