Key result
GSK3-β inhibition prevents muscle atrophy in mice by blocking desmin phosphorylation and depolymerization.
Why the study?
Myofibril loss in muscle wasting requires depolymerization of the desmin cytoskeleton activated by phosphorylation, but the responsible kinase and mechanism were unclear.
Does GSK3-β inhibition prevent myofibril breakdown and atrophy in mice?
Does GSK3-β inhibition prevent myofibril breakdown and atrophy in mice?
GSK3-β phosphorylation of desmin is a key molecular event required for calpain-1-mediated depolymerization and myofibril destruction, making GSK3-β a potential drug target for muscle atrophy.
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-β (GSK3-β) as responsible for desmin phosphorylation. GSK3-β inhibition in mice prevented desmin phosphorylation and depolymerization and blocked atrophy upon fasting or denervation. Desmin was phosphorylated by GSK3-β 3 d after denervation, but depolymerized only 4 d later when cytosolic Ca2+ levels rose. Mass spectrometry analysis identified GSK3-β and the Ca2+-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-β is a key molecular event required for calpain-1–mediated depolymerization, and the subsequent myofibril destruction. Consequently, GSK3-β represents a novel drug target to prevent myofibril breakdown and atrophy.
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Aweida et al. (2018) studied Muscle wasting and atrophy. GSK3-β inhibition was evaluated on Desmin phosphorylation, depolymerization, and muscle atrophy. GSK3-β inhibition in mice prevented desmin phosphorylation and depolymerization, blocking muscle atrophy upon fasting or denervation.
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