Arp2/3 iso-complexes limit t-tubule overgrowth to ensure myofiber formation and synchronous contraction

Abstract

SummaryT-tubules are long plasma membrane invaginations that form contact sites with two adjacent endoplasmic reticulum compartments to generate a skeletal muscle triad. Although the importance of t-tubules is well established, and abnormalities are found in multiple muscle disorders, the mechanisms of t-tubule growth are currently unknown. We found that the branched actin nucleator Arp2/3 regulates t-tubule organisation in myofibers. Cortical actin limits t-tubule growth, suggesting that it must be locally disassembled to allow the t-tubule to grow. T-tubule overgrowth is limited by Arpc5-containing Arp2/3 iso-complexes, but not those containing Arpc5L. Loss of Arpc5 results in malformed t-tubule clusters, impaired triads, and asynchronous muscle contraction, as found in multiple muscle disorders. Therefore, limiting t-tubule overgrowth has a role in triad formation and myofiber contraction, providing a possible pathophysiological mechanism for these muscle disorders.Graphical abstract