CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to β-Adrenergic Stimulation

Background/Aims: Cyclic ADP-ribose (cADPR) is a Ca2+ -mobilization messenger that acts on ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum (SR) Ca2+ stores. Moreover, it has been proposed that cADPR serves an additional role in activating the sarcoendoplasmic reticulum Ca2+ -ATPase (SERCA) pump. The aim of this study was to determine the exact mechanism by which cADPR regulates SR Ca2+ stores in physiologically relevant systems. Methods: We analyzed Ca2+ signals as well as the production of Ca2+ mobilizing messengers in the skeletal muscle cells of mice subjected to intensive exercise or in the SR fractions from skeletal muscle cells after β-adrenergic receptor (β-AR) stimulation. Results: We show that cADPR enhances SERCA activity in skeletal muscle cells in response to β-AR agonists, increasing SR Ca2+ uptake. We demonstrate that cADPR is generated by CD38, a cADPR-synthesizing enzyme, increasing muscle Ca2+ signals and contractile force during exercise. CD38 is upregulated by the cAMP response element–binding protein (CREB) transcription factor upon β-AR stimuli and exercise. CD38 knockout (KO) mice show defects in their exercise and cADPR synthesis capabilities, lacking a β-AR agonist-induced muscle contraction when compared to wild-type mice. The skeletal muscle of CD38 KO mice exhibits delayed cytosolic Ca2+ clearance and reduced SERCA activity upon exercise. Conclusion: These findings provide insight into the physiological adaptive mechanism by which the CD38- cADPR-SERCA signaling axis plays an essential role in muscle contraction under exercise, and define cADPR as an endogenous activator of SERCA in enhancing the SR Ca2+ load.