Detyrosinated Microtubules Modulate Mechanotransduction in Heart and Skeletal Muscle

ABSTRACT: In striated muscle, X-ROS is the mechanotransduction pathway by which mechanical stress transduced by the microtubule network elicits reactive oxygen species. X-ROS tunes Ca2+ signalling in healthy muscle, but in diseases such as Duchenne muscular dystrophy (DMD), microtubule alterations drive elevated X-ROS, disrupting Ca2+ homeostasis and impairing function. Here we show that detyrosination, a post-translational modification of α-tubulin, influences X-ROS signalling, contraction speed and cytoskeletal mechanics. In the mdx mouse model of DMD, the pharmacological reduction of detyrosination in vitro ablates aberrant X-ROS and Ca2+ signalling, and in vivo it protects against hallmarks of DMD, including workload-induced arrhythmias and contraction-induced injury in skeletal muscle. We conclude that detyrosinated microtubules increase cytoskeletal stiffness and mechanotransduction in striated muscle and that targeting this post-translational modification may have broad therapeutic potential in muscular dystrophies.

• Autores: Colorado Becerra, Natalia Yiset; Raiteri, Roberto; Kerr P., Jaclyn; Robison, Patrick; Shi, Guoli; Bogush, Alexey; Kempema, Aaron; Hexum, Joseph; Harki, Daniel; Martin, Stuart; Prosser, Benjamin; Ward, Christopher
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2015
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/36449
• Acceso en línea: https://hdl.handle.net/10495/36449
• Palabra clave: Fenómenos Biomecánicos; Biomechanical Phenomena; Calcio; Calcium; Ratones Endogámicos C57BL; Mice, Inbred C57BL; Microscopía de Fuerza Atómica; Microscopy, Atomic Force; Fibras Musculares Esqueléticas; Muscle Fibers, Skeletal; Miocitos cardíacos; Myocytes, Cardiac
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/2.5/co/