Arginylation of Myosin Heavy Chain Regulates Skeletal Muscle Strength

• Published in: Cell reports (Cambridge) 2014-07, Vol.8 (2), p.470-476
• Main Authors: Cornachione, Anabelle S., Leite, Felipe S., Wang, Junling, Leu, Nicolae A., Kalganov, Albert, Volgin, Denys, Han, Xuemei, Xu, Tao, Cheng, Yu-Shu, Yates, John R.R., Rassier, Dilson E., Kashina, Anna
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Aminoacyltransferases - genetics; Aminoacyltransferases - metabolism; Animals; Mice; Muscle Contraction; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Myofibrils - metabolism; Myosin Heavy Chains - metabolism; Protein Processing, Post-Translational
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.06.019

Protein arginylation is a posttranslational modification with an emerging global role in the regulation of actin cytoskeleton. To test the role of arginylation in the skeletal muscle, we generated a mouse model with Ate1 deletion driven by the skeletal muscle-specific creatine kinase (Ckmm) promoter. Ckmm-Ate1 mice were viable and outwardly normal; however, their skeletal muscle strength was significantly reduced in comparison to controls. Mass spectrometry of isolated skeletal myofibrils showed a limited set of proteins, including myosin heavy chain, arginylated on specific sites. Atomic force microscopy measurements of contractile strength in individual myofibrils and isolated myosin filaments from these mice showed a significant reduction of contractile forces, which, in the case of myosin filaments, could be fully rescued by rearginylation with purified Ate1. Our results demonstrate that arginylation regulates force production in muscle and exerts a direct effect on muscle strength through arginylation of myosin. [Display omitted] •Knockout of arginyltransferase in mouse skeletal muscle results in muscular weakness•Structural and regulatory components of the skeletal myofibrils are arginylated•Nonarginylated myosin forms fewer cross bridges with the actin filaments•Weakened contractility of nonarginylated myosin can be reversed by arginylation In this study, Cornachione et al. show that a skeletal-muscle-specific knockout of arginyltransferase ATE1 in mice results in muscular weakness, correlated with the lack of arginylation of myosin heavy chain and several other structural components of the myofibrils. Purified nonarginylated myosin forms fewer cross bridges with the actin filaments, resulting in weakened contractile force, and this effect can be directly rescued by myosin rearginylation. This demonstrates a direct effect of arginylation on motor activity.