Intramuscular glycogen phosphorylase inhibition blunts sarcoplasmic reticulum calcium release in skeletal muscle

Intramuscular glycogen is a primary energy source for fuel in skeletal muscle and depletion of glycogen is associated with exercise-induced fatigue caused by decreased sarcoplasmic reticulum (SR) Ca2+ release. However, it is unknown if acute pharmacological inhibition of glycogen utilization can cause decreased sarcoplasmic reticulum calcium release without depleting muscle glycogen content. We hypothesized that inhibiting glycogen phosphorylase activity within the skeletal muscle using the drug CP-316819 would result in decreased SR Ca2+ release due to decreased localized SR triad [ATP], whereby decreased [ATP] would inhibit ryanodine receptor opening. Mouse flexor digitorum brevis muscle was enzymatically dissociated and loaded with Indo-1 to measure myoplasmic free [Ca2+] ([Ca2+]i). Our results indicate that inhibiting glycogen phosporylase via CP-316819 results in decreased SR calcium release at all stimulation frequencies (15 – 150Hz), it blunted total SR calcium release assessed with supraphysiological [5mM] caffeine treatment, and it reduced resting [Ca2+]i. These results may suggest that skeletal muscle utilizes glycogen at a localized level to regulate SR Ca2+ release.