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In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the  mdx  mouse, a model of Duchenne muscular dystrophy (DMD), microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the  mdx  mouse pathology. We now report that increased expression of the beta 6 class V  β -tubulin (tubb6) contributes to the microtubule changes of  mdx  muscles. Wild-type muscle fibers overexpressing green fluorescent protein (GFP)-tubb6 (but not GFP-tubb5) have disorganized microtubules whereas  mdx  muscle fibers depleted of tubb6 (but not of tubb5) normalize their microtubules, suggesting that increasing tubb6 is toxic. However, tubb6 increases spontaneously during differentiation of mouse and human muscle cultures. Furthermore, endogenous tubb6 is not uniformly expressed in  mdx  muscles but is selectively increased in fiber clusters, which we identify as regenerating. Similarly,  mdx -based rescued transgenic mice that retain a higher than expected tubb6 level show focal expression of tubb6 in subsets of fibers. Tubb6 is also upregulated in cardiotoxin-induced mouse muscle regeneration, in human myositis and DMD biopsies, and the tubb6 level correlates with that of embryonic myosin heavy chain, a regeneration marker. In conclusion, modulation of a  β -tubulin isotype plays a role in muscle differentiation and regeneration. Increased tubb6 expression and microtubule reorganization are not pathological  per se  but reflect a return to an earlier developmental stage. However, chronic elevation of tubb6, as occurs in the  mdx  mouse, may contribute to the repeated cycles of regeneration and to the pathology of the disease.

Persistent upregulation of the β -tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle