Calcium signaling recruits substrate transporters GLUT4 and CD36 to the sarcolemma without increasing cardiac substrate uptake

Activation of AMP-activated protein kinase (AMPK) in cardiomyocytes induces translocation of glucose transporter GLUT4 and long-chain fatty acid (LCFA) transporter CD36 from endosomal stores to the sarcolemma to enhance glucose and LCFA uptake, respectively. Ca2+/calmodulin-activated kinase kinase-beta (CaMKK beta) has been positioned directly upstream of AMPK. However, it is unknown whether acute increases in [Ca2+](i) stimulate translocation of GLUT4 and CD36 and uptake of glucose and LCFA or whether Ca2+ signaling converges with AMPK signaling to exert these actions. Therefore, we studied the interplay between Ca2+ and AMPK signaling in regulation of cardiomyocyte substrate uptake. Exposure of primary cardiomyocytes to inhibitors or activators of Ca2+ signaling affected neither AMPK-Thr(172) phosphorylation nor basal and AMPK-mediated glucose and LCFA uptake. Despite their lack of an effect on substrate uptake, Ca2+ signaling activators induced GLUT4 and CD36 translocation. In contrast, AMPK activators stimulated GLUT4/CD36 translocation as well as glucose/LCFA uptake. When cardiomyocytes were cotreated with Ca2+ signaling and AMPK activators, Ca2+ signaling activators further enhanced AMPK-induced glucose/LCFA uptake. In conclusion, Ca2+ signaling shows no involvement in AMPK-induced GLUT4/CD36 translocation and substrate uptake but elicits transporter translocation via a separate pathway requiring CaMKK beta/CaMKs. Ca2+ -induced transporter translocation by itself appears to be ineffective to increase substrate uptake but requires additional AMPK activation to effectuate transporter translocation into increased substrate uptake. Ca2+ -induced transporter translocation might be crucial under excessive cardiac stress conditions that require supra-physiological energy demands. Alternatively, Ca2+ signaling might prepare the heart for substrate uptake during physiological contraction by inducing transporter translocation