Author Topic: Testosterone-PPARs-PGC1a-Irisin axis  (Read 4695 times)


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Testosterone-PPARs-PGC1a-Irisin axis
« on: September 08, 2021, 03:27:43 PM »
So this thread means yet another shift in the focus of my research as I came to realize that FAAH inhibition is not predominantly involved in my case. Although most FAAH inhibitors seem to have at least some minor benefit, but this doesn't implicate them as major factors. As a further proof recently I have done some preliminary tests on CBD oil, quercetin and galangal (kaempferol) and they just don't have a considerable effect on my symptoms. The same is possibly true for AKR1C3 inhibitors and lucerne/alfalfa probably has another effect that makes it so potent as in the case of saffron.

I also decided to make a kind of supplementation topographic map as this should pinpoint the origin of the problems eventually.

Based on this it became evident that I react well to testosterone boosters as they provide the best general effect. So far these were the most beneficial: Maca (yellow), Tribulus, Ecdysterone, Tongkat Ali. The 5a-reductases I have tried so far usually have a weak or moderate effect. These were: fenugreek, Pygeum, beta-sitosterol, Reishi Ganoderma. Aromatase inhibitors could be considered as another source of free testosterone. Damiana could be tested for this, however Pygeum is both a potent 5a-reductase and aromatase inhibitor and still it only had a weak to moderate effect, which probably means that my problems are not directly related to either DHT or estrogen.
Interestingly medicinal mushrooms also generally work and have a rather good effect: Lion's mane, Reishi ganoderma, beta-glucan (maitake), Cordyceps, which probably indicates a role for beta-glucan, but more medicinal mushrooms have to be tested to claim this with great certainty.
Another major category involves supplements that are supposed to restore hormonal balance and by this I mean even those that target women. These are beneficial so far: Wild yam root, lavender tea, tea tree oil, shatavari.
Adaptogens could be considered as well, however there are many overlaps with previous categories.

So at first it would seem like I am really lucky to have found so many remedies, however the real picture is not so wonderful. I mainly test supplements separately this time, however I tried some combinations and the effects are usually not additive. I also have the problem of supplements losing effectiveness over time, however I am not worried that they will completely lose the benefit. Some supplements seem to have a greater benefit when I am in worse condition, but less when I am feeling relatively well. From the perspective of POIS it is a good thing as I at least can avoid being severely ill, however my aim is to treat the CFS condition as well and it seems to be a more difficult barrier to overcome. Lately I had to work a lot and sometimes I used combinations of the most beneficial supplements. Even so I had exercise intolerance induced POIS symptoms and this was actually in the chronic phase (over 7 days). This made me think that I have to pay more attention to the possible causes of CFS as well.

Of course exercise intolerance is the major symptom of CFS and the cause is still mostly unknown. However recently I have found something that seems to be rather interesting. A few years ago researchers discovered a kind of new myokine hormone called irisin, which is also considered as an exercise hormone. I wonder why none had mentioned this before as irisin seems to be a major factor in regulating the benefits of physical exercise and could be implicated in CFS as well.
Even more interesting is the fact that irisin is mainly regulated by peroxisome-proliferator-activated receptor-gamma co-activator-1 alpha (PGC-1a). PGC-1a has intrigued me for a while now due to its relation to PPARs and studying it a bit more one can easily realize how likely its involvement in POIS pathology. PGC-1a has a considerable role in glucose, lipid and energy homeostasis and is at the nexus to regulate skeletal muscle adaptations to increased work load. As PPAR ligands are likely to have a role in POIS state modification I have to assume that the PPAR - PGC-1a relation must be at the core of our issues. PGC-1a functions kind of like a hub and may even serve to unify earlier theories (e.g. BDNF, calcineurin, lactate, NRF-2, etc).
Some background information on irisin and PGC-1a:
We also observed an independent correlation with serum concentrations of high-sensitivity C-reactive protein (hs-CRP), thus suggesting that inflammation may influence irisin production. The inflamed patients exhibited higher serum irisin concentrations. Irisin concentrations were significantly correlated with age (r=-0.44; p <0.001), creatinine (r=-0.35; p <0.05), and fibrinogen (r=0.40; p <0.05) concentrations. No association was observed between irisin, interleukine-6 and tumor necrosis factor alpha. This study confirms the association between inflammation and irisin concentrations.

The time course study revealed that circulating irisin increased immediately after high-intensity interval exercise and declined 1 hour thereafter. In vitro experiments showed that irisin facilitates glucose and lipid metabolism in human muscle through AMP kinase phosphorylation.
Exercise is considered a cornerstone in the prevention and treatment of chronic metabolic diseases such as obesity, type 2 diabetes mellitus, and age-related muscle wasting.
Irisin regulates gene expression of metabolic enzymes in human muscle. Gene modulation was followed by enhanced lactate production.
We confirmed that irisin-mediated gene regulation is dependent on AMPK.
Irisin induces mitochondrial biogenesis and uncoupling.
The role of irisin in metabolic regulation indicates the existence of an irisin receptor that has yet to be identified, which triggers downstream AMPK activation.

