Monday, September 27, 2010

9. Sulfur Deficiency and Muscle Wasting Diseases

In browsing the Web, I recently came upon a remarkable article [Dröge1997] which develops a persuasive theory that low blood serum levels of two sulfur-containing molecules are a characteristic feature of a number of diseases/conditions. All of these diseases are associated with muscle wasting, despite adequate nutrition. The authors have coined the term "low CG syndrome" to represent this observed profile., where "CG" stands for the amino acid "cysteine," and the tripeptide "glutathione," both of which contain a sulfhydryl radical "-S-H" that is essential to their function. Glutathione is synthesized from the amino acids cysteine, glutamate, and glycine, and glutamate deficiency figures into the disease process as well, as I will discuss later.

The list of diseases/conditions associated with low CG syndrome is surprising and very revealing: HIV infection, cancer, major injuries, sepsis (blood poisoning), Crohn's disease (irritable bowel syndrome), ulcerative colitis, chronic fatigue syndrome, and athletic over-training. The paper [Drage1997] is dense but beautifully written, and it includes informative diagrams that explain the intricate feedback mechanisms between the liver and the muscles that lead to muscle wasting.

This paper fills in some missing holes in my theory, but the authors never suggest that sulfur deficiency might actually be a precursor to the development of low CG syndrome. I think that, particularly with respect to Crohn's disease, chronic fatigue syndrome, and excessive exercise, sulfur deficiency may precede and provoke the muscle wasting phenomenon. The biochemistry involved is complicated, but I will try to explain it in as simple terms as possible.

I will use Crohn's disease as my primary focus for discussion: an inflammation of the intestines, associated with a wide range of symptoms, including reduced appetite, low-grade fever, bowel inflammation, diarrhea, skin rashes, mouth sores, and swollen gums. Several of these symptoms suggest problems with the interface between the body and the external world: i.e., a vulnerability to invasive pathogens. I mentioned before that cholesterol sulfate plays a crucial role in the barrier that keeps pathogens from penetrating the skin. It logically plays a similar role everywhere there is an opportunity for bacteria to invade, and certainly a prime opportunity is available at the endothelial barrier in the intestines. Thus, I hypothesize that the intestinal inflammation and low-grade fever are due to an overactive immune system, necessitated by the fact that pathogens have easier access when the endothelial cells are deficient in cholesterol sulfate. The skin rashes and mouth and gum problems are a manifestation of inflammation elsewhere in the barrier.

Ordinarily, the liver supplies cholesterol sulfate to the gall bladder, where it is mixed into bile acids, and subsequently released into the digestive system to assist in the digestion of fats. If a person consistently eats a low-fat diet, the amount of cholesterol sulfate delivered to the digestive system from the liver will be reduced. This will logically result in a digestive system that is more vulnerable to invasion by pathogens.

The sulfate that's combined with cholesterol in the liver is synthesized from cysteine (one of the two proteins that are deficient in low CG syndome). So insufficient bioavailability of cysteine will lead to a reduced production of cholesterol sulfate by the liver. This will, in turn, make it difficult to digest fats, likely, over time, compelling the person to adhere to a low-fat diet. Whether low-fat diet or sulfur deficiency comes first, the end result is a vulnerability to infective agents in the intestines, with a consequential heightened immune response.

[Dröge1997] further discussses how a reduction in the synthesis of sulfate from cysteine in the liver leads to increased compensatory activity in another biological pathway in the liver that converts glutamate to arginine and urea. Glutamate is highly significant because it is produced mainly by the breakdown of amino acids (proteins in the muscles); i.e., by muscle wasting. The muscle cells are triggered to cannibalize themselves in order to provide adequate glutamate to the liver, mainly, in my view, in order to generate enough arginine to replace the role of sulfate in muscle glucose metabolism (i.e., these activities in the liver and muscles are circular and mutually supportive).

