Reduced passive force in skeletal muscles lacking protein arginylation

Area of Science:

• Muscle physiology
• Posttranslational modifications
• Biochemistry

Background:

• Arginylation, a posttranslational modification, is globally important in mammals.
• Mice lacking arginyltransferase in skeletal muscles show reduced contractile forces, linked to myosin cross-bridge issues.
• The role of arginylation in passive skeletal myofibril forces remains unexplored.

Purpose of the Study:

• Investigate the role of arginylation in passive skeletal myofibril forces.
• Determine the impact of arginylation on titin, the primary protein responsible for passive force generation.
• Elucidate the mechanism by which arginylation regulates passive forces.

Main Methods:

• Single sarcomere and myofibril mechanical measurements.
• Mass spectrometry to identify arginylation sites on titin.
• Comparative analysis of wild-type and arginylation-deficient muscle tissues.

Main Results:

• Muscles lacking arginyl-tRNA-protein transferase (ATE1) exhibited significantly reduced active and passive forces.
• Mass spectrometry identified five arginylation sites on titin, all within the A band.
• These sites are located in a region crucial for protein-protein interactions within the sarcomere.

Conclusions:

• Arginylation of titin is essential for proper passive force development in skeletal muscles.
• Arginylation may regulate passive force by modulating protein-protein interactions between titin and the thick filament.
• This study reveals a novel mechanism for passive force regulation through posttranslational modification.