A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation

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.

Supplementing Soy-Based Diet with Creatine in Rats: Implications for Cardiac Cell Signaling and Response to Doxorubicin

“…The inhibitory effects of the soy-based diet on Akt and ERK could be mediated by genistein, known to inhibit Tyr kinases (for a review, see [54]) and to have an anti-proliferative effect, consistent with indirect AMPK activation [55][56][57][58][59]. The activation of Akt and ERK seen with Cr supplementation was also reported for skeletal muscle [60,61] and suggested by recent database meta-analysis [62]. Such rather pro-anabolic effects could mediate many cytoprotective aspects of Cr supplementation, such as in cardioprotection [18,19], muscular dystrophies, neuromuscular and neurodegenerative disorders [16,63], brain health [64], or wound healing [65].…”

Nutritional Strategies in the Rehabilitation of Musculoskeletal Injuries in Athletes: A Systematic Integrative Review

“…Its administration results in increases in the total musculoskeletal creatine pool by around 25% (up to ≈37% if accompanied with physical exercise) [ 86 ] which benefits the athlete’s recovery time and improves athletic performance (increased strength, muscle mass, and power) [ 87 ]. It has been reported that the increase in muscle creatine after CrM supplementation might optimize the function of the creatine kinase/phosphocreatine system and subsequently benefit energy- and mechanical-dependent processes in different tissues [ 88 , 89 ].…”

“…Consequently, maintaining or increasing muscle creatine levels during periods of inactivity or recovery from injury may offer benefits [ 93 ]. Indeed, several studies have evaluated the potential effects of CrM supplementation during periods of immobilization [ 94 ] revealing: (i) Maintenance of muscle mass or cross-sectional area, muscle strength, and endurance; (ii) maintenance or increase in total muscle creatine concentration; (iii) maintenance of GLUT-4 concentration [ 95 ]; (iv) increased muscle glycogen; and (v) increased expression of growth factors (IGF-1) and myogenic regulatory factors [ 88 , 93 ]. However, it is difficult to draw definitive conclusions due to heterogeneity in study designs (e.g., duration, immobilized limb, experience level of participants, etc.).…”

A Bioinformatics-Assisted Review on Iron Metabolism and Immune System to Identify Potential Biomarkers of Exercise Stress-Induced Immunosuppression

“…Manual curation of literature and bioinformatics data was performed by one author (D.A.B. ), with experience in the extraction of kinase-substrate interactions from the literature [55,56], who also participated in the data extraction for the development of the Kinase Enrichment Analysis version 2 by the Ma'ayan Laboratory (capstone project) [57]. A second author, with extensive experience in bioinformatics and systems biology (D.A.F.…”