Elevated Inosine Monophosphate Levels in Resting Muscle of Patients with Stable COPD

[pattismith]

This study got my interest because:

1- muscle weakness is also a frequent feature in CFS/ME
2-COPD/Chronic Obstructive Pulmonary Disease) genes seem to be potential risk factor for Fibromyalgia (see here)
3-Inbalance between ATP/ADP/Adenosine was found in ME/CFS
4-I solved my own muscle weakness when I took Inosine, a metabolite of IMP

Summary:

In summary, in patients with stable COPD elevated muscular IMP content was found under resting conditions. IMP levels were negatively related to the ATP/ADP ratio, suggesting an imbalance between ATP utilization and resynthesis. The fact that these abnormalities were already found under resting conditions suggests that muscular energy status in COPD patients might even be more compromised during exercise. The cause and consequences of these disturbances in muscle energy metabolism in COPD patients need further exploration

Intro:
Impaired exercise performance is a frequently occurring problem in patients with chronic obstructive pulmonary disease (COPD= chronic obstructive pulmonary disease) (1).

The two dominant symptoms limiting exercise tolerance in COPD are dyspnea and a sensation of fatigue in leg muscles (1).

Recently, it has been shown that both skeletal and respiratory muscle weakness contribute to the severity of these symptoms (2) and to reduced exercise tolerance, independent of lung function impairment (2, 3).

The cause of muscle weakness in COPD patients is incompletely understood. It has been shown that the development of muscle weakness is frequently associated with loss of body mass and in particular loss of muscle mass…


DIscussion:

In the present study, elevated muscular IMP levels and decreased ATP/ADP and PC/C ratios were found in patients with stable COPD compared with healthy control subjects under resting conditions. ATP, ADP, AMP, and TAN did not differ between patients and control subjects.

Within the patient group, two subgroups could be distinguished: a subgroup with muscular IMP content > 0.06 mmol/kg dry weight (IMP1 patients) and a subgroup with an IMP content , 0.06 mmol/kg dry weight (i.e., below the detection level) (IMP2 patients).
This division seemed relevant since only one of eight control subjects also had a measurable IMP content. In the IMP1 patients, lower ATP/ADP and PC/C ratios were found compared with IMP2 patients.
Clinically, IMP1 patients differed from IMP2 patients in that they had a significantly lower DLCO. IMP and ammonia (NH3) are produced during deamination of AMP (AMP→IMP 1 NH3).
...
In healthy subjects, IMP content in resting muscle is very low. Elevated IMP levels are only found during high intensity exercise (75% O2max) (8). Several studies in healthy subjects indicated that special conditions, such as hypoxemia (18) or V ·
initial shortage of muscular glycogen, induce enhanced IMP accumulation during exercise (19). It is generally believed that, in these acute situations, IMP formation reflects an imbalance between ATP utilization and resynthesis.

In the present study, we hypothesized, based on the previously observed changes in aerobic and glycolytic capacity (6, 7), that in patients with stable COPD alterations might occur in muscular high-energy phosphate concentrations.
Furthermore, we assumed that IMP measurements would enable us to detect subtle changes in muscular energy balance. Indeed, in this study, elevated IMP levels were found that were associated with lower ATP/ADP ratios. The finding of elevated IMP content in resting muscle, is to our knowledge, unique…

Because of the observed relationship between IMP content and ATP/ADP ratio, other explanations for the enhanced IMP content, such as disturbances in pathways catabolizing IMP (such as degradation of IMP to inosine and further) or disturbances in the purine nucleotide cycle (where IMP is reaminated to AMP), seem less relevant.
An imbalance between ATP utilization and resynthesis can be caused by enhanced ATP utilization, decreased ATP resynthesis, or both. Earlier studies by our group and others have shown that a significant proportion of COPD patients have increased resting energy expenditure (22).

Biopsies were obtained from the tibialis muscle using a conchotome. However, in all the studies quoted here, biopsies were taken from the quadriceps femoris muscle, which has a different fiber type distribution compared with the anterior tibialis muscle (40% and 70% type I fibers, respectively) (25). In healthy subjects during exercise, higher IMP formation has been found in type II fibers compared with type I fibers (8). Therefore, if quadriceps femoris muscle would have been used in this study, results might have been different

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.157.2.9608064

 

[S-VV]

Was your muscle weakness related to lactic acid, ie, they get tired quickly, or did you have less energy to do things, ie, the muscles felt limp.

I'm asking because my main symptom is amazingly rapid acidosis after minimal exertion. I've ordered a lactate meter to confirm.

 

[pattismith]

Was your muscle weakness related to lactic acid, ie, they get tired quickly, or did you have less energy to do things, ie, the muscles felt limp.

I'm asking because my main symptom is amazingly rapid acidosis after minimal exertion. I've ordered a lactate meter to confirm.

I have done some lactic acid testing, and I found some abnormalities.

However, my muscle weakness was not related to any effort nor to any high lactic acid.

 

[S-VV]

Thanks. It's things like this that make me wonder if me/CFS is just a big collection of similar but different diseases.

