Overexpression of β6-tubulin disorganizes the microtubule network of skeletal muscle fibers

Authors

• D Randazzo
• JJ Belanto
• DM Talsness
• A Kenea
• JM Ervasti
• E Ralston

Abstract

Skeletal muscle microtubules are uniquely organized as a dynamic, grid-like lattice. How does such a lattice form, how is it maintained and what roles does it play in adult muscle? These are largely unanswered questions. During muscle (and other tissues') development, microtubules are dramatically reorganized and we still understand little of these changes. A new role for adult muscle microtubules has been suggested by the discovery that microtubules are profoundly disorganized in muscles of the mdx mouse. This mouse lacks the protein dystrophin and is a model for Duchenne muscular dystrophy (DMD). Microtubules also play a role in the abnormal physiology of mdx mice and RNAs for several tubulins are significantly elevated in DMD biopsies. The most elevated RNA encodes β6-tubulin, a ubiquitous tubulin whose overexpression in proliferating cells affects mitosis and alters microtubule stability. Here, we report our preliminary investigation of the role of β6-tubulin in mouse muscle fibers. We find that endogenous β6-tubulin is elevated in mdx compared to wild-type (WT) mouse muscles at both RNA and protein levels. The large protein increase (12-fold) is much beyond that of other tubulins. Interestingly, overexpression of GFP-tagged β6-tubulin in WT muscle fibers leads to a remarkable disorganization of their microtubules, qualitatively similar to that observed in mdx mice. Our results support the hypothesis that elevated expression of β6-tubulin in mdx and DMD contributes to their microtubule defects. Accordingly, β6-tubulin may provide a molecular link between the disorganization of the microtubule cytoskeleton in mdx mice and the pathology of DMD.

Scientific Focus Area: Cell Biology

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