Irisin may enhance NO production and phosphorylation of AMPK, Akt, and eNOS.
Irisin mediates the beneficial effects of exercise on metabolism, inducing the browning of adipocytes and thermogenesis by stimulating uncoupling protein 1 expression (UCP-1).
Circulating irisin is significantly lower in individuals with type 2 diabetes and obesity compared with controls.
Irisin significantly enhances endothelium-dependent vasodilatation (EDV).
Irisin is a novel endothelium-dependent and NO-mediated vasorelaxive agent.

Genetic deletion of irisin impairs cognitive function in exercise, aging and Alzheimer’s disease.
Irisin protects against neuroinflammation by acting directly on glia cells in the brain.

Irisin exhibits antiinflammatory properties via the downregulation of toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 in macrophages, and reduces the expression of inflammatory genes via inhibiting the p38 mitogen-activated protein kinase (p38 MAPK)/NF-kB in endothelial cells. Furthermore, irisin reduces oxidative stress in macrophages and endothelial cells.
Endurance exercise activates the peroxisome proliferator activated receptor (PPAR)-gamma coactivator 1a (PGC1a) which in turn stimulates the FNDC5 expression in SKMs (skeletal muscle) leading to increased levels of circulating irisin. Myocytes treated with irisin in vitro showed increased PGC1a, nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), glucose transporter 4 (GLUT4), UCP-3 and irisin itself, indicating the existence of a positive autoregulatory loop between FNDC5 and PGC1a and suggesting that irisin positively regulates muscle metabolism in an autocrine manner.
This activation of FNDC5 positively regulates the hippocampal expression of BDNF, the master regulator of neuronal cells proliferation and differentiation. This PGC1a/FNDC5/BDNF axis that ultimately leads to improved cognitive function, learning and memory, suggests the existence of a direct SKM-brain cross-talk that further contributes to the beneficial effects of exercise on the brain.
Irisin is released into the circulation during exercise and when exposed to cold.
Muscle-specific PGC-1a overexpression renders mice resistant to age-related obesity and diabetes and increases lifespan.
Overexpression of irisin led to an increase in total body energy expenditure and modest improvements in glucose intolerance. Irisin stimulates glucose uptake in muscles.
Acute exercise did not affect expression of the Fndc5 gene, although PGC1-a was substantially (7.4-fold) upregulated under these conditions.
Cells were treated with exercise-mimicking agents such as caffeine, ionomycin, and forskolin. Although PGC1-a was substantially induced in response to these agents, the level of Fndc5 mRNA was even decreased under these conditions.
Fndc5 gene expression is regulated by a Pgc1alpha/ERRalpha (a Pgc1alpha cofactor) complex.
The findings that peripheral delivery of FNDC5 is sufficient to induce CNS expression of Bdnf suggest that a circulating form of FNDC5, possibly irisin, travels to CNS targets (including BDNF-producing retina cells) and in a Pgc1alpha-dependent manner, directly and in addition with local FNDC5 pathway, enhances BDNF production with subsequent TrkB activation. It may be that similar pathways mediate exercise-induced retinal neuroprotection.

The demonstration of irisin presence in central and peripheral areas as the testes suggests that this peptide may play a role in the gonadal axis by regulating some reproductive processes.
PPARG, a nuclear receptor that regulates fatty acid deposition, glucose metabolism and adipocyte differentiation. Together with PGC-1a, PPARG is involved in the regulation of irisin. Furthermore, the expression of FNDC5 strictly depends on increased levels of PPARG, which is known to regulate the genes in response to nutritional and physiological signals, particularly during exercise.
Studies showed the expression of FNDC5 in the human and rat ovaries, as well as in different areas of the brain, muscle, both cardiac and skeletal, brown adipose tissue, pituitary, placenta and testis.
Since these discrepancies are apparently unrelated to irisin dosages used in these different experiments, varying from physiological to pharmacological concentrations, we can speculate that species as well as cell type play a fundamental role.
Irisin has been shown to play a role in the control of reproduction by modulating pituitary gonadotropin secretion in different species by means of a classical endocrine effect.

