Phosphocreatine is a high-energy phosphate compound that is abundant in muscle and brain [1]. Under non-steady-state conditions, Phosphocreatine maintains the ATP homeostasis at specific high-energy turnover sites (such as muscle fibers), especially in rapidly contracting skeletal muscles, and prevents a significant increase in the intracellular free ADP concentration, thereby minimizing the loss of intracellular adenosine nucleotides [2]. Phosphocreatine has been widely used to alter lipid phase transitions, influencing the aggregation of membranes and protecting cell membranes from various damages[3].
In vitro, Phosphocreatine treatment (30mM) for 2 hours significantly inhibited the apoptosis of human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (oxLDL), and reduced the loss of mitochondrial membrane permeability [4]. Phosphocreatine (5mM) treatment for 4 hours significantly inhibited the increase in intracellular reactive oxygen species (ROS) in rat striatal slices induced by 6-hydroxydopamine, restored the level of tyrosine hydroxylase (TH), and reduced cell death[5]. 500μM Phosphocreatine pretreatment for 1 hour significantly inhibited doxorubicin (1μM; 24h)-induced necrotic cell death in H9c2 cells, accompanied by a decrease in the expression of RIP3 and CaMKII[6].
In vivo, Phosphocreatine treatment via intraperitoneal injection at a dose of 20mg/kg/day for 8 weeks significantly improved the renal function of the diabetic-nephropathy fibrosis rat model, inhibited renal inflammation, and restored mitochondrial function[7]. Intraperitoneal injection of 40mg/kg/day dose of Phosphocreatine for 6 weeks significantly alleviated renal damage in the diabetic rat model and lowered blood glucose levels[8].
References:
[1] Chen L, Schär M, Chan K W Y, et al. In vivo imaging of phosphocreatine with artificial neural networks[J]. Nature communications, 2020, 11(1): 1072.
[2] Greenhaff P L. The creatine-phosphocreatine system: there's more than one song in its repertoire[J]. The Journal of physiology, 2001, 537(Pt 3): 657.
[3] Tokarska-Schlattner M, Epand R F, Meiler F, et al. Phosphocreatine interacts with phospholipids, affects membrane properties and exerts membrane-protective effects[J]. 2012.
[4] Ahsan A, Han G, Pan J, et al. Phosphocreatine protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway[J]. Apoptosis, 2015, 20(12): 1563-1576.
[5] Cunha M P, Martín-de-Saavedra M D, Romero A, et al. Both creatine and its product phosphocreatine reduce oxidative stress and afford neuroprotection in an in vitro Parkinson’s model[J]. ASN neuro, 2014, 6(6): 1759091414554945.
[6] Wang C, Hu L, Guo S, et al. Phosphocreatine attenuates doxorubicin-induced cardiotoxicity by inhibiting oxidative stress and activating TAK1 to promote myocardial survival in vivo and in vitro[J]. Toxicology, 2021, 460: 152881.
[7] Wang F H, Alwesabi A K, Liu W, et al. Phosphocreatine Attenuates Diabetes-Exacerbated Kidney Fibrosis via TGF-β/Smad and PI3K/Akt Pathways in a Dual Rat Model[J]. Tissue and Cell, 2026: 103439.
[8] Shopit A, Niu M, Wang H, et al. Protection of diabetes-induced kidney injury by phosphocreatine via the regulation of ERK/Nrf2/HO-1 signaling pathway[J]. Life sciences, 2020, 242: 117248.