By the way, uric acid, a metabolite of inosine, is a strong antioxidant

Novel disease-preventing antioxidant pathway

Uric acid is a major intracellular antioxidant, possibly even more important than the antioxidants we try to eat, researchers have found. They also discovered how uric acid helps to prevent aging and disease and how it helps in the treatment of cancer

https://www.sciencedaily.com/releases/2014/05/140527101352.htm

Coincidentally, one of my few blood test abnormalities is low uric acid.

 

[pattismith]

@S-VVMy NH3 was a bit high, and low potassium was worsening my muscle weakness.

Uric acid can have good ( especially on ALS, MS) and bad effects (gout arthritis and other side effects on heart), so it must be monitored when using high amounts of Inosine.

What I think we have in common may be an unbalance between ATP/ADP/IMP/Adenosine (and Inosine), outside and Inside the cells, which produces lot's of symptoms, especially in basal ganglia in the brain and in muscles.

The supplements we can take that have direct effects on this balance are Inosine (adenosine agonist), caffeine (adenosine antagonist), adenosine reuptake inhibitors (dipyridamole, Nimodipine, and many others), and xanthine oxidase inhibitors (which stop the uric acid production, example = Inositol, quercitin)

There is a salvage pathway that increases IMP from hypoxanthine. This means that blocking Xanthine oxidase (XOR) will block hypoxanthine-uric acid transformation which will probably increase IMP:

 

[S-VV]

Great write up!

I gather you experienced benefits from Nimodipine as well right?

It's one of the few things that consistently helps me.

Is there a common lab test to measure ATP, AMP and IMP or do you go by indirect measurements like uric acid?

 

[pattismith]

Great write up!

I gather you experienced benefits from Nimodipine as well right?

It's one of the few things that consistently helps me.

Is there a common lab test to measure ATP, AMP and IMP or do you go by indirect measurements like uric acid?

I added two examples of xanthine oxidase inhibitors: inositol and quercitin (and some other flavonoids)

Uric acid is the easier parameter and the cheapest we can measure, I don't think that others are easy to get.

I tryed Nimodipine, but with few effect.

Currently I do a mix caffeine + Inosine + Inositol, and the result is impressive.
This means that I may benefit from Inosine independantly of its adenosine receptor activation and independantly of its catabolism to uric acid.
This is interesting because few is known about intracellular effects of Inosine.
I found an article about its potency to raise catecholamines production in neurons for example.
The salvage pathway from hypoxanthine to AMP si another possibility

 

[S-VV]

Very interesting. So basically you are blocking the inosine from being oxidized to uric acid via inositol, plus blocking the effects on the adenosine receptors with caffeine. This way the pool of inosine monophosphate increases, which may increase AMP, from there, is can be phosphorylated to ADP and ATP via normal metabolism.

I f you like caffeine, you may like pentoxyfiline, which like caffeine is a xanthine derivative, but thanks to its long hidrocarbon tail is more fat soluble:

Pentoxyfiline

Caffeine

 

[pattismith]

Very interesting. So basically you are blocking the inosine from being oxidized to uric acid via inositol, plus blocking the effects on the adenosine receptors with caffeine. This way the pool of inosine monophosphate increases, which may increase AMP, from there, is can be phosphorylated to ADP and ATP via normal metabolism.

I f you like caffeine, you may like pentoxyfiline, which like caffeine is a xanthine derivative, but thanks to its long hidrocarbon tail is more fat soluble:

Pentoxifylline, like propentofylline (but unlike caffeine), is an adenosine reuptake inhibitor, like dipyridamole:


https://en.wikipedia.org/wiki/Adenosine_reuptake_inhibitor


it blocks adenosine and inosine transport through cell membrane.

So on the paper, pentoxyfylline could be interesting for it's antagonism to Adenosine A2 receptors, if you need to activate other adenosine receptors (A1 and A3). Maybe I will try it, but as it is also a phosphodiesterase inhibitor , I really don't know what to expect from it. I 've already tryed Dipyridamole but didn't feel very well on it.

 

[S-VV]

I started taking pentoxyfiline after the OMF study in order to increase peripheral blood flow, so in my case PDE inhibition is just what I want.

Wow! You really know your stuff. I didn't know pentoxyfiline was a adenosine reuptake inhibitor.

I will definitely keep a close eye on your nucleotide investigations. It's a topic where I have much to learn

 

[pattismith]

@S-VV

well I am not more an expert than anyone, I just like to experiment and try to learn from the successes and failures that come out of it.

We all know that our disease is prone to escape when we try to force our cells to work properly, so I don't know if the benefit I had yesterday will be still here tomorrow.
Still working today though!

 

[pattismith]

I started taking pentoxyfiline after the OMF study in order to increase peripheral blood flow, so in my case PDE inhibition is just what I want.

Wow! You really know your stuff. I didn't know pentoxyfiline was a adenosine reuptake inhibitor.

I will definitely keep a close eye on your nucleotide investigations. It's a topic where I have much to learn

caffeine is also supposed to have PDE inhibition properties (PDE1, PDE4, PDE5), but I don't get nausea from it, whereas when I started Propentopfylline today I got strong nausea. Did you get that side effect from pentoxifylline?

 

[S-VV]

No náusea, only a small increase in energy (maybe due to its antiviral or antiinflammatory effects) that faded after a few days