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Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile and vascular dysfunction

ABSTRACT: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with no known underlying mechanisms, diagnostic tools, or treatments. Multiple areas of dysfunction have been extensively studied, but rarely examined together. We recruited age- and sex-matched ME/CFS patients and healthy controls for a multi-modal study examining energy metabolism, immune profiles and plasma protein levels. Adenosine monophosphate (AMP) were higher in immune cells from MECFS patients, with a similar but non-signficant trend observed in plasma. Additionally, immune cells showed higher levels of adenosine diphosphate (ADP) and a reduced adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio. These findings imply decreased ATP generation and the presence of energy stress within the immune cell population. Adaptive immune cell populations were skewed towards less mature effector subsets of CD4+, CD8+ and γδ T cells, and proportions of CD1c+CD141- conventional DC type 2 (cDC2) and CD56lowCD16+ terminal natural killer (NK) cells were also reduced. Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Using Classification and Regression Tree (CART) modelling, we identified variables from each mode of investigation with strong predictive potential for ME/CFS. Together, this study provides new insights intothe somatic symptoms and underlying biology of ME/CFS.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Chronic Fatigue Syndrome

SUBMITTER: Shivani Krishnamurthy

LAB HEAD: Dr. Benjamin Heng

PROVIDER: PXD068504 | Pride | 2025-11-14

REPOSITORIES: Pride

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			Action	DRS
	20231129_ZenoToF7600_CFS_ME1.timeseries.data	Other
	20231129_ZenoToF7600_CFS_ME1.wiff	Wiff
	20231129_ZenoToF7600_CFS_ME1.wiff.scan	Wiff
	20231129_ZenoToF7600_CFS_ME1.wiff2	Wiff
	20231129_ZenoToF7600_CFS_ME10.timeseries.data	Other

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Project description:Objectives: To explore how modulation of cardiomyocyte SIRT5 levels affects the development of pathological cardiac remodeling and dysfunction. Background: SIRT5 is a mitochondrial NAD+-dependent deacylase, which regulates metabolic enzymes upon desuccinylation, demalonylation, and deglutarylation. Its role in the development of heart failure is not completely understood. Methods: Mice with cardiomyocyte-specific Sirt5 deletion (Sirt5-/-) or Sirt5 overexpression (cSirt5-Tg) underwent transverse aortic constriction (TAC) or Sham surgery. Cardiac structure and function were assessed by echocardiography and quantification of myocardial fibrosis and cardiomyocyte cell size. Metabolomic analysis and RNA sequencing were performed to identify potential novel pathways regulated by SIRT5. Results: While cardiac structure and function were similar in cSirt5-Tg compared to control mice, cSirt5-/- mice displayed exacerbated cardiac dilation, dysfunction, and fibrosis following TAC. Accumulation of metabolites involved in purine metabolism, particularly inosine and hypoxanthine, and reductions in nucleosides, adenosine and adenine, and nucleotides, AMP and ADP, were observed in hearts of cSirt5-/- mice and following TAC. Moreover, transcriptional analysis revealed upregulation of purine-nucleoside phosphorylase (PNP) and 5' nucleotidase, ecto (NT5E) and downregulation of adenosine kinase (ADK), which is likely to contribute to enhanced degradation of purine nucleotides and resulting accumulation of inosine and hypoxanthine in hearts of cSirt5-/- mice following TAC. Lastly, reduced SIRT5 expression and protein succinylation in left-ventricular tissue of patients with heart failure correlates with reduced ADK expression. Conclusions: Loss of SIRT5 aggravates cardiac remodeling and dysfunction in response to chronic pressure-overload possibly by dysregulation of genes involved in purine and pyrimidine metabolism, resulting in impaired ATP regeneration from adenosine.

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Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile and vascular dysfunction

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