Reduced passive force in skeletal muscles lacking protein arginylation

Arginylation is a posttranslational modification that plays a global role in mammals. Mice lacking the enzyme arginyltransferase in skeletal muscles exhibit reduced contractile forces that have been linked to a reduction in myosin cross-bridge formation. The role of arginylation in passive skeletal...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2016-01, Vol.310 (2), p.C127-C135
Main Authors: Leite, Felipe S, Minozzo, Fábio C, Kalganov, Albert, Cornachione, Anabelle S, Cheng, Yu-Shu, Leu, Nicolae A, Han, Xuemei, Saripalli, Chandra, Yates, 3rd, John R, Granzier, Henk, Kashina, Anna S, Rassier, Dilson E
Format: Article
Language:English
Subjects:
Aminoacyltransferases - genetics
Aminoacyltransferases - metabolism
Animals
Binding sites
Connectin - chemistry
Connectin - physiology
Elastic Modulus - physiology
Mass spectrometry
Mice
Mice, Knockout
Molecules
Muscle Proteins - chemistry
Muscle Proteins - physiology
Musculoskeletal system
Myofibrils - chemistry
Myofibrils - physiology
Myofibrils - ultrastructure
Protein Processing, Post-Translational - physiology
Proteins
Stress, Mechanical
Structure-Activity Relationship
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Summary:Arginylation is a posttranslational modification that plays a global role in mammals. Mice lacking the enzyme arginyltransferase in skeletal muscles exhibit reduced contractile forces that have been linked to a reduction in myosin cross-bridge formation. The role of arginylation in passive skeletal myofibril forces has never been investigated. In this study, we used single sarcomere and myofibril measurements and observed that lack of arginylation leads to a pronounced reduction in passive forces in skeletal muscles. Mass spectrometry indicated that skeletal muscle titin, the protein primarily linked to passive force generation, is arginylated on five sites located within the A band, an important area for protein-protein interactions. We propose a mechanism for passive force regulation by arginylation through modulation of protein-protein binding between the titin molecule and the thick filament. Key points are as follows: 1) active and passive forces were decreased in myofibrils and single sarcomeres isolated from muscles lacking arginyl-tRNA-protein transferase (ATE1). 2) Mass spectrometry revealed five sites for arginylation within titin molecules. All sites are located within the A-band portion of titin, an important region for protein-protein interactions. 3) Our data suggest that arginylation of titin is required for proper passive force development in skeletal muscles.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00269.2015