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T3 intracellular calcium and caffeine

Discussion in 'Other Health News and Research' started by pattismith, Jun 3, 2018.

  1. pattismith

    pattismith Senior Member

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    3,5,3′-Triiodothyronine deprivation affects phenotype and intracellular [Ca2+]i of human cardiomyocytes in culture

    2001

    Abstract

    Objective: A decrease in plasma T3 concentration is a frequent finding in patients with heart failure. However, the role of this ‘low T3 syndrome’ on disease evolution has never been clarified. As phenotypic and functional cardiomyocyte impairments are alterations that correlate with the failing myocardium, we studied the long-term effects of T3 deprivation on human cardiomyocyte structure and calcium handling.

    Methods:
    Atrial cardiomyocytes and myocardial tissue were cultured with or without 3 nM T3. Microscopical examination of structural features was followed by analysis of α-sarcomeric actinin and sarcoplasmic reticulum calcium ATP-ase (SERCA-2) content. Calcium handling was studied by [Ca2+]i imaging.

    Results:
    When stimulated with cyclopiazonic acid, a SERCA-2 inhibitor, T3-deprived cardiomyocytes showed significantly faster (P=0.03) and more transient (P=0.04) increases in [Ca2+]i than T3-supplemented cells.
    Moreover, in the T3-free cultures a significantly lower number of cells (P=0.003) responded to caffeine, a typical activator of sarcoplasmic reticulum Ca2+-release channel.
    T3-deprived cardiomyocytes also presented altered morphology with larger dimensions than T3-supplemented cells (P<0.0001).
    Additionally, in T3-deprived samples α-sarcomeric actinin and SERCA-2 protein levels were reduced to 65.6±3% (P<0.0001) and 74.1±4% (P=0.005), respectively, when compared with the T3-supplemented group.

    Conclusions:
    Our data show that human cardiomyocyte calcium handling and phenotype are strongly influenced by T3 suggesting important implications of the ‘low T3 syndrome’ on the progression of heart failure.
     
  2. pattismith

    pattismith Senior Member

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    My trials with T3 and cortisol have lead me to the conclusion that I have intracellular calcium flux abnormalities in my muscles and brain cells.

    I only found transient but total relief of my symptoms when supplementing with T3 and prednisolone, but mostly losing the good effect when supplementing on a regular basis.

    I experimented that a hugh emotional stress associated with T3 and cortisol is doing a great job to relieve my symptoms, so i have to investigate why I benefited so much from this association.

    When the stress was lower, i was back to the broken doll state....So I found this article and decided to try again caffeine.

    I have taken it in the past, but it made me worse, and this phenomenon was more marked with time going by.

    I had to take a full cup of coffee to get the effect, while still supplementing with T3 but miracle, it worked!

    So coffee and stress may have the same effect!

    So caffeine, a typical activator of sarcoplasmic reticulum Ca2+-release channel, doesn't work well if cells are T3 deprived, but the association is working!


    This makes me think that my main problem is a dysfunction of this sarcoplasmic reticulum Ca release channel, with a T3 insufficiency/blockage.

    I still can't say why T3 alone can't do the job and my journey to recovery is far from finished, but I am now able to manage a bit more my disability, and to have more control on it, so I have hope!
     
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  3. Ema

    Ema Senior Member

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    Have you ever tried nimodipine?
     
  4. pattismith

    pattismith Senior Member

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    no I don't have access to it in my country, but I doubt it would help me.

    Nimodipine is blocking sarcoplasmic reticulum Ca channels, whereas drugs that have shown to help me are activators of these channels (T3 + caffeine).


    Thyroid hormone regulates Ca(2+)-ATPase mRNA levels of sarcoplasmic reticulum during neonatal development of fast skeletal muscle.

