Under static conditions, mammalian red blood cells (RBCs) require a continuous supply of energy, typically via glucose, to maintain their biconcave disc shape. Mechanical distortion, in a complementary way, should lead to increased energy demand that is manifest in accelerated glycolysis. The experimental challenge in observing this phenomenon was met by reversibly and reproducibly distorting the cells and noninvasively measuring glycolytic flux. This was done with a gel-distorting device that was coupled with 13C nuclear magnetic resonance (NMR) spectroscopy. We measured [3-13C]l-lactate production from [1,6-13C]d-glucose in the RBCs suspended in gelatin gels, and up to 90% rate enhancements were recorded. Thus, for the first time, we present experiments that demonstrate the linkage of mechanical distortion to metabolic changes in whole mammalian cells. In seeking a mechanism for the linkage between shape and energy supply, we measured transmembrane cation flux with Cs+ (as a K+ congener) using 133Cs NMR spectroscopy, and the cation flux was increased up to fivefold. The postulated mechanism for these notable (in terms of whole-body energy consumption) responses is stimulation of Ca-adenosine triphosphatase by increased transmembrane flux of Ca2+ via the channel protein Piezo1 and increased glycolysis because its flux is adenosine triphosphate demand-regulated.