Store-Operated Calcium Entry (SOCE): role in skeletal muscle function and disease

Store operated calcium entry (SOCE) is a mechanism that is triggered by depletion of intracellular calcium stores (endoplamic and sarcoplasmic reticulum, ER and SR). SOCE mediates recover of extracellular calcium through STIM1 and Orai1 interaction, and is modulated in muscle by Calsequestrin-1 (CASQ1). Mutations in STIM1, Orai1, and CASQ1 have been linked to tubular aggregate myopathy (TAM), a disease which causes muscle pain, cramping, and weakness and leads in some people to joint deformities in the arms and legs. TAM is characterized by presence of tubular aggregates, unusual accumulation of SR tubes. The mechanisms linking human mutations to SOCE dysfunction, and development of TAM are still unknown. TAM prevalence is currently unknown and no cure is available for patients. The main aim of the present proposal is to improve the current understanding of the pathophysiology of TAM. To achieve this goal, we have now generated mouse models carrying human mutations Orai1 (G98S) and CASQ1 (D44N) linked to TAM in humans. We have already collected Preliminary Results in the first of these mice (Orai1-G98S): very encouraging the fact that this mouse develops TAs, which makes the Orai1-G98S mice a good animal model for the study of TAM. The work proposed in this application has the potential to provide the basis for the future development of therapeutic interventions.This project will potentially provide new therapeutic target(s) for the development of strategies designed to improve muscle function, limit muscle fatigue, weakness, and dysfunction in various human myopathies caused by altered calcium homeostasis (including TAM).