Myofibrillar malformations that arise in mdx muscle fibers are driven by detyrosinated microtubules

Abstract

In Duchenne muscular dystrophy (DMD), alterations in the myofibrillar structure of skeletal muscle fibers that impair contractile function and increase injury susceptibility arise as a consequence of dystrophic pathology. In murine DMD (mdx), myofibrillar alterations are abundant in advanced pathology (>4 months), an age where we formerly established the densification of microtubules (MTs) post-translationally modified by detyrosination (deTyr-MTs) as a negative disease modifier. Given the essential role of MTs in myofibrillar growth, maintenance, and repair, we examined the increased abundance of deTyr-MTs as a potential mechanism for these myofibrillar alterations. Here we find increased levels of deTyr-MTs as an early event in dystrophic pathology (4 weeks) with no evidence of myofibrillar alterations. At 16 weeks, we find the level of deTyr-MTs is significantly increased and co-localized to areas of myofibrillar malformation. Profiling the enzyme complexes responsible for deTyr-tubulin, we found vasohibin 2 (VASH2) significantly elevated in the mdx muscle at 4 and 16 wks. Genetically increasing VASH2 expression in 4 wk, wild-type mice we now find densified deTyr-MTs that co-segregate with myofibrillar malformations similar to those in the 16 wk mdx. Given that no changes were identified in fibers expressing EGFP as a control, we conclude that disease altered microtubules underscore the altered myofibrillar structure in dystrophic skeletal muscle fibers.