Substrate utilisation of cultured skeletal muscle cells in patients with CFS

Abstract

Chronic fatigue syndrome (CFS) patients often suffer from severe muscle pain and an inability to exercise due to muscle fatigue. It has previously been shown that CFS skeletal muscle cells have lower levels of ATP and have AMP-activated protein kinase dysfunction. This study outlines experiments looking at the utilisation of different substrates by skeletal muscle cells from CFS patients (n = 9) and healthy controls (n = 11) using extracellular flux analysis. Results show that CFS skeletal muscle cells are unable to utilise glucose to the same extent as healthy control cells. CFS skeletal muscle cells were shown to oxidise galactose and fatty acids normally, indicating that the bioenergetic dysfunction lies upstream of the TCA cycle. The dysfunction in glucose oxidation is similar to what has previously been shown in blood cells from CFS patients. The consistency of cellular bioenergetic dysfunction in different cell types supports the hypothesis that CFS is a systemic disease. The retention of bioenergetic defects in cultured cells indicates that there is a genetic or epigenetic component to the disease. This is the first study to use cells derived from skeletal muscle biopsies in CFS patients and healthy controls to look at cellular bioenergetic function in whole cells.

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

“…However, the metabolic quiescence and greater death rates of ME/CFS lymphocytes [ 2 , 68 ] may have obscured differences, as may have the loss of cytoplasmic context due to permeabilisation. Respiration rates provisioned by fatty acid utilisation were also found to be unchanged in skeletal muscle cells from ME/CFS patients, contrary to the authors’ expectations of elevated, compensatory β-oxidation as part of a shift away from glucose metabolism [ 9 ]. The expected increase may have been absent due the reduced exercise that ME/CFS patients can undertake, since exercise upregulates mitochondrial biogenesis and function in muscle [ 69 ].…”

“…Other studies have instead employed Seahorse respirometry to investigate real-time parameters of respiration and glycolysis in live cells from ME/CFS patients and compared to healthy controls. While the rate of glycolysis was found to be reduced in ME/CFS CD4 + and CD8 + T cells [ 7 ], we found no difference in glycolytic rate in ME/CFS lymphoblasts [ 2 ], nor did Tomas et al in ME/CFS PBMCs or skeletal muscle cells [ 8 , 9 ]. Overall, the role of glycolysis in ME/CFS is unclear and would benefit from continued investigation.…”

Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome

“…Impaired Energy Metabolism in ME/CFS. Metabolomic studies have reported evidence of impaired ATP production from oxygen, glucose, fatty acids, and amino acids in multiple cell types (41,42,(91)(92)(93)(94). Not just oxidative phosphorylation but also glycolysisand possibly, the citric acid and urea cycles-are incriminated.…”

Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study

“…Interestingly, reduced activation of the PDH has been reported in other studies, but by upregulation of the PDH kinase instead of downregulation of the PDH phosphatase [29]. Recent studies in muscle cells from ME/CFS patients point to a PDH dysfunction as a potential cause of mitochondrial dysfunction [67].…”