| First Author | Aweida D | Year | 2018 |
| Journal | J Cell Biol | Volume | 217 |
| Issue | 10 | Pages | 3698-3714 |
| PubMed ID | 30061109 | Mgi Jnum | J:265907 |
| Mgi Id | MGI:6201955 | Doi | 10.1083/jcb.201802018 |
| Citation | Aweida D, et al. (2018) GSK3-beta promotes calpain-1-mediated desmin filament depolymerization and myofibril loss in atrophy. J Cell Biol 217(10):3698-3714 |
| abstractText | Myofibril breakdown is a fundamental cause of muscle wasting and inevitable sequel of aging and disease. We demonstrated that myofibril loss requires depolymerization of the desmin cytoskeleton, which is activated by phosphorylation. Here, we developed a mass spectrometry-based kinase-trap assay and identified glycogen synthase kinase 3-beta (GSK3-beta) as responsible for desmin phosphorylation. GSK3-beta inhibition in mice prevented desmin phosphorylation and depolymerization and blocked atrophy upon fasting or denervation. Desmin was phosphorylated by GSK3-beta 3 d after denervation, but depolymerized only 4 d later when cytosolic Ca(2+) levels rose. Mass spectrometry analysis identified GSK3-beta and the Ca(2+)-specific protease, calpain-1, bound to desmin and catalyzing its disassembly. Consistently, calpain-1 down-regulation prevented loss of phosphorylated desmin and blocked atrophy. Thus, phosphorylation of desmin filaments by GSK3-beta is a key molecular event required for calpain-1-mediated depolymerization, and the subsequent myofibril destruction. Consequently, GSK3-beta represents a novel drug target to prevent myofibril breakdown and atrophy. |
