Shaping transverse-tubules: central mechanisms that play a role in the cytosol zoning for muscle contraction

Abstract

A transverse-tubule (T-tubule) is an invagination of the plasma membrane penetrating deep into muscle cells. An extensive membrane network of T-tubules is crucial for rapid and synchronized signal transmission from the cell surface to the entire sarcoplasmic reticulum for Ca2+ release, leading to muscle contraction. T-tubules are also indispensable for the formation and positioning of other muscle organelles. Their structure and physiological roles are relatively well established; however, the mechanisms shaping T-tubules require further elucidation. Centronuclear myopathy (CNM), an inherited muscular disorder, accompanies structural defects in T-tubules. Membrane traffic-related genes, including MTM1 (Myotubularin 1), DNM2 (Dynamin 2), and BIN1 (Bridging Integrator-1), were identified as causative genes of CNM. In addition, causative genes for other muscle diseases are also reported to be involved in the formation and maintenance of T-tubules. This review summarizes current knowledge on the mechanisms of how T-tubule formation and maintenance is regulated.

Keywords: BIN1/Amph; MTM; T-tubule; dynamin; tubulation.

Graphical Abstract

Fig. 1

T-tubule in excitation-contraction coupling. Acetylcholine released from the motor neuron triggers depolarization of the sarcolemma (1). The electrical signal then propagates deep into the muscle cells via the T-tubule network (2). The signal is transmitted to the SR through the T-tubule-SR junctions and then activates RyR on the SR (3). This results in Ca2+ release from the SR to the cytoplasm (4). The increased Ca²⁺ concentration induces muscle contraction (5).

Fig. 2

Human and Drosophila Amphiphysin. Amphiphysin contains the N-BAR domain and SH3 domain at the N-terminus and C-terminus, respectively. The skeletal muscle-specific splicing isoform of human BIN1 contains the PI-binding motif that interacts with PI(4)P and PI(4,5)P2. There is no PI-binding motif in Drosophila Amph.

Fig. 3

Overview of mechanisms for T-tubule formation and maintenance. Cav3, Cavin1, and Cavin4 regulate the initiation of T-tubule formation. BIN1/Amph and wild-type DNM2 are required for the formation of the T-tubule. JPs are involved in the formation of the T-tubule-SR junction and the maturation of the T-tubule. MTM1 plays a role in the maintenance of T-tubules by regulating endosomal membrane traffic.