GSK3-β promotes calpain-1-mediated desmin filament depolymerization and myofibril loss in atrophy

Area of Science:

• Muscle physiology and molecular biology
• Cellular mechanisms of muscle atrophy

Background:

• Myofibril breakdown causes muscle wasting, common in aging and disease.
• Desmin cytoskeleton depolymerization, activated by phosphorylation, is crucial for myofibril loss.

Purpose of the Study:

• To identify the kinase responsible for desmin phosphorylation.
• To investigate the role of GSK3-β and calpain-1 in desmin depolymerization and muscle atrophy.

Main Methods:

• Developed a mass spectrometry-based kinase-trap assay.
• Utilized mouse models of fasting and denervation.
• Performed mass spectrometry to identify proteins bound to desmin.

Main Results:

• Identified glycogen synthase kinase 3-β (GSK3-β) as the kinase phosphorylating desmin.
• GSK3-β inhibition prevented desmin phosphorylation, depolymerization, and muscle atrophy in mice.
• GSK3-β and calpain-1 were found to bind desmin, catalyzing its disassembly.
• Calpain-1 down-regulation also prevented desmin loss and atrophy.

Conclusions:

• Desmin phosphorylation by GSK3-β is essential for calpain-1-mediated depolymerization and myofibril destruction.
• GSK3-β is a potential therapeutic target to prevent muscle wasting.