AMPD3 in ME

Adenosine monophosphate deaminase (AMPD) converts AMP to inosine monophosphate (IMP).

The AMP deaminase gene family:
AMPD1, muscle (m) isoform
AMPD2, liver (l) cells isoform
AMPD3, erothrocyte (e) isoform

The isoforms are named after their predominant location, but are also expressed in other tissue. Fx. AMPD3 is also expressed in muscles.

The purine nucleotide cycle of muscles consist of the conversion of AMP→IMP→AMP and requires AMP deaminase. Flux through this cycle increases during exercise.

Genomics in ME

A gene variant of AMPD3 has been identified as a risk locus in ME (1):

Slide from. Whole Genome Sequencing and Analysis of ME/CFS

https://www.youtube.com/watch?v=nIJX-Q7w_Z4

Epigenomics in ME

The genes AMPD2 and AMPD3 were epigenetic changed in peripheral blood mononuclear cells (PBMC) from ME patients in two studies (2, 3). Some of the DNA methylations in AMPD2 and AMPD3 were related to quality of life in the ME patients (3). AMPD2 and AMPD3 were differntially methylated in PBMC from ME patient subtypes (4).

Transcriptomics in ME

AMPD3 gene expression was downregulated in biopsies from the vastus lateralis muscle in ME patients (5).

Metabolomics in ME

Metabolic profiling of ME patients showed disturbances in purine metabolism (6, 7, 8). Fx, IMP was decreased in plasma from ME patients (8). 

HDAC3 and AMPD3

Depletion of histone deacetylase 3 (HDAC3) in skeletal muscle in mice causes lower glucose utilization and greater lipid oxidation. AMPD3 is involved in the regulation of the fuel switch (9).

Interestingly, very low density lipoprotein receptor (VLDLR) was found to be up-regulated in the ME muscle biopsies in ref 5. VLDLR is responsible for VLDL uptake into the fiber and is involved in the primary pathway of fatty acid transport in skeletal muscle (5). 

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was down-regulated (5). PFKFB3 belongs to a family of bifunctional proteins that are involved in both the synthesis and degradation of fructose-2,6-bisphosphate, a regulatory molecule that controls glycolysis.

Transducin beta like 1 X-linked receptor 1 (TBL1XR1) was up-regulatede in women and down-regulted in men (5). TBL1XR1 is thought to be a component of both nuclear receptor corepressor (N-CoR) and HDAC3 complexes.

ME is associated with purine and histone deacetylation dysregulation (10). 

References:

1) Whole Genome Sequencing and Analysis of ME/CFS https://www.youtube.com/watch?v=nIJX-Q7w_Z4

2) ) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

3) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns. Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

4) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

5) Pietrangelo et al: Transcription profile analysis of vastus lateralis muscle from patients with chronic fatigue syndrome. Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):795-807. https://www.ncbi.nlm.nih.gov/pubmed/19822097

6) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113

7) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371 https://pubs.rsc.org/en/Content/ArticleLanding/2017/MB/C6MB00600K#!divAbstract

8) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.
https://www.ncbi.nlm.nih.gov/pubmed/30563204

9) Hong et al: Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat Med. 2017 Feb;23(2):223-234. doi: 10.1038/nm.4245. Epub 2016 Dec 19. https://www.ncbi.nlm.nih.gov/pubmed/27991918

10) Mcgregor et al: Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases Diagnostics (Basel). 2019 Jul 4;9(3). pii: E70. doi: 10.3390/diagnostics9030070. https://www.ncbi.nlm.nih.gov/pubmed/31277442