Protective effects of phosphocreatine against Doxorubicin-Induced cardiotoxicity through mitochondrial function enhancement and apoptosis suppression via AMPK/PGC-1α signaling pathway

• Published in: International immunopharmacology 2025-01, Vol.144, p.113677, Article 113677
• Main Authors: Qaed, Eskandar, almoiliqy, Marwan, Liu, Wu, Al-mashriqi, Haitham Saad, Alyafeai, Eman, Aldahmash, Waleed, Mahyoub, Mueataz A., Tang, Zeyao
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK activation; Animals; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - toxicity; Apoptosis - drug effects; Cardioprotection; Cardiotoxicity - drug therapy; Cell Line; Doxorubicin - toxicity; Doxorubicin-induced cardiotoxicity; Humans; Male; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial function; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Phosphocreatine (PCr); Phosphocreatine - metabolism; Rats; Signal Transduction - drug effects
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113677

•PCr demonstrates significant reduction in Doxorubicin-induced cardiotoxicity.•PCr enhances mitochondrial integrity and energy metabolism in cardiac cells.•PCr activates key pathways such as AMPK/PGC-1α that regulate cellular energy and cardiac health.•PCr effectively reduces apoptosis under chemotherapeutic stress. Doxorubicin (DOX), a potent chemotherapy drug, is limited by its cardiotoxic effects, which can lead to heart damage. This study explores the cardioprotective potential of Phosphocreatine (PCr) in vitro and in vivo models, focusing on its impact on the AMPK and PGC-1α pathways, apoptosis reduction, and mitochondrial function preservation. Advanced methodologies, including high-resolution respirometry (HRR), were employed to assess mitochondrial bioenergetics, AMPK activity, and apoptotic rates in cardiomyocytes. Electrocardiography (ECG) and echocardiography (echo) were used to monitor cardiac function in vivo. Results showed that PCr significantly activated the AMPK and PGC-1α pathways, reduced apoptosis, and stabilized mitochondrial function in cardiomyocytes exposed to DOX. There was an upregulation of AMPK and PGC-1α target genes, stabilization of mitochondrial membranes, and improvements in cellular energy production and antioxidant defenses. PCr also markedly reduced apoptotic markers, enhancing cardiomyocyte viability. ECG and echocardiography revealed that PCr preserved cardiac function, indicated by improved heart rate variability, reduced QT interval prolongation, and enhanced ejection fraction. These findings highlight PCr’s potential in mitigating DOX-induced cardiotoxicity by enhancing mitochondrial function and reducing apoptosis. The study underscores the promise of PCr as an agent to reduce chemotherapy-related cardiac injuries, paving the way for further research to improve patient outcomes in cancer treatment.