In this study, we demonstrated that serum irisin levels were significantly higher in the T2DM patients with hypertriglyceridemia compared with the controls, and serum irisin was positively correlated with BMI, FBG, TC, and HDL, suggesting that irisin could play an important role in the delicate balance of energy metabolism and insulin resistance.
Our findings are in contrast to some recent studies indicating that circulating irisin was significantly lower in patients with T2DM. However, our results align with other studies indicating that circulating irisin was significantly higher in patients with insulin resistant diseases, such as metabolic syndrome and polycystic ovary syndrome, and that it was associated with an increased risk of metabolic syndrome, cardiometabolic variables, and cardiovascular diseases in humans. There may be a compensatory increase of irisin to overcome insulin resistance. We hypothesize that the increased irisin levels in T2DM with hypertriglyceridemia in our study might have represented irisin resistance, reflecting a compensatory result to counterbalance the increasing needs for irisin (similar to the increased insulin levels in insulin resistance) and to improve metabolic features. Additionally, we also hypothesize that, at different stages of T2DM, irisin levels might change from overcompensating to failing to compensate (similar to different insulin levels in different stages of T2DM).
Accumulating evidence has demonstrated that PPARA is an important modulator of metabolic syndrome and that it might be a therapeutic target for treating some of its features. Its known that target genes are involved in most aspects of lipid metabolism and lipid transport. PPARA agonist fenofibrate has been proven to be effective at improving lipid parameters. Importantly, we report for the first time here that fenofibrate treatment administered to T2DM patients with hypertriglyceridemia for 8 weeks resulted in a significant decrease in serum irisin levels, although fenofibrate was reported to increase irisin gene expression in diet-induced male obese mice. We hypothesize that the PPARA agonist fenofibrate could induce the increase of UCP1 and browning of WAT by activating PPARA and that the increased UCP1 levels and browning programme might compensatively inhibit the FNDC5 expression and then reduce the irisin levels.

As irisin is a novel myokine secreted in response to PGC-1a activation. Studies suggest that PGC-1a is important for mitochondrial homeostasis for it regulates mitochondrial biogenesis and oxidative metabolism, and mitochondrial function also plays a role in IR. Furthermore, expression and activity of PGC1-a are lower in patients with T2DM.
The association between irisin and glucose homeostasis was confirmed by several studies, indicating that irisin may be a predictor and protective factor for developing diabetes. However, whether it is negatively or positively concerned, still remains controversial.

PGC-1a is the master regulator of mitochondrial biogenesis. PGC-1a is also the primary regulator of liver gluconeogenesis, inducing increased gene expression for gluconeogeneis.
PGC-1a is a transcriptional coactivator that regulates the genes involved in energy metabolism.
This protein can interact with, and regulate the activity of, cAMP response element-binding protein (CREB) and nuclear respiratory factors (NRFs).
Endurance exercise has been shown to activate the PGC-1a gene in human skeletal muscle. Exercise-induced PGC-1a in skeletal muscle increases autophagy and unfolded protein response.
PGC-1a protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.
PGC-1a upregulation of sirtuin 3 makes mitochondria healthier.
PGC-1a is known to be activated by:
- Reactive oxygen species (ROS) and reactive nitrogen species (RNS)
- Cold exposure
- Endurance exercise: prevents high lactate levels and makes lactate as an energy source more efficient
- cAMP response element-binding (CREB) proteins
- Protein kinase B / Akt is thought to downregulate PGC-1a, but upregulate its downstream effectors, NRF1 and NRF2. Akt itself is activated by PIP3, often upregulated by PI3K after G-protein signals.
- PGC-1a may have positive feedback on upstream regulators:
1. PGC-1a increases Akt (PKB) and Phospho-Akt (Ser 473 and Thr 308) levels in muscle
2. PGC-1a leads to calcineurin activation
Akt and calcineurin are both activators of NF kappa B (p65).Through their activation PGC-1a seems to activate NF kappa B. Increased activity of NF kappa B in muscle has recently been demonstrated following induction of PGC-1a. The finding seems to be controversial. Other groups found that PGC-1s inhibit NF kappa B activity. The effect was demonstrated for PGC-1 alpha and beta.
PGC-1a and beta has furthermore been implicated in polarization to anti-inflammatory M2 macrophages by interaction with PPARG with upstream activation of STAT6.
PGC-1a has been recently proposed to be responsible for B-aminoisobutyric acid secretion by exercising muscles. The effect of B-aminoisobutyric acid. Hence, the B-aminoisobutyric acid could act as a messenger molecule of PGC-1a and explain the effects of PGC-1a increase in other tissues such as white fat.

To observe the effect of electroacupuncture (EA) of "Zusanli" (ST 36) on mitochondrial oxidative stress of skeletal muscle in rats with chronic fatigue syndrome (CFS) based on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/ peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1a) signaling, in order to reveal its mechanism underlying improvement of CFS.
Compared with the normal group, the grabbing force, and the expression levels of ATP synthase and PGC-1a proteins and mRNAs were significantly decreased (P<0.05, P<0.01), while the expression of SIRT 1 protein was significantly up-regulated (P<0.05) in the CFS model group. Following EA intervention, the grabbing force and the expression levels of ATP synthase mRNA, SIRT 1 and PGC-1a proteins and mRNAs, and p-AMPK/AMPK were significantly up-regulated in the EA-Zusanli (ST 36) group (P<0.05, P<0.01).
EA of ST 36 can raise the grabbing force of CFS rats, which may be related to its effects in up-regulating the expression of ATP synthase mRNA, SIRT 1 and PGC-1a proteins and mRNAs, and p-AMPK/AMPK to reduce mitochondrial oxidative stress reaction and in increasing ATP synthesis.

