Phosphocreatine

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.

Phosphocreatine是一种在肌肉和大脑中含量丰富的高能磷酸化合物^[1]。在非稳态条件下，Phosphocreatine可维持特定高能量转换部位（如肌纤维），尤其是快速收缩骨骼肌中的ATP稳态，防止细胞内游离ADP浓度显著升高，从而减少细胞内腺苷核苷酸的损失^[2]。Phosphocreatine已被广泛用于改变脂质相变，影响膜聚集，并保护细胞膜免受各种损伤^[3]。

在体外，30mM的Phosphocreatine处理26小时显著抑制了氧化低密度脂蛋白诱导的人脐静脉内皮细胞凋亡，并减少了线粒体膜通透性的丧失^[4]。5mM的Phosphocreatine处理大鼠纹状体脑片4小时，显著抑制了6-羟基多巴胺诱导的细胞内活性氧增加，恢复了酪氨酸羟化酶水平，并减少了细胞死亡^[5]。500μM的Phosphocreatine预处理H9c2细胞1小时，显著抑制了阿霉素诱导的坏死性细胞死亡，同时伴随着RIP3和CaMKII表达的下调^[6]。

在体内，每日腹腔注射20mg/kg剂量的Phosphocreatine，持续8周，显著改善了糖尿病肾病纤维化大鼠模型的肾功能，抑制了肾脏炎症，并恢复了线粒体功能^[7]。每日腹腔注射40mg/kg剂量的Phosphocreatine，持续6周，显著减轻了糖尿病大鼠模型的肾脏损伤，并降低了血糖水平^[8]。