    Abstract
    In gastrocnemius muscle from newborn rats the mRNA for the fast sarcoplasmic reticulum (SR) Ca(2+)-ATPase isoform (SERCA1) comprised over 90% of total SR Ca(2+)-ATPase mRNA content and increased 5-fold between day 5 and 20 after birth, whereas in hypothyroid muscle the SERCA1 message level remained constant. Triiodothyronine (T3) treatment of 2-day-old euthyroid rats induced a precocious stimulation of SERCA1 mRNA levels, indicating that T3 is the determining factor in the stimulation of SERCA1 message levels and that this stimulation underlies the previously reported effect of the thyroid status on the neonatal development of SR Ca(2+)-ATPase activity. The low mRNA level for the slow SR Ca(2+)-ATPase isoform (SERCA2) was constant in both euthyroid and hypothyroid muscle development. Nevertheless, T3 treatment of hypothyroid neonates induced a transient stimulation of SERCA2 message levels, indicating that SERCA2 is responsive to higher levels of T3.


    Thyroid hormone differentially affects mRNA levels of Ca-ATPase isozymes of sarcoplasmic reticulum in fast and slow skeletal muscle.

    Abstract
    mRNA levels for the type I and type II isoforms of sarcoplasmic reticulum (SR) Ca-ATPase were determined in soleus (SOL) and extensor digitorum longus (EDL) muscle of euthyroid (normal), hypothyroid, and hyperthyroid rats. Total Ca-ATPase mRNA content of hyperthyroid muscle was 1.5-fold (EDL) and 6-fold (SOL) higher compared to hypothyroid muscle, with corresponding increases in total SR Ca-ATPase activity. EDL contained only type II Ca-ATPase mRNA. In SOL type I mRNA was the major form in hypothyroidism (98%), but the type II mRNA content was stimulated 150-fold by T3, accounting for 50% of the Ca-ATPase mRNA in hyperthyroidism.
     
  5. Ema

    Ema Senior Member

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    Am I reading this wrong then? It doesn’t sound like it antagonize those channels, but (at high doses) stimulates them.


    This effect does not exclude additional cytosolic sites of action. In addition to its sarcolemmal action, nimodipine was shown to stimulate Ca2+ sequestration in skeletal and cardiac sarcoplasmic reticulum vesicles (11). Because this effect was observed only at concentrations ( M) considerably higher than that required for its sarcolemmal effect, the cytosolic sites of action of nimodipine probably are not relevant for its therapeutic activity. Nimodipine was also found to stimulate Na+-K+-dependent ATPase (57). Therefore, the possibility exists that in addition to its effects on the entry of Ca2+into the cell, nimodipine may also facilitate CaZ+efflux.


    https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1527-3466.1985.tb00479.x
     
  6. pattismith

    pattismith Senior Member

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    Nimodipine is a Calcium channel blocker, which decreases cytoplasmic calcium level, it is a L-type VGCC blocker
     
  7. Ema

    Ema Senior Member

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    Yes, but it appears that is doesn’t only act that way. That was my question.
     
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  8. Iritu1021

    Iritu1021 Breaking Through The Fog

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    I have independently arrived at the same conclusion as @pattismith this summer. I believe that my primary problem is abnormal intracellular calcium regulation. In fact I've been able to document either borderline low or slightly below normal levels of ionized calcium several times (dating back to 2014 which at that time was ignored) - and who knows how low they are inside the cells. My non-ionized calcium, however, is always within the normal range but just like with free T3, it's only ionized calcium that's biologically active so it's the only thing that matters.

    I believe that I was also used T3 to regulate calcium channels but it's not a good way to do it since both hypo and hyperthyroidism are associated with lowered ionized calcium and there's a very narrow "sweet spot" range that's hard to maintain. I believe T3 really only messed up my calcium settings further in a long run and I now stay away from it completely. Internet is full of myths about the greatness of T3 but I have yet to meet anyone who is truly thriving on it, long term. I now only take small dose of T4 to make sure I'm not hypothyroid.