Ectopic expression of PGC-1a in muscle results in increased mitochondrial number and function as well as an increase in oxidative, fatigue-resistant muscle fibers. Moreover, skeletal muscle-specific PGC-1a knock-out animals (MKO) have reduced endurance capacity and exhibit fiber damage and elevated markers of inflammation following treadmill running.
Interestingly, MEF2 and PGC-1a also control PGC-1a gene transcription in an autoregulatory loop. Metabolic genes, including those responsible for mitochondrial oxidative phosphorylation, are induced by a transcriptional cascade with coactivation of the estrogen-related receptor alpha (ERRa, official nomenclature NR3B1), the nuclear respiratory factor 2 (NRF-2, alternatively called GA-binding protein, GABP), and the nuclear respiratory factor 1 (NRF-1) by PGC-1a and subsequent increase in the levels of mitochondrial transcription factor A (TFAM) and mitochondrial transcription specificity factors TFB1M and TFB2M.
PGC-1a apparently controls most if not all of the transcriptional changes induced by motor neuron signaling in skeletal muscle.
Whole body PGC-1a knock-out animals have a dominant central nervous system phenotype that might mask the effects of loss-of-function of PGC-1a in peripheral tissues. These mice are hyperactive, show circadian abnormalities, and have constitutively activated AMP-activated kinase in skeletal muscle, all of which might compensate for the loss of PGC-1a in this tissue.
Strikingly, skeletal muscle of MKOs has a low level of damaged and regenerating fibers. This compromised skeletal muscle integrity is dramatically exacerbated by physical exercise and accompanied by elevated markers of systemic inflammation.
PGC-1a transcription is induced by exercise and repressed by disuse.
However, MKOs are hypoactive compared with control mice. These findings are in stark contrast to the hyperactive PGC-1a total knock-out animals. Interestingly, the decrease in physical activity in MKOs is similar in the light and the dark period. The hyperactivity of PGC-1a total knock-out mice was predominantly caused by abnormal activity during the light period.
Lack of skeletal muscle PGC-1a leads to a 60% reduction in grip strength performance in MKOs.
Interestingly, PGC-1a total knock-out animals performed even worse than MKOs in treadmill running. This might reflect additional defects in heart function and the motor neuron system in whole body PGC-1a knock-out mice that also contribute to physical endurance.
Increased muscle fiber regeneration is often a sign of muscle damage in mice, and muscle damage leads to higher serum creatine kinase levels in the blood leaking from muscle fibers.
MKOs exhibit low grade muscle damage, even in the basal state.
Skeletal muscle PGC-1a is required in maintaining muscle fiber integrity in the sedentary state; this is even more so during and following physical exertion.
In addition, circulating interleukin 6 levels in the blood were elevated in MKOs compared with controls, but we did not see a significant difference in circulating TNFa levels in the non-exercised context.
Remarkably, transcript levels of TNFa were massively increased in exercised MKOs compared with pre-exercised MKOs, whereas no change in TNFa expression was observed in control mice before and after physical activity.
Thus, increased cytokine levels, in particular those for TNFa in MKOs, likely contribute to fiber damage by inducing an inflammatory myopathy.
Despite the protection observed in PGC-1a muscle transgenic animals against denervation-induced muscle atrophy, MKOs show no increased propensity for disuse-mediated muscle atrophy.
Reactive oxygen species detoxification is crucially regulated by PGC-1a and the levels of a number of reactive oxygen species detoxification genes are reduced in MKOs, including superoxide dismutase 1, superoxide dismutase 2, adenine nucleotide transporter, and glutathione peroxidase 1.
In addition, we recently found that PGC-1a regulates the gene program involved in postsynaptic neuromuscular junction plasticity. MKOs have a lower number of acetylcholine clusters on muscle fiber membranes and thus might be insufficiently innervated.
The decrease in body weight and fat mass, reduced physical activity, skeletal muscle damage, increased body temperature and basal metabolic rate, and diminished food intake4 are compatible with symptoms observed in animal models and human patients suffering from chronic inflammation.

