MITOCHONDRIA

[lars999]

Hello Fellow Statin Victims!!

In various threads there have been mentions of roles that statin-damaged mitochondria have in producing the symptoms we each suffer from. Some posters, David and Nancy especially, have informed us of the vast number of mitochondrial diseases and the myriad of observable diseases that can result. As a result I have decided to do some Internet searches in an effort to mine this diverse literature for information useful to us statin-victims.

As I find articles that seem to me useful to us, I will post links here. Here is the first one. This article is good for a general introduction to this complex subject. I will say no more about it and leave each of you to decide what it may be worth to you individually.

http://biochemgen.ucsd.edu/mmdc/ep-3-10.pdf

Here is a second link, in this case to the section on aging. There is a list of references at end of this section.
http://www.circuitblue.com/biogerontology/mito.shtml

And now there are three. This link takes you to what appears to be most useful information for us. You will see some of those nasty symptoms that have moved into your body.
http://www.mitoresearch.org/treatmentdisease.html

And a fourth. This one is short and in outline form.
http://www.emdn-mitonet.co.uk/PDF/MitoDiseaseDescription.pdf

Number 5. This article makes me think "we" need to get some statin-victims into these studies.
http://www.nejm.org/doi/full/10.1056/NEJM200002103420616

Number 6. I just could not pass up having something from Nobel Foundation!
http://nobelprize.org/nobel_organizations/nobelfoundation/symposia/medicine/ns90/index.html

Number 7. And, of course, Yahoo has a mito group. Think I recall that someone mentioned this group previously.
http://health.groups.yahoo.com/group/Mito/

Happy Reading,
Lars

[damaged]

Good info.

Thanks for taking the time.

mike

[lars999]

Poking around today in Swedish-language stuff on Internet and from Karolinska Instititutet. Found interesting summarized info about some research by Eva Jansson, Clinical physiologist. Some of what is summarized goes back to 1997 or earlier. In it I find comment that [b]"Ordinary conditioning training increases, for example, in a couple of weeks, the number of mitochondria by 20-40% and stamina improves noticably." [/b]Here is original Swedish sentence "Vanlig konditionsträning ökar t ex inom ett par veckor mängden mitokondrier i muskulaturen med 20-40 procent och uthålligheten förbättras påtagligt."

Here is link to Swedish language article
http://ki.se/ki/jsp/polopoly.jsp?d=2050&a=4301&l=sv

[b]SO, what has happened to us statin victims that prevents this improvement when we try to workout, ski, swim, even walk for some folks? [/b]

This very summarized article leads me to think I must learn more about what Eva and colleages are doing to understand better how external factors, such as shortage of oxygen, and factors controling growth of capillaries affect or interplay with changes in mitochondria in leg muscles. Maybe there is something in this research for us.

An epost to Eva and perhaps also Uffe Ravenskov seems in my future,

Lars

[lars999]

Back to doing more searches today, this time in English-language stuff and with search term "Exercise intolerance and mitochondrial damage" Here are 5 quick, seemingly relevant-to-us selections from what I found immediately. Frankly, as I read these I feel like a lost soul dropped in deep kimchi, what with all the gene terminology. Hopefully, I will soon get some primitive, even useful grasp of these informations.

Here is first link: http://www.mitochondrial.net/showabstract.php?pmid=10502593 Title of abstract: Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA.

Second link: http://www.mitochondrial.net/showabstract.php?pmid=11357960
Title: Exercise intolerance in mitochondrial myopathy is not related to lactic acidosis.

Third link: http://www.mitochondrial.net/showabstract.php?pmid=12618654
Title: Exploration of exercise intolerance by 31P NMR spectroscopy of calf muscles coupled with

Fourth link: http://www.mitochondrial.net/showabstract.php?pmid=12838448
Title: Metabolic intolerance to exercise
FINALLY! A reference to statins!! "In addition, myoglobinuria can be observed in patients under statin treatment, particularly if associated with fibrates, due to an alteration in the assembly of the complex IV of the MRC."

Fifth link: http://www.mitochondrial.net/showabstract.php?pmid=10937858
Title: Exercise intolerance and the mitochondrial respiratory chain.


