Abstract
Creatine (Cr) and phosphocreatine (PCr) are physiologically essential molecules for life, given they serve as rapid and localized support of energy- and mechanical-dependent processes. This evolutionary advantage is based on the action of creatine kinase (CK) isozymes that connect places of ATP synthesis with sites of ATP consumption (the CK/PCr system). Supplementation with creatine monohydrate (CrM) can enhance this system, resulting in well-known ergogenic effects and potential health or therapeutic benefits. In spite of our vast knowledge about these molecules, no integrative analysis of molecular mechanisms under a systems biology approach has been performed to date; thus, we aimed to perform for the first time a convergent functional genomics analysis to identify biological regulators mediating the effects of Cr supplementation in health and disease. A total of 35 differentially expressed genes were analyzed. We identified top-ranked pathways and biological processes mediating the effects of Cr supplementation. The impact of CrM on miRNAs merits more research. We also cautiously suggest two dose–response functional pathways (kinase- and ubiquitin-driven) for the regulation of the Cr uptake. Our functional enrichment analysis, the knowledge-based pathway reconstruction, and the identification of hub nodes provide meaningful information for future studies. This work contributes to a better understanding of the well-reported benefits of Cr in sports and its potential in health and disease conditions, although further clinical research is needed to validate the proposed mechanisms.
Highlights
Creatine (Cr), or alpha-methylguanidinoacetic acid (PubChem CID: 586), and its phosphorylated form, phosphocreatine (PCr), are essential molecules for the optimal functioning of tissues with high and fluctuating energy demands [1]. They provide an evolutionary advantage via several creatine kinase (CK) isozymes that functionally connect places of adenosine triphosphate (ATP) synthesis with sites of ATP consumption [2]; Cr and PCr are physiologically essential for life through a rapid and localized support of energy- and mechanical-dependent processes [3,4]
The use of a systems biology approach might contribute to better comprehension of the molecular, cellular, tissue, and systemic effects of creatine monohydrate (CrM) and its applications to health and disease; the aim of this study was to perform for the first time a convergent functional genomics (CFG) analysis to identify relevant pathways and biological processes mediating the effects of Cr supplementation in health and disease
We previously suggested that the CK/PCr system works as a dynamic biosensor of chemomechanical energy transduction [3] with ‘concurrent reactions with exchange motifs’ [77] that might account for the wide range of diseases after alterations in intracellular Cr concentrations
Summary
Creatine (Cr), or alpha-methylguanidinoacetic acid (PubChem CID: 586), and its phosphorylated form, phosphocreatine (PCr), are essential molecules for the optimal functioning of tissues with high and fluctuating energy demands [1]. The CK/PCr system can be enhanced through supplementation with creatine monohydrate (CrM), which is the most studied, safe, and effective nutritional supplement to optimize physical performance [5,6,7,8], with potential benefits in health and disease [9,10,11,12,13,14,15,16,17,18,19] It seems that the elevation of intracellular PCr concentration causes a greater capacity for phosphagens to contribute to energy metabolism, while working to reduce the accumulation of Pi and H+ and improving Ca2+ handling as important mediators of fatigability in young and older adults [20,21,22,23]. It is necessary to point out the complementary features of low- and high-throughput analysis, given that subsequent validation of the identified metabolic hubs requires the high sensitivity, lower noise, and reproducibility of low-throughput techniques (e.g., post-transcriptional regulation assessment, targeted-molecules expression, protein–protein interactions) [53]
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