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Identifying potential treatments for the metabolic defects in myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS)
thesisposted on 2021-01-01, 00:00 authored by Zahra Alizada
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious chronic illness characterized by pathological fatigue that is afflicting millions of patients world-wide. Despite the poor quality-of-life experienced by many patients, there are currently no treatments or cures for ME/CFS. While the underlying causes of ME/CFS remain unclear, multiple studies have identified metabolic impairments muscle cells including reduced mitochondrial oxidative phosphorylation (OXPHOS). Thus, drugs capable of increasing OXPHOS may have therapeutic potential in the treatment of ME/CFS. Using a mouse C2C12 muscle myoblast model, we have shown that two PPARγ agonists, Pioglitazone and Rosiglitazone, are not only able to increase cell growth and viability, but also increase mitochondrial membrane potential. Conversely, Cardarine and Pemafibrate, that activate PPARα, PPARδ respectively had no impact on cellular growth, viability, suggesting that the PPARγ isoform was primarily associated with the observed cellular responses. In addition, we have found that the GSK-3 inhibition by Tideglusib, resulted in increased cell growth and viability, as well as increased mitochondrial membrane potential. Furthermore, activation of the mTOR pathway using MHY1485 resulted in increased mitochondrial membrane potential. Together these findings suggest that activation of PPARγ and mTOR as well as inhibition of GSK-3 may lead to increased mitochondrial metabolism and improved cellular growth and viability in C2C12 muscle myoblasts. There findings raise the possibility that compounds targeting PPARγ, mTOR and GSK-3 may have therapeutic potential in illnesses such as ME/CFS where mitochondrial metabolism is impaired. Further studies examining the therapeutic potential of drugs targeting PPARγ, mTOR and GSK-3 in ME/CFS patient samples are warranted.