Any feed back, especially from folks conversant with this subject matter, about relevance of these articles to statin muscle damage is much appreciated. So is informed guidance as to how to use these informations in understanding our individual situations, maybe even finding useful means of countering our statin-induced limitations.

Lars

[ironic]

Quote:
There is increasing evidence that genetic variants influence susceptibility to serious side effects in muscle with the use of cholesterol-lowering drugs such as statins. In 2006, our laboratory reported a pilot study of biochemical and molecular effects in severely affected patients with myopathic symptoms that developed during statin therapy. Some of these patients recovered as soon as the drug therapy was terminated and others did not. Some people with long-term effects actually suffered increased severity of symptoms post-therapy as though some process had been unleashed that would not stop and they have never recovered.

Full article:
http://www.spacedoc.net/statins_personalized_medicine

[lars999]

Getting the magic search terms is always great - "Mechanisms of statin damage to mitochondria" was what I used this time. Sometimes just entering what you actually want does the trick.

FYI: First 3 hits are from Duane's writtings.

First hit: Link: http://www.mitochondrial.net/showabstra ... d=18243052 TITLE: New insights into mechanisms of statin-associated myotoxicity. Key sentence: "It is proposed that mitochondrial impairment leads to a mitochondrial calcium leak that directly interferes with the regulation of sarcoplasmic reticulum calcium cycling without excluding a direct effect of statin on the sarcoplasmic reticulum."

Second hit: In this one, a complete article, some toxicologists from Pfizer report on a study of statin-induced damage by cervistatin in female rats. This is an article one can sink their teeth into! Lots of additional links to references given in text.
Link#1: http://toxsci.oxfordjournals.org/content/88/2/551.full
Link#2: http://journal.shouxi.net/qikan/article.php?id=249577
TITLE: Roles of Exercise and Pharmacokinetics in Cerivastatin-Induced Skeletal Muscle Toxicity

Third hit: This one is from personal blog of Dr. Stephanie Seneff at MIT. She is one of Dr. Uffe Ravenskov's Cholesterol Skeptics (www.thincs.org)
Link: http://people.csail.mit.edu/seneff/stat ... ilure.html
TITLE: Statins and Myoglobin:How Muscle Pain and Weakness Progress to
Heart, Lung and Kidney Failure

Fourth Hit: Statins are killers of breast cancer cells?!?
Link: http://www.mitochondrial.net/showabstra ... d=18582466
TITLE: Statins activate a mitochondria-operated pathway of apoptosis in breast tumor cells by a mechanism regulated by ErbB2 and dependent on the prenylation of proteins.

Fifth Hit: Link: http://ajpcell.physiology.org/cgi/conte ... 91/6/C1208
TITLE: Statin-induced apoptosis and skeletal myopathy

I left a bunch more references out there for you to chose from. Just use the search terms I did -- given above.

Happy Travels In The Mitrochondrial Forest!!
Lars

[lars999]

ionic,

Thanks for that reference! As I read through it, I recognized some of content, but not from having read it on this site, or even in English.

Link to published medical report of this work is:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1832194/

Note that this work "Genetic determinants of statin intolerance" was funded by Canada and done in University of Ontario. Why am I not surprized?
QUOTE: "This work was supported by operating grants from the Canadian Institutes of Health Research (MT14030), the Heart and Stroke Foundation of Ontario, and Genome Canada through the Ontario Genomics Institute. Dr. Hegele is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics and the Jacob J. Wolfe Distinguished Medical Research Chair."

From her family name, is she one of the many women doctors that immigrated to USA from Georgia, USSR? She even looks very Georgian! I used to encounter some of them in the Safeway store near where I lived for a few years. Never know where they were from till I walked into a seminar and found that one of the featured speakers was one of them.

Thanks again,
Lars

[lars999]

Some of these articles mention "complex I, complex II, complex III, complex IV. These refer to specific electron transport chains in mitochondria. To learn more than you might ever have wanted to know about this subject, check out this article in Wikipedia
LINK: http://en.wikipedia.org/wiki/Electron_transport_chain

Happy self-education!
Lars

[lars999]

If you want to get into possible answers, or maybe deep kimchi, really fast go to
http://ajpcell.physiology.org/cgi/content/full/291/6/C1208 and then scan down to section "Statin-Induced Apoptosis".

