also see: New Knowledge about Cholesterol Drugs and Muscle Problems Q&A with PHI
Many people, despite a diagnosis of high cholesterol, refuse to take Lipitor, Simvistatin, Crestor, or other "statins" because they are afraid of muscle pain and weakness which are adverse effects of these medications. Such problems occur greater than 15 percent of the time in clinical practice. (1) Among polio survivors, many more individuals refuse these drugs not just because of their association with muscle problems in non-polio patients but because it is possible that these drugs may unmask sub-clinical post-polio symptoms. Yet there is a strong case to be made that many Western men and women would do much better in the long run if they took action to lower cholesterol with a statin. Here is why. Among native peoples: American Indians, indigenous Japanese, in primitive people, and even in many animals, the total cholesterol is lower. (1) For example, the total cholesterol in mg/dl in the Baboon is 110, Howler monkey100, Elephant110, Rhinoceros.80 Pygmy tribes 100 Rural Chinese 125 , but in adult Americans 208 is the total average cholesterol level.(3). In these animals and indigenous human groups cardiovascular disease is rare. The groups mentioned above are close to half of the average total cholesterol found in Americans where cardiovascular disease is common. Human cord blood at birth has a "bad cholesterol" LDL-C of about 70 mg/dl And babies have a "bad cholesterol" less than 40mg/dl, (4), yet treatment begins with statins, if we have no other risk factors, when our "bad cholesterol" LDL-C is 160 mg/dl. The lower the LDL-C in our blood the greater our protection. (4) Since it is known that cardiovascular diseases are the number 1 killer in our society we would be foolish to ignore this. As Polio Survivors, the question is how can we utilize these statin medications, which are very effective in lowering cholesterol, without worrying about adverse muscle effects?
If one reads current medical literature addressing statin drugs to try to find out what it is about statins that causes the adverse muscle effects ( myopathy) one will invariably find "It is not known". There was a finding about 12 years ago that carriers of a certain gene were more likely to develop muscle problems, yet still, the cause of the muscle damage itself was not known. However, because of a confluence of events the probable answer to the question of cause has been worked out simultaneously in Japan, Harvard, and at Beth Israel Hospital in Boston, Massachusetts.(4),(5) The biological roots of statin myopathy (muscle damage) are similar, coincidentally, to the atrophy we experience with polio. Researcher's have performed a series of elegant
experiments which reveal how statins produce the adverse affect of myopathy in some patients. Their research will be explained in this article.
Figure 1: DNA double helix bound at atrogen-1 gene to an inducer. Atrogen-1 is activated by this contact. What produces the inducer? What does atrogen-1 do?
Because of the new knowledge countermeasures are already being planned to develop agents which will eliminate these troublesome muscle problems due to statin therapy. There was a patent application for such agents on the Web posted by the same people who provided the likely answer to statin induced myopathy. However, Dr. Lecker of Harvard, a leader in this group of researchers, couldn't provide an answer regarding a medicine or substance one can take to eliminate the possibility of myopathy resulting from statin drug.therapy. Instead he recommended a trial of CoQ10, since this important compound has multiple functions in energy production and is decreased significantly by statins, as is cholesterol. CoQ10 is not only used, extensively, by the processes leading to myopathy, but it is reduced in amount during the same process that lowers cholesterol concentration. Statins themselves lower CoQ10 blood concentration.
The biochemistry of muscle damage is complex. The aforementioned researcher's leading explanation of this damage is that a gene within our DNA called atrogen-1. Statins turn it on (Figure 1). Age turns it on. Diseases like Polio and Cancer and infection can turn it on. Once it is on it provides the information for the muscle fiber to produce an enzyme called Ubiquitin ligase (Coenzyme Q10 ligase).. This molecule binds with several Coenzyme Q10 molecules until the entire structure has a shape that allows it to snatch up small repair proteins in the muscle. Once these proteins are bound they are deposited into a tiny body called a proteosome, which breaks up these repair proteins into smaller pieces. This effectively removes the ability of the muscle to repair itself, and atrophy of the fiber occurs. Exercise inhibits this entire process and more repairs can be made but if the exercise is too intense, too frequent, or too long the process is stimulated again. Such intense exercise in the presence of a statin turns on atrogen-1 much more readily in most people.(5) One should be careful with extreme vigorous exercise while on a statin.
HOW STATINS LOWER CHOLESTEROL ILLUSTRATION 1: Replacement of Mevalonate stops myopathy because the reactions that follow carry on normally. Replacement of geranylgeranyl pyrophosphate saves from myopathy too. But neither Squalene, Farnesyl pyrophosphate nor Rho prevent myopathy. Conclusion: Myopathy is due to a geranylgeranylation defect probably due to a lower concentration of this chemical as a result of statin therapy.
