Volume 68, February 2023, 102347Author links open overlay panelAbstract

Store-Operated Ca2+ entry (SOCE) is recognized as a key mechanism in muscle physiology necessary to refill intracellular Ca2+ stores during sustained muscle activity. For many years the cell structures expected to mediate SOCE in skeletal muscle fibres remained unknown. Recently, the identification of Ca2+ Entry Units (CEUs) in exercised muscle fibres opened new insights into the role of extracellular Ca2+ in muscle contraction and, more generally, in intracellular Ca2+ homeostasis. Accordingly, intracellular Ca2+ unbalance due to alterations in SOCE strictly correlates with muscle disfunction and disease. Mutations in proteins involved in SOCE (STIM1, ORAI1, and CASQ1) have been linked to tubular aggregate myopathy (TAM), a disease that causes muscle weakness and myalgia and is characterized by a typical accumulation of highly ordered and packed membrane tubules originated from the sarcoplasmic reticulum (SR). Achieving a full understanding of the molecular pathways activated by alterations in Ca2+ entry mechanisms is a necessary step to design effective therapies for human SOCE-related disorders.

Section snippetsStore-operated Ca2+ entry in skeletal muscle Ca2+ handling

Calcium ions (Ca2+) in striated muscles serve as a second messenger that controls myofibril contraction and relaxation: contraction is activated by Ca2+ release from the sarcoplasmic reticulum (SR) during a mechanism known as Excitation-Contraction (EC) coupling, which causes transient elevations in intracellular Ca2+ concentrations ([Ca2+]i) [1]. Relaxation is then achieved by re-uptake of Ca2+ by SR proteins known as SERCA-pumps (Sarco-Endoplasmic Reticulum Ca2+ ATP-ases) [2]. As EC coupling

SOCE in muscle dysfunction and disease

SOCE plays a key role in muscle function by supporting SR Ca2+ refilling [37,60] and contributing to muscle cell differentiation and development [30,35]. Alterations in SOCE have been reported in MG29-deficient mice [98], in mice knockout for sarcalumenin [99] or in mice knockdown for junctophilins [100]. SOCE dysfunction in skeletal muscle is associated with defects in Ca2+ homeostasis that result in muscular hypotonia and in myopathy, but that may also contribute to exacerbate muscle

Open questions

The role of extracellular Ca2+ in skeletal muscle function, neglected for many years, is now receiving new attention. SOCE, the Ca2+ entry mechanism discussed in this review, is one of the main pathways that allows external Ca2+ to contribute to the contractility of fibres. While in the last 15 years the understanding of this mechanism in muscle has grown, some issues remain to be solved:

- The mechanisms controlling the assembly of additional CEUs during exercise (and their disassembly during

Credit author statement

Feliciano Protasi, Barbara Girolami, Sara Roccabianca and Daniela Rossi.

Feliciano Protasi: Conceptualization, Writing – review & editing; Barbara Girolami: Visualization; Sara Roccabianca: Visualization; Daniela Rossi Conceptualization, Writing – review & editing.

Conflict of interest statement

Nothing declared.

Acknowledgement

This research was funded by grants: (1) GGP19231 from the Italian Telethon ONLUS; and (2) subcontract of AR059646 to F.P. from the National Institutes of Health USA.

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