An ordered loss ofdesminfilaments precedesand promotes muscle atrophy
Myofibril breakdown is a hallmarkof muscle wasting and an inevitable sequel of aging and disease. The desmincytoskeleton is critical for skeletal muscle architecture and function, and itsdepolymerization is required for myofibril loss and atrophy. We uncovered thesequence of events leading to desmin loss, which is activated byphosphorylation. We developed a mass spectrometry-based kinase-trap assay andidentified glycogen synthase kinase 3-b (GSK3-b) as responsible for desmin phosphorylation. GSK3-b inhibition in mouse muscle prevented desmin phosphorylationand depolymerization, and blocked atrophy upon fasting or denervation. Hence,GSK3-b represents a novel drug target to prevent myofibril breakdownand atrophy. Phosphorylation by GSK3-b mediatedthe subsequent cleavage and depolymerization of desmin filaments by the Ca2+-specificprotease, calpain-1, when cytosolic Ca2+ levels rose. Consistently,calpain-1 downregulation prevented loss of phosphorylated desmin and blockedmyofibril breakdown and atrophy. Intriguingly, the depolymerization of desminfilament is facilitated by an understudied protein complex, the AAA-ATPase,Atad1. Atad1 bound phosphorylated desmin filaments, and together with its two previouslyunidentified co-factors, PLAA and Ubxn4, promoted desmin filament solubilizationand loss. Our studies uncovered a cooperative role for Atad1 and calpain-1 inpromoting desmin solubilization and loss, because downregulation of both genesin atrophying muscles had an additive beneficial effect on desmin filaments andoverall proteolysis. In addition, cleavage of desmin filaments by calpain-1 invitro was more efficient in the presence of Atad1. Therefore, we propose the“Pull and cut” mechanism, in which Atad1 and calpain-1 cooperate to facilitatedesmin loss in atrophy.