Exercise can significantly influence PGC-1a and AMPK-SIRT1 pathway, as it is involved in the regulation of energy metabolism and mitochondrial biogenesis.
Studies have shown that various organelles within the cell can generate ROS such as mitochondria, sarcoplasmic reticulum and peroxisomes in exercise condition.
Prolonged exercise increases the NO production, resulting in vasodilation in the heart and skeletal muscles. However, strenuous exercise increases the chances of superoxide production, thereby decreasing the bioavailability of NO, as superoxide combines with NO to produce peroxynitrite—a potent cellular damager. In this scenario, we mainly review about PGC-1 alpha and AMPK, and how NO can act with AMPK synergistically to upregulate the PGC-1 alpha.
Fiber-type switching toward the oxidative type by PGC-1a is characterized by increased mitochondrial production, density, and oxidative metabolism. Conversely, glycolytic fiber of muscles decreased the endurance activity. Taken together, PGC-1a is a key mediator of several cellular processes required for endurance capacity.
Conversely, ROS are involved in the regulation of PGC-1a. For example, H2O2 regulates the expression PGC-1a via AMPK pathway and indirectly it is involved in upregulation of PGC-1a by lactate, a by-product of glycolytic pathway. Therefore, it is a multi-dependent process of PGC-1a, antioxidants, and ROS. Ample evidence supported that muscle contraction during exercise increased the production of ROS in the form of superoxide (O2), hydrogen peroxide (H2O2), and hydroxyl (OH) radicals. H2O2 is an important signaling molecule for muscle adaptation. However, ROS have been shown to increase the expression of PGC-1a and metabolic adaptation in the muscles, but at what level the production of ROS could help regulate PGC-1a during exercise needs more study. Additionally, reactive nitrogen species (RNS) play an important role in the regulation of PGC-1a; particularly, NO increases the PGC-1a expression via AMPK activation and Ca2+/calmodulin. Nitric oxide production is increased during physical exercise. Several studies have suggested the role of NO in the PGC-1a regulation, mitochondrial biogenesis, and fiber type changes.
Exercise like stimuli induces the PGC-1a expression, which contributes the muscular contraction activity. This contraction activates the Ca2+ channels leading to increased amount of Ca2+ in the cytosol. This increased amount of Ca2+ stimulates the calcium/calmodulin-dependent protein kinase, which further phosphorylates the PGC-1a. In another way, muscle contraction-mediated AMPK and p38 MAPK induces PGC-1a expression. PGC-1a can also regulate the homeostasis of oxidants and antioxidants by increasing the stimulation of superoxide dismutase-2, catalase, and GPx expression. Taken together, PGC-1a plays a crucial role in response to external stimuli like exercise to increase the mitochondrial biogenesis by mimicking the many metabolic responses and transcription factors including NRF.
A single bout of exercise can activate AMPK, resulting in stimulation of many metabolic pathways and
also its activation leads to mimic several signaling factors in response to muscle adaptation.
In addition to physical exercise, other forms of stresses including hypoxia also increased the AMPK level in the skeletal and cultured muscles.
Interestingly, AMPK and SIRT1 mediate the PGC-1a expression in mitochondrial biogenesis and glucose metabolism. Altogether, SIRT1, AMPK, and PGC-1a have an imperative role to increase the mitochondrial adaptation to exercise.

Pharmacological activation of the nuclear receptor PPARG is linked to numerous beneficial effects in the contexts of inflammation, lipid homeostasis, Type-2 Diabetes (T2D) and atherosclerosis. These beneficial effects include priming of circulating monocytes for differentiation towards an ‘alternative’ anti-inflammatory M2 macrophage phenotype.
Changes in expression of PPARs and the PPARG co-activators PGC-1a and PGC-1B; Th2 (IL-4; IL-10) and Th1 (IL-6) cytokines; and markers for the M2 (AMAC1, CD14, MR, IL-4) and the ‘classical’ pro-inflammatory M1 (MCP-1, TNFa, IL-6) phenotypes were determined.
Exercise was associated with upregulation of M2 markers, PGC-1a and PGC-1B, and with downregulation of M1 markers. Moreover, plasma levels of Th2 cytokines increased after exercise, while those of Th1 cytokines decreased. However, other PPARs (PPARA; PPARB/D) did not undergo marked exercise-induced activation or upregulation. Thus, participation in low-intensity exercise may prime monocytes for differentiation towards an M2 macrophage phenotype via PPARG/PGC-1a/B

Taken together some of these facts suggest that I have a very low expression of irisin/PGC-1a or a KO genotype, however other facts point towards an overexpression, so based on scientific data alone a clear correlation can't be drawn.
Hormone balance modifiers may have yet unknown effects on irisin level and hopefully studies will uncover this in the near future.

The downregulation of PPARG by testosterone was indicated earlier as a possible mechanism, but at the time I was more concerned with FAAH inhibition. Some beneficial supplements I take also downregulate PPARG activity (testosterone itself, crocin (saffron), papaya, beta-glucan (medicinal mushrooms), garlic, apigenin(?)), however there are beneficial PPARG agonists (e.g. berberine) as well, so it is not a definitive answer. Metformin is indicated to be an agonist of PPARG however a study claims that it downregulates PPARG which makes it a good idea to try.
Testosterone also changes the activity of PGC-1a, but the studies I found are unfortunately controversial in this regard. One study indicates downregulation while two others show PGC-1a upregulation by testosterone.
Saffron (crocin) can also significantly increase PGC-1a. Biotin significantly decreases PGC-1a.
A lowered PGC-1a thus seems very likely, however it is not clear how PPARG antagonism would correlate to this.