Each of the structures above (biochemicals inside muscle cells) are a different shape abd they are transformed into one another in a cascade of reactions. These are the reactions inside muscle that result in cholesterol production, and as you can see the production of several other biochemicals which have their own job inside the muscle fiber. The first chemical is on top and each step along the way requires a helper, (an enzyme), to make the reaction happen,. The first reaction of the chain has much less functioning enzyme because a statin inhibits it. All the dominoes (chemicals) that come after this first chemical are slowed considerably, but if one adds mevalonate the entire process will speed up and be repaired.
It is logical that by inhibiting the first chemical in the chain with a statin everything that comes after is produced slower than it ordinarily would be, so cholesterol, the final product here, is diminished. Rho is a molecule that causes inflammation, especially inside arteries, so it's inhibition by the same process will benefit cardiovascular health also. Some even contend it's the anti-inflammatory affect of statins that lowers CVD risk and not cholesterol. (4) But every major clinical end point trial undertaken has shown that a lower LDL-C level is associated with a lower level of cardiovascular disease.(4) And LDL-C is a large component of the total cholesterol level.
The scientists from Harvard, Beth Israel in Boston, and Japan used zebrafish embryo muscle, mouse muscle, and human muscle in their experiments. First they used human cadavers from individuals who had been treated before death with statins. They removed tissue and showed that the atrogen-1 gene was activated when a statin was in the blood but not activated in those where it was not used as a treatment for that individual.(5)
A NEW UNDERSTANDING BRINGS NEW HOPE
If they treated zebrafish embryo muscle or mouse leg muscle, each with lovastatin, there was a clear deterioration of the muscle. If they did the same thing but added mevalonate (above, after the inhibition by statin) the muscles remained normal and atrogen-1 was not expressed, and therefore did not produce ubiquitin ligase. They used animals without the atrogen-1 gene or where it was chemically prevented from being expressed (null mice, knockout zebrafish.) and muscle remained healthy despite high concentrations of lovastatin.(5) They went through several experiments one by one adding this subtracting that and meticulously examined the resultant muscle and found, this May, that if they inhibited geranylgeranyl pyrophosphate (a substance in the chemical reaction flowsheet to cholesterol above) they saw damaged muscle, but muscle remained healthy if they left geralnylgeranyl pyrophosphate alone and inhibited squalene or Rho.(6) So, the muscle damage that results from statin use (in a much less severe way, characteristically, than in polio and not in a significant irreversible way in most people), appears to come from a geranylgeranyl defect in one of the reactions resulting from geranylation. Geranylation is a process whereby energy storing molecules are bound and attached to several amino acids. This structure is then attached to the membrane of the energy generator of the cell, the mitochondrion. The geranylation process occurs so that it's product is placed in just the right location on the mitochondrial membrane. There are a number of steps here so just one defect in the process of geranylation could be the one that results in either faulty placement or faulty production of a product. In any event it is from the lower concentration of geranylgeranyl pyrophosphate that the inducer for atrogen-1 results, possibly from mitochondria that are not working properly. Of course, and coincidentally polio, other neuromuscular diseases, spinal cord injury, and cancer also result in the induction of the atrogen-1 gene by a different process. Then the atrogen-1 produces ubiquitin ligase which gets rid of repair proteins in the muscle by dumping them into a proteosome. This has been known to researchers as the Ubiquitin Proteosome Pathway. We can hopefully expect, in the foreseeable future, a new generation of statins that will sidestep the activation of atrogen-1, or we may find separate compounds that can stop atrogen generation after we identify what happens with geranylgeranyl pryrophosphate that induces the atrogen-1 gene. There are a few available nutrients that inhibit atrogen activation now: alanine, cucurmin, branched chain amino acids, and others.(7) But these experiments were done in the lab so taking them may not provide the needed concentration to inhibit atrogen. CoQ10 levels, as mentioned above, markedly diminish during statin therapy. It is not on our simplified flowsheet, but as mentioned, it too is produced by this series of reactions and it is used extensively in the process of ubiquitination (ubiquitin ligase formation and muscle repair inhibition). So supplementing Q10 may be a good idea. And, of course, there are different forms of the atrogen gene in different people, which could explain why some patients have no trouble while others do. In the future we should be able to check the genetics before statin therapy. The prospects look much better now so with luck and work in the foreseeable future statin myalgia may be an unpleasant memory. We may even be able to keep muscle fibers from undergoing atrophy when neuromuscular diseases occur, and if neuronal rehabilitation by stimulation of nerve end fiber growth becomes a reality, individuals suffering from these diseases could be able to improve, and enervation of muscles without nerves to stimulate them will no longer be impossible because induced motor neuron sprouts could be provided before extensive atrophy and muscle death occur.
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