Myofibrillar Malformations are Driven by Aberrant Microtubule Detyrosination in Aging and Dystrophy

Abstract

The highly ordered structure of the myofibrillar matrix is essential for optimal muscle function. However, in dystrophy and aging myofibrils become misaligned resulting in misorientation of force vectors and dyssynchronous activation of sarcomeres. Alterations in muscle fiber structure have been linked to the decreased contractile force, increased susceptibility to injury and the activation of signaling pathways that predispose muscle atrophy. Remodeling of the microtubule (MT) network, marked by increased MT density and post-translational modification by detyrosination, are also pathognomonic of skeletal muscle disease/dysfunction. Our work in Duchenne muscular dystrophy, and new work in aging, align these MT changes to increased cytoskeletal stiffness and dysregulated excess in mechano-activated reactive oxygen species (ROS) and calcium (Ca2+) signals that contribute to contraction-induced injury. Given the essential role of deTyr-enriched MT arrays in myofibrillar growth, maintenance, and repair, we hypothesize that in healthy aging and in disease, alterations in cytoarchitecture, including increased densification, detyrosination, and disorganization of the MT network, underscore myofibrillar malformations and deleterious changes in sarcomere alignment.

To this end, our recent work has focused on characterizing morphological changes to myofiber structure in relation to the structure and properties of the MT network across the trajectory of dystrophy and healthy aging. Evidence that myofibers with structural malformations also arise in these conditions to promote muscle damage, led us to question whether these myofibrillar malformations co-segregate with MT alterations. Using an automated imaging approach, we profiled myofiber, sarcomere, and cytoskeletal structure to quantify the coincidence of altered myofibrillar structure, altered MT density, and shifts in MT mediated mechanotransduction. At areas of myofibrillar malformation, we find increased MT density and concomitant increase in MT post-translational modification. Through genetic increase in the detyrosinating enzyme complex VASH2/SVBP expression in otherwise health mice, we find densified deTyr-enriched MT arrays that co-segregate with the onset of myofibrillar malformations. We further show that the suppression of contraction injury, by targeting MTs, may have been due to their effect at these structures. We conclude that disease-dependent densification of deTyr-enriched MT arrays underscores the altered myofibrillar structure in dystrophic skeletal muscle fibers. Ultimately, this work implicates a relationship between disease-dependent MT alterations and the genesis of disordered myofiber and sarcomere structure.