I will provide links in a later post.
Now I have a lot more to read and test, but at least this seems a prospective path.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Testosterone-PPARs-PGC1a-Irisin axis
« Reply #1 on: October 04, 2021, 02:26:01 PM »
I think I have just found the best model for my case yet. This is all due to the fact that PDE4 inhibitors turned out to be really beneficial for me as well. For now I only tested drotaverine (No-Spa), but it makes me considerably better, so I am going to try other PDE4 inhibitors like Kanna (Zembrin) and luteolin too. So while searching for a link between PGC-1a and PDE4, it became apparent that they are actually closely connected through cAMP.
In a study researchers drew up a model on how coenzyme Q10 may be beneficial in the case of metabolic disease. The best thing is that this model aligns very well with the effects of supplements I have tried so far. So PDE4 inhibitors should be beneficial and activators of PGC-1a, AMPK, SIRT1, PPARA usually make me better as well. The model also indicates the downregulation of PPARG which possibly solves the mystery why PPARG acts so controversially as PPARG activation is normally considered more beneficial due to NF-kB inhibition, however as it is possible that free fatty acids induce the inflammation in the first place, lessening the burden would resolve the need for NF-kB inhibition. The attached figure is from this study and possibly outlines the foundation for POIS etiology. Of course more work has to be done to expand this model and identify the exact entry point where POIS upsets the whole mechanism. This model can be probably applied to other conditions (e.g. CFS, long-covid, Alzheimer etc.) as well and thus could explain why there are so many similarities in both symptoms and medications regarding these ailments.

In the present study, we show that dietary supplementation with CoQ10H2 significantly reduced white adipose tissue content and improved the function of brown adipose tissue by regulating expression of lipid metabolism-related factors in KKAg mice, a model of obesity and type 2 diabetes. In the liver, CoQ10H2 reduced cytoplasmic Ca2+ levels and consequently inhibited the phosphorylation of CaMKII. CoQ10H2 also regulated the activity of the transcription factor C-FOS and inhibited gene expression of PDE4, a cAMP-degrading enzyme, via the CaMKII-MEK1/2-ERK1/2 signaling pathway, thereby increasing intracellular cAMP. This increased cAMP activated AMPK, enhanced oxidative decomposition of lipids, and inhibited de novo synthesis of fatty acids, inhibiting the development and progression of obesity and type 2 diabetes.
CoQ10H2 treatment also increased expression of Sirt1, Pgc-1a and PPARA, enhanced mitochondrial function and promoted B-oxidation of fatty acids in the liver, as well as increased levels of intracellular cAMP. We also found that CoQ10H2 enhanced the expression and function of SERCA2 and inhibited the increase of cytoplasmic Ca2+, and subsequently inhibited activity of the transcription factor C-FOS, which in turn inhibited the expression of phosphodiesterase 4 (PDE4) in the in vitro experiments. Our results demonstrate that dietary CoQ10H2 can suppress lipid accumulation and mitigate metabolic dysfunction.
These data indicate that CoQ10H2 enhanced intracellular cAMP concentrations by inhibiting PDE4 gene expression rather than activity.
These data suggest that CoQ10H2 regulates binding of AP-1 to the PDE4 promoter, thereby reducing PDE4 levels and inhibiting cAMP hydrolysis.
(Attached figure: CoQ10_PDE4_PGC1a)

By the way I actually tried a CoQ10 supplement several years ago, however I took it rather sparsely and I just can't recall my exact experiences with it even though it should work rather well based on theory. It could be interesting to test it in comparison and conjunction with saffron.
Saffron inhibits c-jun and c-fos which leads to PDE4 inhibition and activation of AMPK, SIRT1 and PGC1 and it also has a dual effect on PPARG, which is probably the reason why it works so well.
In an earlier thread it was also indicated that "estradiol enhances and testosterone attenuates novelty stress-stimulated increases in c-Fos mRNA".

I had to wonder if this could be the link for the antidepressive effect, so I tried to find further associations. Most interestingly diosgenin also downregulates c-fos, c-jun and thus AP-1. The following articles may also imply a possible cause for POIS:

In addition, macrophage inflammation is a major factor in the occurrence and development of atherosclerosis, which can aggravate the symptoms of atherosclerosis. It is reported that the activation of macrophages is mediated by NF-kB, AP-1 and mitogen-activated protein kinase (MAPK) pathways. Diosgenin has been shown to significantly suppress LPS/IFN-g-induced CK2, JNK, NF-kB, and AP-1 activity which may be involved in the downregulation of c-Jun and c-Fos protein levels in macrophages, suggesting a new mechanism of diosgenin on macrophages, which may provide a new insight to study the effect of diosgenin on macrophages in the future.

Lee et al. have examined the effect of Diosgenin (DG) on chronic pain and functional deficit resulting from sciatic crushed nerve injury in rats. DG treatment increased the sciatic function index and suppressed the nerve injury-induced overexpression of BDNF, TrkB, COX-2, iNOS, and c-Fos in the ventrolateral periaqueductal gray and paraventricular nucleus, suggesting that DG treatment could prolong pain control and extended functional recovery after peripheral nerve injury.
Also an alternative possibility for diosgenin's antidepressant effect:
Chronic administration of DG can reduce the expression of IL-2, an indicator of neuroimmune function, in the brains of ovariectomized rats, suggesting that DG might relieve depressive behavior via the modulation of the neuroimmune system.

Now the most important task is to find the connection to TRPV1 activation as it is surely involved in my case.
The upstream CaMKII factor could be considered, however its role is not straightforward if we consider the following study, which provides a great overview on the possible factors influencing TRPV1 activation.

