Store-Operated Calcium Entry in Skeletal Muscle: What Makes It Different?

Abstract

Current knowledge on store-operated Ca2+ entry (SOCE) regarding its localization, kinetics, and regulation is mostly derived from studies performed in non-excitable cells. After a long time of relative disinterest in skeletal muscle SOCE, this mechanism is now recognized as an essential contributor to muscle physiology, as highlighted by the muscle pathologies that are associated with mutations in the SOCE molecules STIM1 and Orai1. This review mainly focuses on the peculiar aspects of skeletal muscle SOCE that differentiate it from its counterpart found in non-excitable cells. This includes questions about SOCE localization and the movement of respective proteins in the highly organized skeletal muscle fibers, as well as the diversity of expressed STIM isoforms and their differential expression between muscle fiber types. The emerging evidence of a phasic SOCE, which is activated during EC coupling, and its physiological implication is described as well. The specific issues related to the use of SOCE modulators in skeletal muscles are discussed. This review highlights the complexity of SOCE activation and its regulation in skeletal muscle, with an emphasis on the most recent findings and the aim to reach a current picture of this mesmerizing phenomenon.

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

“…In mammalian skeletal muscle, STIM1 and STIM2 are expressed together with some of their alternative spliced isoforms. STIM1L is a longer splice variant of STIM1 that, in the C-terminal region, contains an additional 106 amino acids encoding an actin-binding domain that allows STIM1 to interact with the subcortical actin filaments ( Darbellay et al, 2011 ; Lilliu et al, 2021 ). This interaction supports the permanent assembly of STIM1L clusters in proximity to ORAI1 channels on the plasma membrane.…”

Ryanodine receptor activity and store‐operated Ca2+ entry: Critical regulators of Ca2+ content and function in skeletal muscle

“…A potential solution to detecting the role of Ca 2+ entry in intact fibre preparations is the use of pharmacological agents to block t‐system Ca 2+ channels (for a review of SOCE pharmacology, see Lilliu et al . 2021). These modulators can be used in the presence of normal Ca 2+ levels of the bathing solution during electrical stimulation trains.…”

“…2010; Lilliu et al . 2021). As a result of the dimensions of the skeletal muscle fibre, the outer plasma membrane (sarcolemma) can be mechanically skinned, or peeled away, with fine forceps (Lamb & Stephenson, 2018).…”

“…Second, the use of antagonists that affect EC coupling (micromolar levels of BTP‐2, 2ABP) or depleting extracellular Ca 2+ do not provide functional data reflecting an acute isolation of the role of SOCE during repetitive tetanic stimulations of the muscle as presumed, for the reasons outlined above and by Olivera & Pizarro (2010), Meizoso‐Huesca & Launikonis (2021) and Lilliu et al . (2021).…”

“…The Ca 2+ influx is deactivated by the return of the resting ER Ca 2+ level. To understand the activation of this mechanism and its physiological role(s), one must consider the Ca 2+ microenvironments of the cell, the associated Ca 2+ -handling and regulatory proteins in the microdomain, and the functions of the cell (Soboloff et al 2012;Prakriya & Lewis, 2015;Lilliu et al 2021).…”