Proteasome dysfunction induces muscle growth defects and protein aggregation.

Area of Science:

• Muscle biology
• Cellular degradation pathways
• Molecular genetics

Background:

• The ubiquitin-proteasome system and autophagy-lysosome system are key cellular clearance pathways.
• The in vivo role of the proteasome pathway in mammalian muscle remains underexplored.

Purpose of the Study:

• To investigate the in vivo function of the proteasome pathway in mammalian muscle.
• To examine the effects of deleting a specific proteasomal gene (Rpt3/Psmc4) on muscle development and function.

Main Methods:

• Generated muscle-specific Rpt3 (Psmc4) knockout mice.
• Assessed proteasomal activity, autophagy pathway markers, and muscle morphology.
• Performed microscopic analysis of myofiber integrity and sarcomere organization.

Main Results:

• Muscle-specific deletion of Rpt3 (Psmc4) led to significant muscle growth defects and reduced force production.
• Dysregulated proteasomal activity and impaired autophagosome formation were observed.
• Accumulation of basophilic inclusions and sarcomere disorganization occurred in affected muscles.

Conclusions:

• Adequate proteasomal activity is essential for muscle growth and myofiber integrity, working in concert with autophagy.
• Disruption of proteasome function contributes to myofiber degeneration and weakness in muscle disorders associated with inclusion bodies.