Arginine is the major source of nitric oxide (NO) and NO is the next best thing for muscle glucose metabolism in the absence of cholesterol sulfate. NO is a poor substitue for SO4-2, but it can function in some of the missing roles. As you will recall, I propose that cholesterol SO4-2 accomplishes a number of important things in muscle cells: it delivers oxygen to myoglobin, it supplies cholesterol to the cell membrane, it helps break down glucose, protects the cell's proteins from glycation and oxidation damage, and provides energy to the cell. NO can help in reducing glycation damage, as nitrogen can be reduced from +2 to 0 (whereas sulfur was reduced from +6 to -2). It also provides oxygen, but it is unable to transfer the oxygen directly to myoglobin by binding with the iron molecule, as was the case for sulfate. NO does not supply cholesterol, so cholesterol deficiency remains a problem, leaving the cell's proteins and fats more vulnerable to oxidative damage. Furthermore, NO itself is an oxidizing agent, so myoglobin becomes disabled, due to both oxidation and glycation damage. The muscle cell, therefore, engages in mitochondrial oxidation of glucose at its own peril: better to revert to anaerobic metabolism of glucose to decrease the risk of damage. Anaerobic metabolism of glucose results in a build-up of lactic acid, which, as explained in [Dröge1997] further enhances the need for the liver to metabolize glutamate, thus augmenting the feedback loop.

Furthermore, as you'll recall, if I'm right about cholesterol sulfate seeding lipid rafts, then, with a cholesterol sulfate deficiency, the entry of both glucose and fat into the muscle cell are compromised. This situation leaves the cell with little choice but to exploit its internal proteins as fuel, manifested as muscle wasting.

In summary, a number of different arguments lead to the hypothesis that sulfur deficiency causes the liver to shift from producing cholesterol sulfate to producing arginine (and subsequently nitric oxide). This leaves the intestines and muscle cells vulnerable to oxidation damage, which can explain both the intestinal inflammation and the muscle wasting associated with Crohn's disease.

The immune system depends upon abundant cholesterol to defend against severe stress. I have previously argued that high serum cholesterol is protective against sepsis. It is worth repeating here the abstract from [Wilson2003], who studied changes in blood cholesterol levels following trauma, infection, and multiple organ failure:

"Hypocholesterolemia is an important observation following trauma. In a study of critically ill trauma patients, mean cholesterol levels were significantly lower (119 ± 44 mg/dl) than expected values (201 ± 17 mg/dl). In patients who died, final cholesterol levels fell by 33% versus a 28% increase in survivors. Cholesterol levels were also adversely affected by infection or organ system dysfunction. Other studies have illustrated the clinical significance of hypocholesterolemia. Because lipoproteins can bind and neutralize lipopolysaccharide, hypocholesterolemia can negatively impact outcome. New therapies directed at increasing low cholesterol levels may become important options for the treatment of sepsis."

Thus, many of these conditions/diseases that lead to muscle wasting may do so because cholesterol (and therefore cholesterol sulfate) is depleted from the blood serum. This results in the same feedback loop between the liver and the muscles that I discussed with regard to Crohn's disease. So I think it's plausible that the muscle wasting associated with all of these conditions is caused by this same feedback mechanism.

I have discussed the role cysteine plays in providing sulfate to the liver. But what is the role of glutathione, the other sulfur-containing protein that's depleted in low GC syndrome? Muscle cells ordinarily contain significant levels of glutathione, and its depletion leads to mitochondrial damage [Martensson1989]. Patients undergoing surgical trauma have been found to exhibit reduced glutathione levels in their skeletal muscles [Luo1996]. It is tempting to speculate that cholesterol sulfate provides the sulfur needed for glutathione synthesis, so that the deficiency would be explained by the reduced availability of cholesterol following the immune system's heightened response to surgical trauma. Glutathione is a potent antioxidant, so its deficiency will further contribute to dysfunction of the muscle cell's mitochondria, therefore greatly impairing its energy supply.

There is a growing awareness that glutathione deficiency may play a role in many diseases. You may want to check out this Web site describing a long list of diseases that may be impacted by glutathione deficiency. Whether the problems arise just due to insufficient supply of the glutathione molecule itself, or whether a more general sulfur deficiency is the root cause, is perhaps hard to say, but provocative nonetheless.


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"We previously demonstrated a novel function of phylloquinone (vitamin K(1)) and menaquinone 4 (MK-4; a major form of vitamin K2) in protecting pre-OLs and immature neurons against glutathione depletion-induced oxidative damage"

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