    I know that Jay Goldstein used nimpodipine with great success, however I recently talked to another member here who also has low ionized calcium and she developed agranulocytosis from calcium channel blocker. Since subclinical hypePARAthyroidism is also associated with fatigue and brain fog, it might be that there are two types of CFS patients: those who have subclinical hypercalcemia and those who have subclinical hypocalcemia. The latter should probably stay as far away from calcium chanell blockers as possible. The question with nimodipine mechanism however is not clear but given the risk involved and that it's really hard to find, I think one should consider other alternatives:

    1) Low dose lithium - resets "calciostat", decreases urinary calcium loss and stimulates PTH (needs to be used with caution if one is hypothyroid or has low dopamine/norepinephrine), requires an adjustment phase of 1-2 weeks.

    2) Hydrochlorothiazide (diuretic) - increases rental tubular calcium reabsorption (I made great strides with that).

    3) Hydralazine (if one has hypertension)

    4) Sodium bicarbonate to alkalize urine.

    Since I think my primary problem is inborn defect in cellular calcium sensors, is broken, I also found that it's pretty easy for me to overshoot into hypercalcemia, especially if I take calcium supplements. And given that I have higher than normal 24 hour urine calcium excretion, I think calcium supplements in the absence of the right settings, will just flush through me and only increase my risk of kidney stones.
     
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  9. Learner1

    Learner1 Forum Support Assistant

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    This is an interesting discussion.

    I've been on T3 for about 8 years, first T3 only as my rT3 was very high, but with T4 for the past year. (I can't take NDT due to allergies to the fillers...) I feel well balanced but TSH is suppressed.

    But I do have problems with calcium, and would like any insight as to what might be going on. Some observations:
    1. Serum calcium is usually low normal, around 9.2-9.4
    2. RBC calcium is low, at 2nd percentile
    3. Amlodipine, a CCB, caused my hematoctit to drop from 42 to 27, platelets to drop from 310 to 100, hemoglobin to drop from 12.5 to 9, RBC to drop to 2.8 from 4.5 and WBC to drop to 2.8 from 5.
    4. I had a bad DEXA scan last year, and all markers of bone activity show bone is being lost.
    5. Diet has adequate calcium, I supplement 100% DV of calcium, take testosterone and lift weights, which should all help but don't seem to.
    So, I'm wondering where the calcium is coming from and going? Is it a signalling problem, a storage problem, a gall bladder problem, or??? There's also the TRPM3 paper...
     
  10. Learner1

    Learner1 Forum Support Assistant

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    Just found this as well:

     
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  11. Mary

    Mary Moderator

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    @Learner - are you taking sufficient magnesium? I believe the standard calcium/magnesium ratio is 2:1, but my former doctor said it was fine to go up to 1:1, and to take magnesium up to bowel tolerance. This article talks about how magnesium is needed for proper calcium utilization and that calcium supplements can do more harm than good. High calcium intake can actually cause osteoporosis. It also talks about how magnesium is a necessary co-factor for vitamin D3 utilization, which is needed for calcium absorption. For a layman's article it packs in a lot of good information, e.g.:

    I'm sure you know about vitamin K2 as well and strontium for bone health.

    You mention a possible gall bladder problem - are you having digestive issues? Years ago I had trouble with my gallbladder and was given AF Betafood by Standard Process, by my chiropractor. It's an amazing product, it helped so much, and it was after this that I learned I needed to take betaine HCL with pepsin - I was low in stomach acid, which is typical of so many of us with ME/CFS.
     
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  12. Iritu1021

    Iritu1021 Breaking Through The Fog

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    @pattismith, I didn't know about coffee but I also feel like my thyroid hormone changes how I react to it so it makes sense.

    My theory is that I was born with CaSR mutation (predisposition) but since most of them are mild and asymptomatic I managed to live relatively normal (although looking back I can now see clues that I never was fully normal) but I fell apart after I lost my compensatory mechanisms.

