Min 2017 Skelet Muscle
|Min K, Lawan A, Bennett AM (2017) Loss of MKP-5 promotes myofiber survival by activating STAT3/Bcl-2 signaling during regenerative myogenesis. Skelet Muscle 7:21.|
Abstract: 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.
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.
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.
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, Buffer z • Bioblast editor: Kandolf G
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, mtDNA;mt-genetics, Genetic knockout;overexpression, Pharmacology;toxicology
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS Pathway: N HRR: Oxygraph-2k