TRPA1 is associated with pain sensations and inflammation and TRPV1 is associated with pain and temperature regulation.
Data indicate that TRPV1 may prevent the development of mature adipocytes from pre-adipocytes, and decrease their lipid content by increasing lipolysis. This may partially explain the decreased lipid accumulation during dietary supplementation of capsaicin.
Browning is a process whereby WAT becomes thermogenic in nature, similar to BAT. The calcium influx from TRPV1 activation may mediate this process by activating the peroxisome proliferator-activated receptor gamma (PPARG) and positive regulatory domain containing 16 (PRDM16) pathways. Calcium binds and activates calmodulin-dependent protein kinase II (CaMKII) leading to the subsequent activation of adenosine monophosphate activated protein kinase (AMPK) and sirtuin-1 (SIRT-1). SIRT-1 deacetylates PRDM and PPARG causing browning events such as thermogenesis.
The PPARG and PRDM16 pathway, previously mentioned in WAT, has been shown to be activated by TRPV1, via SIRT1, in BAT. Further, SIRT1 also activates peroxisome proliferator activated receptor gamma coactivator 1-a (PGC-1a). PGC-1a transcriptionally activates PPARA subsequently leading to the production of uncoupling protein-1 (UCP-1). UCP-1 is a mitochondrial protein that uncouples the respiratory chain triggering a more efficient substrate oxidation and thus heat generation.
Capsaicin can also evoke a heat-loss response which could conceivably result in compensatory thermogenesis to maintain thermal homeostasis. Capsaicin evoked complex heat-loss responses have been shown in various mammals including the rat, mouse, guinea-pig, rabbit, dog, goat, and humans. In humans, cutaneous vasodilation and sweating in response to hot chili consumption is well recognized. In the rat it has been demonstrated that capsaicin elicited cutaneous vasodilation resulting in a reduction in core body temperature. Simultaneously, capsaicin also enhanced heat production.
For example, three different TRPV1 ligands known to antagonize TRPV1 had different effects on thermoregulation (e.g., hyperthermia, hypothermia, or no effect). In fact, TRPV1 can be manipulated in such a way, by action at different domains, to eliminate some functions of the TRPV1 channels without affecting others. For example, some antagonists block activation by capsaicin and high temperatures but not activation by low pH, and other antagonists block activation by capsaicin but not the activation by high temperature. However, this raises further questions on whether, for example, the observed effects are cell type specific.
(Click on download full-text, Figure 5 is attached to the post as TRPV1-PGC1a)

Other possibilities for TRPV1 involvement:
As the previous model suggests an excess of free fatty acids this may still implicate arachidonic acid or its metabolites (prostaglandins, leukotrienes) as capsaicin-like compounds.

Another interesting factor to consider is CREB (cAMP response element-binding protein) as its under-functioning is associated with major depression and it is involved in the development of drug addiction and psychological dependence. Could this mean the connection to opioid receptors or sexual activity? These questions still need to be answered, however I have too little experience with opioid receptor modifiers to be able to judge this currently. Opioid induced hyperalgesia or withdrawal may still have a role in TRPV1 activation.

Although at first I thought that coumestrol is the most active component of alfalfa I searched some more and it turns out that another compound called alpha-spinasterol is a very good TRPV1 antagonist without a negative thermogenic effect.
In conclusion, alpha-spinasterol is a novel efficacious and safe antagonist of the TRPV1 receptor with antinociceptive effect.

The most perplexing thing of course is that drotaverine is a structural analog of papaverine which is an alkaloid found in poppy seeds. As I mentioned earlier eating poppy seeds considerably potentiate POIS and with a concurrent O I can get extremely ill. Papaverine is known to inhibit all PDEs and is also a mu- and kappa-opioid agonist. So this either means that I have a problem with other PDEs (e.g. PDE3, PDE5) or opioids are really involved. I would opt for the latter of course, however one major contradiction to this is that VSmasher had success with mostly the same things as I do (alfalfa, maca, Tongkat ali), but he also had success with Tianeptine, Oxycodone, Kratom and Kanna which are all clearly mu- and kappa-opioid agonists. This makes me question my earlier suspicions about opioids. Fortunately Kratom and Kanna are both legally available supplements without a need for a prescription. Sceletium tortuosum (Kanna / Zembrin) is especially interesting as besides being a mu- and delta2-opioid agonist (also kappa to a lesser degree), it is also a good PDE4 (also PDE3 to a lesser degree) and a serotonin reuptake inhibitor. Additionally kanna has agonistic activity at GABAA, cholecystokinin-1, melatonin-1 and E4-prostaglandin receptors, however it also prevents the adrenal steroidogenesis by blocking the CYP17, 3BHSD, and 17BHSD enzymes, so it could be a good idea to take some testosterone boosters along with it.