    Calcium is controlled by PTH (parathyroid hormone), calcitonin, and to a lesser degree by thyroid, cortisol and estrogen (increases). People with CaSR depend on tight hormonal regulation so if you develop thyroid issues, get pregnant, get ovaries removed, go on/off birth control, go through severe stress(cortisol) or take steroids, it can be a trigger that leads to full blown illness.

    If the total serum calcium is within normal range than I think an absorption issue would be unlikely. You can check 24 hour urine to see if you are losing too much. If the ionized calcium is low but the body is not holding on to calcium that implied disordered sensing and regulation. That's also probably why I always felt terrible on gluten free diet since it's calcium defficient. I need a lot of wheat and dairy to feel my best.
     
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  13. Iritu1021

    Iritu1021 Breaking Through The Fog

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    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264458/


    The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter’s syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.
     
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  14. debored13

    debored13 Senior Member

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    caffeine and thyroid are both mitochondrial uncouplers that affect the metabolic rate. also coffee has a lot of magnesium apparently? which could affect thyroid effects
     
  15. Iritu1021

    Iritu1021 Breaking Through The Fog

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    what pattismith was implying is that taking thyroid changes how body reacts to coffee. If the issue was low metabolism, then she would actually get more mileage out of coffee before she went on thyroid but back then she could not tolerate it. That's because intracellular hypocalcemia increases neuroexcitability. My reactions to coffee depending on the form and dose of thyroid I have taken, have ranged from complete overstimulation to a mild barely noticeable increase in focus (which is what I presume normal people get).
    Caffeine actually decreases absorption of calcium, magnesium and other metals.
     
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  16. Wishful

    Wishful Senior Member

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    I wonder if this is why I never found caffeine to be stimulating. Really strong coffee would make me jittery, and give me insomnia, but it didn't make me feel mentally stimulated. I never noticed a difference when I was taking T4 or T3, or T2 for that matter, but maybe I didn't get the timing right, or lacked an additional nutrient. I switched to decaf for sleep reasons, so I won't experiment further.
     
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  17. Iritu1021

    Iritu1021 Breaking Through The Fog

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    So this whole time I attributed my improvement from selenomethionine to improved T3 peripheral conversion (which my labs seem to support) and now I read that it has direct effect on sarcoplasmic calcium. Maybe the effect on calcium is somehow indirectly linked to the improved conversion. I read that IVIG also causes sarcoplasmic calcium release, a pretty massive one actually - it seems like sarcoplasmic calcium is where all the roads lead...

    https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-016-0134-6

    There is definitely a learning point here for me. I've been humbled so many times over the years with how the obvious explanations never turned out to be the right ones. Just because an autoimmune drug works doesn't mean it's an autoimmune reason. So many different explanations for every effect. Just because a hormone works it doesn't mean there is a hormonal explanation. Nothing is ever what it seems and one simply can't afford to have fixed beliefs when it comes to this illness.
     
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  18. Iritu1021

    Iritu1021 Breaking Through The Fog

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    It could also be mitochondrial calcium.

    I just ordered extended release caffeine tablets. I want to see if that works better than drinking coffee because I do get improved brain function from my lattes but tend to get a mild crash afterwards.

    My mother in law had her thyroid removed several decades ago and she only takes levothyroxine without any T3. She's been drinking coffee pretty much non-stop throughout the day ever since, literally non-stop - and she manages to function pretty well that way. I suspect she's able to keep her T3 at decent level because of that.
     
    Last edited: Sep 14, 2018
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  19. debored13

    debored13 Senior Member

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    Some people think that it's very important to have caffeine with some kind of form of carbohydrate and maybe even protein, because of its effect on metabolism. I noticed better effects having it with a meal or milk and sugar than on its own.
     
  20. debored13

    debored13 Senior Member

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    In my brain fog I missed that. But caffeine does have an effect on metabolism analogous to thyroid hormone, although I'm not sure that that means it's good for us, as I'm not sure about thyroid either.
    https://www.ncbi.nlm.nih.gov/pubmed/22710994



    https://www.ncbi.nlm.nih.gov/pubmed/18279015
     
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