Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) gene expression signatures for the identification of compounds targeting metabolism
Dehlia, Ankush; Alizada, Zahra; Guthridge, Mark Andrew
Background
Pathological fatigue is a debilitating symptom in a range of chronic illnesses, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, drug therapies that are effective at treating pathological fatigue have proved difficult to identify through conventional drug discovery pipelines. We sought to identify an ME/CFS gene expression signature in order to map disease pathways and identify potentially novel therapeutic approaches.
Methods
We analysed ME/CFS patient gene expression profiles obtained from two independent studies (GSE14577 and GSE227375). The identified differentially expressed genes (DEGs) were subjected to CMap L1000 analysis for the identification of functional gene networks as well as compounds with the potential to restore the disrupted gene expression in ME/CFS patients.
Results
We identified 21 up-regulated and 25 down-regulated DEGs common to both gene expression datasets. Subjecting the 46-gene signature to CMap L1000 analysis identified networks involved in cytokine/growth factor signalling, infection and immunity, metabolism and cell growth, lipid metabolism, ubiquitination, nucleotide metabolism, and redox regulation.
Four compounds, pioglitazone, rosiglitazone (PPAR agonists), tideglusib (GSK3 inhibitor), and MHY1485 (mTORC1 agonist), were identified and tested for their ability to regulate the metabolism and growth of C2C12 muscle cells. Pioglitazone, tideglusib, and MHY1485, but not rosiglitazone, induced a modest but significant increase in mitochondrial membrane potential in differentiated C2C12 myoblasts over 24–48 hours.
These changes occurred in the absence of increased mitochondrial mass and ROS production, suggesting enhanced mitochondrial metabolism rather than mitochondrial biogenesis. While pioglitazone and rosiglitazone increased the growth of C2C12 myoblasts, no significant effects were observed for tideglusib and MHY1485.
Conclusions
Our findings, based on reciprocal disease:drug signature-matching, provide a framework for exploring the therapeutic potential of drugs to target impaired metabolic pathways in conditions involving pathological fatigue, such as ME/CFS.
Web | DOI | PDF | Research Square | Preprint
Dehlia, Ankush; Alizada, Zahra; Guthridge, Mark Andrew
Background
Pathological fatigue is a debilitating symptom in a range of chronic illnesses, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, drug therapies that are effective at treating pathological fatigue have proved difficult to identify through conventional drug discovery pipelines. We sought to identify an ME/CFS gene expression signature in order to map disease pathways and identify potentially novel therapeutic approaches.
Methods
We analysed ME/CFS patient gene expression profiles obtained from two independent studies (GSE14577 and GSE227375). The identified differentially expressed genes (DEGs) were subjected to CMap L1000 analysis for the identification of functional gene networks as well as compounds with the potential to restore the disrupted gene expression in ME/CFS patients.
Results
We identified 21 up-regulated and 25 down-regulated DEGs common to both gene expression datasets. Subjecting the 46-gene signature to CMap L1000 analysis identified networks involved in cytokine/growth factor signalling, infection and immunity, metabolism and cell growth, lipid metabolism, ubiquitination, nucleotide metabolism, and redox regulation.
Four compounds, pioglitazone, rosiglitazone (PPAR agonists), tideglusib (GSK3 inhibitor), and MHY1485 (mTORC1 agonist), were identified and tested for their ability to regulate the metabolism and growth of C2C12 muscle cells. Pioglitazone, tideglusib, and MHY1485, but not rosiglitazone, induced a modest but significant increase in mitochondrial membrane potential in differentiated C2C12 myoblasts over 24–48 hours.
These changes occurred in the absence of increased mitochondrial mass and ROS production, suggesting enhanced mitochondrial metabolism rather than mitochondrial biogenesis. While pioglitazone and rosiglitazone increased the growth of C2C12 myoblasts, no significant effects were observed for tideglusib and MHY1485.
Conclusions
Our findings, based on reciprocal disease:drug signature-matching, provide a framework for exploring the therapeutic potential of drugs to target impaired metabolic pathways in conditions involving pathological fatigue, such as ME/CFS.
Web | DOI | PDF | Research Square | Preprint
