Store-operated Ca2+ entry is activated by every action potential in skeletal muscle

Store-operated calcium (Ca 2+ ) entry (SOCE) in skeletal muscle is rapidly activated across the tubular system during direct activation of Ca 2+ release. The tubular system is the invagination of the plasma membrane that forms junctions with the sarcoplasmic reticulum (SR) where STIM1, Orai1 and ryanodine receptors are found. The physiological activation of SOCE in muscle is not defined, thus clouding its physiological role. Here we show that the magnitude of a phasic tubular system Ca 2+ influx is dependent on SR Ca 2+ depletion magnitude, and define this as SOCE. Consistent with SOCE, the influx was resistant to nifedipine and BayK8644, and silenced by inhibition of SR Ca 2+ release during excitation. The SOCE transient was shaped by action potential frequency and SR Ca 2+ pump activity. Our results show that SOCE in skeletal muscle acts as an immediate counter-flux to Ca 2+ loss across the tubular system during excitation-contraction coupling. Xaver Koenig et al. demonstrate the physiological activation of store-operated calcium entry in muscle, pointing to a role for this mechanism. The resulting influx of calcium into the cytoplasm is shaped by action potential frequency and calcium pump activity.