PI(4,5)P₂role in Transverse-tubule membrane formation and muscle function

Abstract

Transverse (T)-tubules, the vast, tubulated domains of the muscle plasma membrane, are critical to maintain healthy skeletal and heart contractions. How the intricate T-tubule membranes are formed is not well understood, with challenges to systematically interrogate in muscle. We established the use of intact Drosophila larval body wall muscles as an ideal system to discover mechanisms that sculpt and maintain the T-tubule membrane network. A muscle-targeted genetic screen identified specific phosphoinositide lipid regulators necessary for T-tubule organization and muscle function. We show that a PI4KIIIalpha-Skittles/PIP5K pathway is needed for T-tubule localized PI(4)P to PI(4,5)P2 synthesis, T-tubule organization, calcium regulation, and muscle and heart rate functions. Muscles deficient for PI4KIIIalpha or Amphiphysin, the homolog of human BIN1, similarly exhibited specific loss of transversal T-tubule membranes and dyad junctions, yet retained longitudinal membranes and the associated dyads. Our results highlight the power of live muscle studies, uncovering distinct mechanisms and functions for sub-compartments of the T-tubule network relevant to human myopathy.