Lars

[lars999]

Here are a couple of links a friend sent me.

Link: http://www.springerlink.com/content/00p2m02100776574/fulltext.pdf
TITLE: Pharmacogenetics of the Response to Statins


Link: http://www.lipidworld.com/content/6/1/7
TITLE: Genetic determinants of statin intolerance

As you can see from just about all these articles, there is lots of research ongoing but in all it seems the researchers are quite a ways from having compiled a widely accepted list of genetic/mitochondrial features (mutations, mistakes, damage, etc.) and specfic statin side effects that result from them.

It is amusing to note the wide ranges given across all these articles in % of persons taking a statin drug that then developed statin-caused adverse side effects. The range seems to go from a high of 25-50% to less than 1,0%. It is also noteworthy that several of these articles cite failure of patients to continue statin therapy as a reason for their research -- would this be research funded by drug companies?

It is a bit annoying that most of the researchers are at least paying "lip service" to the Cholesterol Scam.

Lars

[lars999]

Hello again!!

Anyone attempting to make sense of those perplexing names of genes might find the following document valuable
Link: http://www.genenames.org/guidelines.html#8.
TITLE: Guidelines for Human Gene Nomenclature
by Hester M. Wain, Elspeth A. Bruford, Ruth C. Lovering, Michael J. Lush, Mathew W. Wright and Sue Povey

Lars

[lars999]

Anyone poking around in modern literature about things genetic will quickly encounter the term "haplotype". Should you be as hapless as I about this, here is a good link to get you started on understanding this:
Link: http://en.wikipedia.org/wiki/Haplotype

Much more about haplotypes can be found by Googling "Haplotype".

One of my friends wrote asking, "Which haplotypes have most exposure to /occurance of statin adverse side effects?" Perhaps an excellent question, but, I have no idea what the answer is, or even if anyone knows, or if it is really a pertinent question. Can anyone here shed any light on this?

Should you want to learn about the intracate business of actually determining haplotypes, type "Determination of haplotypes" into Google.

In any case, reading about haplotypes is a lot more fun than reading about statin adverse effects.

Lars

[Nancy W]

Lars,

I have been occupied, researching for a series of classes I am teacing this weekend, so I haven't gotten to dig into your links. Can't wait, though. Thanks!

Nancy

[lars999]

This is first in a series of posts to this thread, where I quote some of the seemingly more relevant parts of specific publications.


This one is from: Lipids in Health and Disease 2007, 6:7doi:10.1186/1476-511X-6-7
TITLE: Genetic determinants of statin intolerance
AUTHORS: Jisun Oh , Matthew R Ban , Brooke A Miskie , Rebecca L Pollex and Robert A Hegele
INSTITUTIONS: Schulich School of Medicine and Dentistry, University of Western Ontario and Vascular Biology Research Group, Robarts Research Institute, London, Ontario, Canada N6A 5K8
LINK: http://www.lipidworld.com/content/6/1/7#B5

Enjoy,
Lars

[lars999]

The following link is not directly in inline with this thread but, may be of interest to some persons here. This is a brief, 2-page report that cites references that are inline with this thread.

LINK: http://www.nejm.org/doi/pdf/10.1056/NEJMc0908215

TITLE: Neuromuscular Symptoms and Elevated Creatine Kinase
after Statin Withdrawal

Lars

[lars999]

Title of this review "Molecular basis of statin-associated myopath" makes one think it contains a big fraction of information we would like to know and understand.

LINK: http://www.scribd.com/doc/14775725/Molecular-Basis-of-StatinAssociated-Myopathy

Brought to us by an All-Greek chorus.
Christos Vaklavasa, Yiannis S. Chatzizisis b,∗, Anthony Ziakas c, Chrysanthos Zamboulisd, George D. Giannoglouc

ABSTRACT
Coronary artery disease (CAD) constitutes the most common cause of morbidity and mortality in developed countries. Statins effectively reduce low-density lipoprotein cholesterol, an important risk factor for CAD and related acute coronary syndromes. They are an extensively studied group of drugs with versatile properties. Overall, they are safe and effective drugs but their myotoxic potential cannot be overlooked. In this review we focus on the pathogenesis of statins’ myopathic side effects. Statins can interfere with protein modification at multiple levels. They can affect protein prenylation, an important post-translational modification of membrane bound proteins. They can also adversely affect selenoprotein synthesis, or can interfere with the biosynthesis of dolichols, which are involved in the process of protein glycosylation. Statin-induced myopathy may be also associated with mitochondrial dysfunction. Statins remain the spearhead of our armamentarium in treating atherosclerotic disease. Consistent with their versatile properties it is anticipated to see in the future their indications to expand. Better understanding of the molecular mechanisms involved in statin-induced myopathy may help identify patient groups susceptible to statin effects, thereby increasing their safety.

