Tubular (T-) System Soce-Pmca Balance Is Regulated By Ryr Leak In Resting Skeletal Muscle

Skeletal muscle possesses a unique, rapidly activating store-operated Ca2+ entry (SOCE) mechanism. SOCE is activated when the activity of the ryanodine receptors increase, following action potential-induced Ca2+release or even increased RyR Ca2+ leak (Koenig et al 2018, Comm Biol; Cully et al 2018, PNAS). The role of SOCE in muscle remains poorly defined, but a role in calcium content regulation is likely, which means it must work in concert with fibre Ca2+ extrusion mechanisms for balance. Kinetics of Ca2+ movements in imaging experiments performed with high spatiotemporal resolution have shown that the t-system PMCA exists in the same microdomain as RyRs and the SOCE protein components; and all components are equally distributed throughout the muscle fibre (Cully et al 2012, AJP). We studied RyR mutant mice (RyR KI; Lopez et al 2018, BJA) and calsequestrin 1 null (CSQKO) mice (Paolini et al 2007, J.Physiol) to examine the regulatory relationship of RyR Ca2+ leak with SOCE and PMCA activity using mechanically skinned fibres. We determined that RyR Ca2+ leak increased in the order WT