Calcium Dyshomeostasis in Tubular Aggregate Myopathy

Abstract

Calcium is a crucial mediator of cell signaling in skeletal muscles for basic cellular functions and specific functions, including contraction, fiber-type differentiation and energy production. The sarcoplasmic reticulum (SR) is an organelle that provides a large supply of intracellular Ca²⁺ in myofibers. Upon excitation, it releases Ca²⁺ into the cytosol, inducing contraction of myofibrils. During relaxation, it takes up cytosolic Ca²⁺ to terminate the contraction. During exercise, Ca²⁺ is cycled between the cytosol and the SR through a system by which the Ca²⁺ pool in the SR is restored by uptake of extracellular Ca²⁺ via a specific channel on the plasma membrane. This channel is called the store-operated Ca²⁺ channel or the Ca²⁺ release-activated Ca²⁺ channel. It is activated by depletion of the Ca²⁺ store in the SR by coordination of two main molecules: stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (ORAI1). Recently, myopathies with a dominant mutation in these genes have been reported and the pathogenic mechanism of such diseases have been proposed. This review overviews the calcium signaling in skeletal muscles and role of store-operated Ca²⁺ entry in calcium homeostasis. Finally, we discuss the phenotypes and the pathomechanism of myopathies caused by mutations in the STIM1 and ORAI1 genes.

Keywords: ORAI1; SOCE; STIM1; calcium; severe combined immunodeficiency; skeletal muscle; tubular aggregate myopathy.

Figure 1

Diagram of excitation–contraction (EC) coupling in skeletal muscles. Depolarization of the action potential from the axon terminal induces the conformational change of the dihydropyridine receptor (DHPR) on transverse tubule (T-tubule) membranes. Calcium ions are released from the sarcoplasmic reticulum (SR) through ryanodine receptor 1 (RyR1), which is activated by DHPR binding. Released Ca²⁺ directly induces contraction. After EC coupling, released Ca²⁺ reuptake is transferred to the SR by sarco/endoplasmic reticulum Ca²⁺ATPase (SERCA1). Upon SR Ca²⁺ depletion, store-operated Ca²⁺ entry is mediated by conformation changes in stromal interaction molecule 1 (STIM1) that are communicated with calcium release-activated calcium channel protein 1 (ORAI1). ATP, adenosine triphosphate; ADP, adenosine diphosphate.

Figure 2

Schematic structures of STIM1 and ORAI1. A single straight STIM1 molecule is depicted. The major site for binding Ca²⁺ is a canonical EF-hand domain (A). Two ORAI1 subunits out of six are illustrated. ORAI1 protein has four transmembrane helices with the N- and C-termini located in the cytoplasm (B). The locations of reported mutations are marked (A,B). SP, signal peptide; cEFh, canonical EF-hand; ncEFh, noncanonical EF-hand; SAM, sterile α-motif; TM, transmembrane; CC, coiled-coil region; ID, inhibitory domain; PS, Pro/Ser-rich domain; K, Lys-rich domain.

Figure 3

Histology and electron microscopy of a muscle biopsy from a patient with tubular aggregate myopathy. Histological analysis reveals tubular aggregates (TAs) in modified Gomori trichrome (A) and NADH-tetrazolium reductase (NADH-TR) (B) stainings; using electron microscopy, TAs are demonstrated as a cluster of single-walled tubules in parallel direction (C), which is also shown in high magnification (D). Arrowheads indicate TAs. Scale bars, 50 µm (A and B), 1 µm (C), and 0.1 µm (D).

Figure 4

Schematic representation of Ca²⁺ overload in tubular aggregate myopathy. STIM1 molecules are in a tight and stable conformation in the resting state when there is an abundance of sarcoplasmic reticulum (SR) Ca²⁺. Upon depletion of SR Ca²⁺, STIM1 is activated and undergoes conformational changes to an elongated shape, binding with ORAI1 in the activated state. Mutated STIM1 can be activated without SR Ca²⁺ depletion, resulting in ORAI1 channel opening (gain-of-function of STIM1). Gain-of-function caused by mutations in ORAI1 allows extracellular Ca²⁺ influx to the cytosol, which is independent of the SR Ca²⁺ concentration or STIM1 activation (gain-of-function of ORAI1).