Differing leukocyte gene expression profiles associated with fatigue

[Ecoclimber]

Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome.

Light KC, Agarwal N, Iacob E, White AT, Kinney AY, Vanhaitsma TA, Aizad H, Hughen RW, Bateman L, Light AR.
Source

Department of Anesthesiology, University of Utah Health Sciences Center, Salt Lake City, UT, USA. Electronic address: kathleen.c.light@hsc.utah.edu.
Abstract

BACKGROUND:

Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions.
METHODS:

Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors.
RESULTS:

PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p<0.005 and r=-0.34, p<0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001).
CONCLUSIONS:

PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue.

This a study that includes Dr. Bateman and the Lights

More can be read here:
http://www.cortjohnson.org/blog/201...cfs-post-cancer-fatigue-share-common-pathway/

Eco

 

[Snow Leopard]

I haven't seen a discussion about this yet, so... (additonal note, threads have now been merged)

http://www.ncbi.nlm.nih.gov/pubmed/24054763

Psychoneuroendocrinology.

2013 Sep 6. pii: S0306-4530(13)00297-7. doi: 10.1016/j.psyneuen.2013.08.008. [Epub ahead of print]
Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome.

Light KC, Agarwal N, Iacob E, White AT, Kinney AY, Vanhaitsma TA, Aizad H, Hughen RW, Bateman L, Light AR.
Source

Department of Anesthesiology, University of Utah Health Sciences Center, Salt Lake City, UT, USA. Electronic address: kathleen.c.light@hsc.utah.edu.
Abstract

BACKGROUND:

Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions.
METHODS:

Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors.
RESULTS:

PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p<0.005 and r=-0.34, p<0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001).
CONCLUSIONS:

PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue.

Most of key details are listed there in the abstract.
Side note, 43% of the post-cancer-fatigue controls had depression, with 51% of CFS patients and 0% of controls.

I was interested in the association of reduced (relative) levels of DBI expression being correlated with increased fatigue.

The finding may be nothing as a Japanese study found increased DBI expression in patients vs health controls. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2442021/

Now the role of DBI is interesting.

DBI (diazepam binding inhibitor) is also known as the acyl-CoA-binding protein (ACBP) and plays a key role in regulating other systems including mitochondrial function.

http://www.ncbi.nlm.nih.gov/pubmed/8232254

Mol Cell Biochem. 1993 Jun 9-23;123(1-2):129-38.
The function of acyl-CoA-binding protein (ACBP)/diazepam binding inhibitor (DBI).

Knudsen J, Mandrup S, Rasmussen JT, Andreasen PH, Poulsen F, Kristiansen K.
Source

Institute of Biochemistry, Odense University, Denmark.
Abstract

Acyl-CoA-binding protein has been isolated independently by five different groups based on its ability to (1) displace diazepam from the GABAA receptor, (2) affect cell growth, (3) induce medium-chain acyl-CoA-ester synthesis, (4) stimulate steroid hormone synthesis, and (5) affect glucose-induced insulin secretion. In this survey evidence is presented to show that ACBP is able to act as an intracellular acyl-CoA transporter and acyl-CoA pool former. The rat ACBP genomic gene consists of 4 exons and is actively expressed in all tissues tested with highest concentration being found in liver. ACBP consists of 86 amino acid residues and contains 4 alpha-helices which are folded into a boomerang type of structure with alpha-helices 1, 2 and 4 in the one arm and alpha-helix 3 and an open loop in the other arm of the boomerang. ACBP is able to stimulate mitochondrial acyl-CoA synthetase by removing acyl-CoA esters from the enzyme. ACBP is also able to desorb acyl-CoA esters from immobilized membranes and transport and deliver these for mitochondrial beta-oxidation. ACBP efficiently protects acetyl-CoA carboxylase and the mitochondrial ADP/ATP translocase against acyl-CoA inhibition. Finally, ACBP is shown to be able to act as an intracellular acyl-CoA pool former by overexpression in yeast. The possible role of ACBP in lipid metabolism is discussed.

More functions are discussed in this paper:
"Fatty acid transport and fatty acid-binding proteins"
http://journals.cambridge.org/download.php?file=/PNS/PNS54_01/S0029665195000073a.pdf&code=006bcc1fe527b47b589a28152cc6112a

Also:
"Fat to the fire: the regulation of lipid oxidation with exercise and environmental stress"
http://bio.mcmaster.ca/fcl/grantm/web/McClelland_CBP_2004.pdf

And:

"Carnitine, mitochondrial function and therapy"
http://www.ncbi.nlm.nih.gov/pubmed/19716391

Recent work has demonstrated that acyl-CoA binding protein (ACBP) in the cytosol both keeps the ‘free’ concentration in the cytosol low and facilitates delivery of the LC-acyl-CoA to these membrane bound enzymes [41].

Under circumstances that increase the energetic utilization of lipids by muscle the sensitivity of RyRC might be positively up-regulated. For instance, during prolonged moderate to hard exercise, muscle is fuelled mainly by long-chain fatty acids supplied by higher fatty acid concentrations in the plasma. This could, under extreme conditions, lead to a large increase in muscle cytosolic [FACoAs], induce alterations in muscle Ca2+ fluxes and thus be involved in the generation of fatigue. Under extreme conditions, moreover, the rate of utilization of FACoAs by mitochondria might decrease owing to the oxygen debt and contribute to elevating muscle cytosolic [FACoAs]. Both transient and irreversible muscle damage by strenuous exercise have been correlated with a marked increase in intracellular Ca2+ levels [30,31].

Abbreviations used: ACBP, fatty acyl-CoA-binding protein; FACoA, fatty acyl-CoA ester

"Fatty acyl-CoA–acyl-CoA-binding protein complexes activate the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum"
http://www.biochemj.org/bj/325/0423/3250423.pdf



But I wondered what effects mood, stress and exercise may have on expression.
So I decided to dig a little deeper:
"Acyl-coenzyme A binding protein expression is fibre-type specific in rat skeletal muscle but not affected by moderate endurance training"
http://link.springer.com/article/10.1007/s004240100716

"Psychological stress, but not physical stress, causes increase in diazepam binding inhibitor (DBI) mRNA expression in mouse brains."
http://www.ncbi.nlm.nih.gov/pubmed/12117556
And the DBI was subsequently reduced after administration of an agonist for central benzodiazepine receptors (Flunitrazepam).

Perhaps more to be added soon...

 

[LisaGoddard]

Thanks for these posts. I was intrigued that DBI affects so many systems - adrenal, insulin etc- that are out of whack with many of us.

How would you promote the levels of DBI? I had a quick search which seemed to suggest acute stress, nicotine or morphine addiction. Mmmm... don't fancy any of these. I wondered about taking Acyl CoA?

Any suggestions?