AUTHOR=Protasi Feliciano , Girolami Barbara , Serano Matteo , Pietrangelo Laura , Paolini Cecilia 

TITLE=Ablation of Calsequestrin-1, Ca2+ unbalance, and susceptibility to heat stroke

JOURNAL=Frontiers in Physiology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.1033300

DOI=10.3389/fphys.2022.1033300

ISSN=1664-042X

ABSTRACT=Introduction. Ca2+ levels in adult skeletal muscle fibers are mainly controlled by excitation-contraction (EC) coupling, a mechanism that translates action potentials in release of Ca2+ from the sarcoplasmic reticulum (SR) release channels, i.e. the ryanodine receptors type-1. Calsequestrin (CASQ) is a protein that binds large amounts of Ca2+ in the lumen of the SR terminal cisternae, near sites of Ca2+ release.  There is general agreement that CASQ is not only important for the SR ability to store Ca2+, but also for modulating the opening probability of the RYR Ca2+ release channels. 
The initial studies. About twenty years ago we generated a mouse model lacking isoform 1 of  CASQ (CASQ1-null mice), the isoform predominantly expressed in adult fast twitch skeletal muscle. While the knockout was not lethal as expected, lack of CASQ1 caused a striking remodeling of the SR and of transverse-tubule (TT) membranes, and mitochondrial damage. Functionally, CASQ1-knockout resulted in reduced SR Ca2+ content and release, and severe SR depletion during repetitive stimulation.
The myopathic phenotype of CASQ1-null mice. After the initial studies, though, we discovered that CASQ1-null mice were prone to sudden death when exposed to halogenated anaesthetics, heat, and even strenuous exercise. These syndromes are similar to human malignant hyperthermia susceptibility (MHS) and environmental-exertional heat stroke (HS). We learned that mechanisms underlying the syndrome involved excessive SR Ca2+ leak and excessive production of oxidative species: indeed, mortality and mitochondrial damage were significantly prevented by administration of antioxidants and reduction of oxidative stress. Though, how CASQ1-null mice could survive without the most important SR Ca2+ binding protein was a puzzling issue that yet was not solved. 
Unravelling the mystery. The mystery was finally solved in 2020, when we discovered that in CASQ1-null mice the SR activates a compensatory mechanism that results in constitutively active store-operated Ca2+ entry (SOCE), a mechanism that allows skeletal fibers to use external Ca2+ when SR stores are depleted. The post-natal compensatory mechanism that allows CASQ1-null mice to survive involves the assembly of new SR-TT junctions (Ca2+ entry units) containing STIM1 and ORAI1, the two proteins that mediate SOCE.