Abstract 169: Constitutively STIM(1)ulated Calcium Entry in Skeletal Muscle

Background: STIM1 plays a key role in mediating Store Operated Calcium Entry (SOCE), which is a critical mechanism in the development and function of excitable tissues such as skeletal muscle. In this study, we use a mouse model with an EF hand mutant (D84G) of STIM1 (SAX) that works as a gain of function model and results in pre-activation of STIM1 to cause constitutive SOCE. Materials and Methods: We used various techniques to characterize the function and calcium signaling in the SAX mouse model. Muscle histology, western blotting, calcium imaging, field stimulation experiments and behavioral studies were conducted to study the mouse model. Results: Our studies showed that SAX mice had increased presence of central nuclei in their skeletal muscle, suggesting a pathology that was also verified by their decreased activity end point measures in the behavioral experiments, such as reduced open field activity and increased number of foot faults/cm moved. The behavioral studies also showed an abnormal response to stress, with markedly reduced vertical open field activity in the SAX mice post exercise. Ca imaging and field stimulation experiments showed that basal calcium levels were elevated in SAX myofibers and they underwent a quick calcium buildup with a subsequent decrement in the amplitude of the pulses on repeated electrical stimulation. Conclusion: Our results provide evidence that the D84G EF hand mutation in STIM1 causes alterations in calcium homeostasis, which is seen in the elevated basal Ca2+ levels of SAX myofibers and the fast calcium buildup and fatigability of the fibers when subjected to repeated field stimulation. Our in vivo behavioral studies and the presence of central nuclei also support the idea that the SAX mouse line has a myopathy that is age dependent, although the presence of tubular aggregates remains unverified. By conducting the future studies mentioned above, we hope to gain further insight into the role of SOCE in the function and development of skeletal muscle