Now, to get our hands on a copy,
Lars

[lars999]

And now you can read a bit of the French perspective on statin adverse side effects.

LINK: http://www.natap.org/2010/newsUpdates/021210_01.htm

TITLE: Ending Statins May Not End Associated Muscle Pains
and
Neuromuscular Symptoms and Elevated Creatine Kinase after Statin Withdrawal. from NEJM Feb 11 2010

KEY SENTENCE: Almost a third of patients who stopped statin treatment because of neuromuscular symptoms still showed myalgia six months later, and creatine kinase levels above 200 units/L persisted in 17%, according to Andoni Echaniz-Laguna, MD, PhD, of Hopitaux Universitaires in Strasbourg.

Enough for today,
Lars

[lars999]

Read through thread "Gene Responsible For Statin-Induced Muscle Pain" started by cjbrooksjc, in which Brooks gives citation reporting that statin-induced muscle pain is caused by Atrogen-1 gene. I was hoping to relate what is in references cited in that thread to what I am posting in this thread. I failed. I am also wondering why articles about Atrogen-1 gene have not appeared in my searches. Anyone got answers, explanations?

LINK: http://www.physorg.com/news115381783.html
TITLE: Scientists identify gene responsible for statin-induced muscle pain

and

LINK: http://diabetes.diabetesjournals.org/content/early/2010/05/26/db10-0207.abstract
TITLE: Atrogin-1 affects muscle protein synthesis and degradation when energy metabolism is impaired by the anti-diabetic drug, berberine.
COMMENT: This article is about diabetes and experiments on mice.

and

LINK: http://www.pnas.org/content/98/25/14440.abstract?related-urls=yes&legid=pnas;98/25/14440&cited-by=yes&legid=pnas;98/25/14440
TITLE: Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy
COMMENT 1: Experiments done on hungry mice.
COMMENT 2: Gene was also cloned. Authors state: "Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the other components of SCF-type Ub-protein ligases (E3s), as well as a nuclear localization sequence and PDZ-binding domain."
COMMENT 3: Maybe when I understand enough of this genetics stuff, what is in COMMENT 2 will give me a useful answer.

Anyone?
Thanks,
Lars

[lars999]

Just quickly read and/or scanned a document that David recommended some time ago. It is a booklet describing a rather comprehensive treatment of Chronic Fatigue Syndrom. It has some rather informative sections on what we need to do to keep our mitochondria functioning properly. It also discusses why those of us with damaged/comprimised function of our mitochondria need to pace ourselves, spanning the range of folks whose hobbies involve endurance activities to those that are dedicated couch potatoes.

LINK: http://drmyhill.co.uk/drmyhill/images/7/76/Cfs_book_27.pdf
TITLE: DIAGNOSING AND TREATING CHRONIC FATIGUE SYNDROME
(CFS)

This link gets you the full, 142 page document.

Lars

[lars999]

NOTICE!! Quote from Dr. Myhill's website "The General Medical Council have placed severe restrictions on my medical practice" This is final result of ongoing actions this calendar year. Suggest that you visit Dr. Myhill's website http://www.drmyhill.co.uk/ to learn particulars and perhaps to determine how this might affect your use of information in her booklet, which I cite in my immediately previous post.

My intention is to consider information Dr. Myhyll provides in her booklet in same light as that in the numerous published reports I and others have posted links to. In summation, NONE of this information constitutes medical advice from persons licensed to practice medicine in any country, no matter how accurate that information might be or how useful any of us find it for us personally.

Frankly, as a non-medical researcher/investigator/practioner of several decades-long standing, I find documents like Dr. Myhill's booklet very useful as I make my way up the very steep learning curve that statin adverse side effects have placed me on.

Regards,
Lars