Glucose intolerance in aging is mediated by the Gpcpd1-GPC metabolic axis

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, muscle mediated metabolic homeostasis is perturbed, contributing to the onset of multiple chronic diseases. Our knowledge on the mechanisms responsible for this age-related perturbation is limited, as it is difficult to distinguish between correlation and causality of molecular changes in muscle aging. Glycerophosphocholine phosphodiesterase 1 (GPCPD1) is a highly abundant muscle enzyme responsible for the hydrolysis of the lipid glycerophosphocholine (GPC). The physiological function of GPCPD1 remained largely unknown. Here, we report that the GPCPD1-GPC metabolic pathway is dramatically perturbed in the aged muscle. Muscle-specific inactivation of Gpcpd1 resulted in severely affected glucose metabolism, without affecting muscle development. This pathology was muscle specific and did not occur in white fat-, brown fat- and liver-deficient Gpcpd1 deficient mice. Moreover, in the muscle specific mutant mice, glucose intolerance was markedly accelerated under high sugar and high fat diet. Mechanistically, Gpcpd1 deficiency results in accumulation of GPC, without any other significant changes in the global lipidome. This causes an "aged-like" transcriptomic signature in young Gpcpd1 deficient muscles and impaired insulin signaling. Finally, we report that GPC levels are markedly perturbed in muscles from both aged humans and patients with Type 2 diabetes, with a high correlation between GPC levels and increased chronological age. Our findings show the novel and critical physiological function of GPCPD1-GPC metabolic pathway to glucose metabolism, and the perturbation of this pathway with aging, which may contribute to glucose intolerance in aging.