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

Abstract

BackgroundThe 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.MethodsTo 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.ResultsWe 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.ConclusionsTaken 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.

Muscle Injury Associated Elevated Oxidative Stress and Abnormal Myogenesis in Patients with Idiopathic Scoliosis

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Dual-specificity MAP kinase phosphatases in health and disease

“…Firstly, deletion of DUSP10 /MKP-5 increases MAPK-dependent phosphorylation of guanine nucleotide exchange factor for the Ras-related protein Rab-3A Rab3A (GRAB) at Serine 169, a site required for secretion of the promyogenic cytokine IL-6 [ 191 ]. Secondly, in the absence of DUSP10 /MKP-5 increased JNK and p38 mediated phosphorylation and activation of STAT3, increases the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl2) thus preventing apoptosis during regenerative myogenesis and also leads to improved antioxidant defence capacity due to a sustained increase in catalase expression that protects mitochondrial function [ 192 ].…”

Functional mechanism of AMPK activation in mitochondrial regeneration of rat peritoneal macrophages mediated by uremic serum

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