Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle.

Jaclyn P Kerr,Aaron M Kempema,Joseph K Hexum,Benjamin L Prosser,Stuart S Martin,Alexey I Bogush,Patrick Robison,Natalia Becerra,Daniel A Harki,Christopher W Ward,Guoli Shi,Roberto Raiteri

doi:10.1038/ncomms9526

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.

Highlights

In striated muscle, X-ROS is the mechanotransduction pathway by which mechanical stress transduced by the microtubule network elicits reactive oxygen species
In the mdx mouse model of Duchenne muscular dystrophy (DMD), we found that increased MT density[4,6] and cytoskeletal stiffness[4] correlated with excessive X-ROS that induced detrimental Ca2 þ signals that are believed to underlie cardiac arrhythmia[6,9] and contraction-induced damage in skeletal muscle[4]
Immunolabeling a-tubulin reveals a MT network favouring a fenestrated organization in skeletal flexor digitorum brevis (FDB) myofibres (Fig. 1a; control), and a longitudinal axis distribution in wild-type (WT) cardiomyocytes (Fig. 1d; control), consistent with previous reports[10,25,26]

Summary

Introduction

X-ROS is the mechanotransduction pathway by which mechanical stress transduced by the microtubule network elicits reactive oxygen species. 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. In the mdx mouse model of DMD, we found that increased MT density[4,6] and cytoskeletal stiffness[4] correlated with excessive X-ROS that induced detrimental Ca2 þ signals that are believed to underlie cardiac arrhythmia[6,9] and contraction-induced damage in skeletal muscle[4]. We demonstrated that an acute pharmacological strategy to promote MT disassembly (colchicine) reduced X-ROS and detrimental Ca2 þ signalling in vitro and proffered therapeutic benefit in vivo, implicating increased MT density in the dysregulation of mechanotransduction in DMD. In light of transcriptional evidence from human DMD samples[4] indicating an upregulation of the X-ROS pathway, as well as a link between MT density and X-ROS in additional dystrophy models[3,7], we initially proposed that the increase in MT network density was a pathological factor in muscular dystrophy

Methods

Results

Conclusion