Tau protein drives microtubule changes in aging skeletal muscle

Tubulin post-translational modifications (PTMs) regulate microtubule (MT) structure and function. Our works in skeletal muscle found that MTs enriched in detyrosinated a-tubulin (deTyr-tubulin) regulate cytoskeletal mechanics, mechanotransduction, and the maintenance of the myofibrillar structure. Our further works in Duchenne muscular dystrophy (DMD) identified the proliferation of deTyr-tubulin-enriched MTs as a consequence of dystrophic pathology that increases the muscle fiber passive mechanics, mechanotransduction, and myofibrillar alterations that impair muscle function. Our new evidence finds similar MT changes in aging muscle. This parallel result has led us to define dystrophy-independent mechanisms that are involved in the loss of muscle function. The microtubule-associated protein, Tau, is responsible for stabilizing and bundling MTs and has been extensively studied in the context of neurodegenerative disease. We find tau progressively increases in aging muscle fibers along with levels of deTyr-tubulin. Both are enriched at areas of disrupted myofibrillar structure, highlighting a potential role in the generation of these disordered regions. We further show that short-term overexpression of tau-GFP in the flexor digitorum brevis (FDB) of young mice phenocopies the observations made in aged muscle. GFP controls have no deleterious impact. We propose that tau accumulation is a consequence of aging that predisposes the proliferation of deTyr-enriched MTs that alter skeletal muscle structure and function. This work was supported with funds from NIH P30 AG028747-17 (JU and CW), NIH R01 AR071618 (CW), and NIH 5T32AR007592-29 (KP). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.