Obestatin signalling counteracts glucocorticoid‐induced skeletal muscle atrophy via NEDD4/KLF15 axis

Abstract

Background A therapeutic approach for the treatment of glucocorticoid-induced skeletal muscle atrophy should be based on the knowledge of the molecular mechanisms determining the unbalance between anabolic and catabolic processes and how to re-establish this balance. Here, we investigated whether the obestatin/GPR39 system, an autocrine signalling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against chronic glucocorticoid-induced muscle atrophy. Methods In this study, we used an in vivo model of muscle atrophy induced by the synthetic glucocorticoid dexamethasone to examine the liaison molecules that define the interaction between the glucocorticoid receptor and the obestatin/GPR39 systems. The findings were extended to in vitro effects on human atrophy using human KM155C25 myotubes. Results KLF15 and FoxO transcription factors were identified as direct targets of obestatin signalling in the control of proteostasis in skeletal muscle. The KLF15-triggered gene expression program, including atrogenes and FoxOs, was regulated via KLF15 ubiquitination by the E3 ubiquitin ligase NEDD4. Additionally, a specific pattern of FoxO post-translational modification, including FoxO4 phosphorylation by Akt pathway, was critical in the regulation of the ubiquitin-proteasome system. The functional cooperativity between Akt and NEDD4 in the regulation of FoxO and KLF15 provides integrated cues to counteract muscle proteostasis and re-establish protein synthesis. Conclusions The effective control of FoxO activity in response to glucocorticoid is critical to counteract muscle-related pathologies. These results highlight the potential of the obestatin/GPR39 system to fine-tune the effects of glucocorticoids on skeletal muscle wasting.

Diabetic Muscular Atrophy: Molecular Mechanisms and Promising Therapies

“…GRs also upregulate the expression of regulated in development and DNA damage responses 1 (REDD1) and Kruppel like factor 15 (KLF15). KLF15 is a member of the KLF transcription factor family; it can regulate muscle catabolism by regulating MAFbx and MuRF1 ( 96 ). The expression of KLF15 has been found to be up-regulated in the livers of diabetic mice, and hyperglycemia is known to up-regulate KLF15 protein, thereby accelerating skeletal muscle atrophy ( 97 ).…”

“…REDD1 is a stress-responsive protein that inhibits the targets of mTOR in mTOR1 ( 98 ). The inhibition of mTOR can upregulate KLF15, which would increase the expression of atrophy-related genes, thereby triggering atrophy ( 96 , 99 ). Overall, GCs participate in skeletal muscle atrophy through multiple pathways.…”

Pyruvate dehydrogenase kinase 4 promotes ubiquitin–proteasome system‐dependent muscle atrophy

“…23 Furthermore, fork-head-box protein O1 (FOXO1), a known transcription factor of PDK4, 38,39 was found to play a role in promoting muscle atrophy via transcriptional regulation of MAFbx to promote protein degrada-tion during muscle atrophy. 8,37 We found that overexpression or DEX-mediated induction of PDK4 enhanced the interaction between MYOG and MAFbx but not with the non-phosphorylatable mutant of MYOG (MYOG AA ). Conversely, knockdown of MAFbx rescued MYOG degradation in the presence of DEX, indicating that PDK4-mediated phosphorylation of MYOG promotes its ubiquitination process and proteasomal degradation via recruitment of MAFbx.…”

Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice

“…First, we tried to inactivate the FoxO pathway, which was activated by knocking out of Akt1 / 2 . We focused on Foxo1 and Foxo4, major isoforms of FoxOs in skeletal muscle which were recently reported to be major FoxOs downstream of Akt 31 , and generated skeletal-specific Akt1 / Akt2 / Foxo1 / Foxo4 quadruple-knockout (mAkt/FoxoQKO) mice (Supplementary Fig. 9a, b ).…”