Muon also linked a rather interesting theory regarding kanna and this proposes the depletion of catecholamines through the decrease of cAMP. Well, I am not entirely sure if this is the case, but it is certainly a possibility. It is true that I had a positive experience with Venlafaxine (SNRI) until my doctor denied it. My mood was really good at the time, but it didn't solve my POIS entirely. Unfortunately this happened such a long time ago, that I simply can't recall the specifics. Recently I also bought an L-Dopa (Mucuna Pruriens) supplement of which I took a few capsules, however as I couldn't experience a considerable change I switched to something else. Of course a longer trial may yet prove some results, so I will get back to it when I can. A local lab also checks urinary catecholamines (adrenaline, noradrenaline and dopamine) which could be a faster means to check this out, however for now I would rather spend my meager income on different supplements than most likely negative test results.

I think the role of PGC-1a shouldn't be under-appreciated either as it is probably the most versatile modulator of POIS even if not the strongest one. The vast majority of supplements that proved beneficial for POISers actually increase PGC-1a expression. This may explain why so many supplements help me at least weakly even if only a few of them make me considerably better. There could be individual differences as well like I have some special problems with zinc and their efficiency could also vary greatly.

A list of PGC-1a activators (work in progress): CLA, caffeic acid, chlorogenic acid, omija, krill oil, zinc, selenium, saffron, fasting, glucagon, catecholamines, bitter melon, anwulignan (Schisandra and nutmeg), Tongkat Ali, ginger, fingerroot, vitamin D3, fenofibrates, resveratrol, Dihydromyricetin, capsaicin, L-Lysine, arginine, sulforaphane, Cordyceps sinensis, quercetin, epicatechin, HMB, niacin, acetyl-l-carnitine, coenzyme Q10, N-acetylcysteine (NAC), vitamin C, vitamin E, vitamin K1, vitamin B, sodium pyruvate, alpha-lipoic acid, maca, neohesperidin,
PGC-1a downregulation (work in progress): biotin, curcumin, oleic acid, palmitic acid,
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Testosterone-PPARs-PGC1a-Irisin axis
« Reply #2 on: October 04, 2021, 03:47:24 PM »
I've been meaning to write a seperate thread on the theory if chronic torpor in humans could be related to POIS somehow, but maybe this blog post interests you already now:

Reduce SIRT1 and AMPK activity with low-fat calorie restriction, Increase them with high-fat feasting!
"the standard advice given to the obese – restrict calories and avoid fat – had the worst effect on the AMPK-SIRT1-PCG1a axis. Feasting on fat did the opposite."
(by high fat they probably mean without lineolic acid..)

EDIT: I also posted on the fried foods thread:


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Re: Testosterone-PPARs-PGC1a-Irisin axis
« Reply #3 on: October 27, 2021, 02:25:21 PM »
I've been meaning to write a seperate thread on the theory if chronic torpor in humans could be related to POIS somehow, but maybe this blog post interests you already now:

Reduce SIRT1 and AMPK activity with low-fat calorie restriction, Increase them with high-fat feasting!
"the standard advice given to the obese – restrict calories and avoid fat – had the worst effect on the AMPK-SIRT1-PCG1a axis. Feasting on fat did the opposite."
(by high fat they probably mean without lineolic acid..)

I am sorry for the late response, but I needed to test some supplements before I could pass judgment on linoleic acid. The article about torpor is really interesting. Earlier I also thought that linoleic acid may have a detrimental role in POIS based on that poppy seeds and walnuts potentiate POIS and they are both rich in linoleic acid.
The only problem with this theory is that I have recently tested safflower oil which contains practically the most linoleic acid of all oil types. Surprisingly though I was not feeling worse, but to the contrary it actually made me somewhat better. It has only a weak or moderate efficacy, but certainly without any ill effects. I don't wish to deny the possibility that on the long run linoleic acid may have ill effects, but in regard of POIS it certainly seems a good thing. Besides this I tested flaxseed oil as well and it proved beneficial, although to a lesser extent than safflower oil. Of course I need to test other types of plant oils (olive oil, canola, etc.), before I can make any firm conclusions.

According to a recent study a high n-6/n-3 PUFAs ratio is indeed beneficial in view of torpor, however the same ratio also increases PGC-1a expression even in the euthermic state which may explain the positive effect of safflower oil in my case.

Additionally, while no change was seen in L-FABP, significantly altered levels of PGC-1a were observed within the white adipose tissue and likely contributes to enhanced lipid metabolism when the diet favors n-6 PUFAs, i.e., high n-6/n-3 ratio, in both the torpid and euthermic state.
Importantly, n-3 PUFAs (e.g., 18:3 n-3, i.e., a-linolenic acid, ALA) tend to effect hibernation in ways opposite to n-6 fatty acids (e.g., 18:2 n-6, i.e., linoleic acid, LA) PUFAs. Hibernating species that are fed a diet high in n-6 but low in n-3 fatty acids are more likely to enter and remain in torpor than animals fed an equivalent amount of PUFAs but with a reversed ratio (low n-6/n-3).
Wherein findings showed that PPARG was upregulated during torpor. Upon binding a fatty acid ligand, PPARs bind a co-activator protein that allows transcription of genes containing a PPAR-response element. For instance, the cold-inducible PPARG coactivator-1a (PGC-1a) regulates mitochondrial metabolism linking PPARA to the thermogenic capacity of tissues in a mechanism shown to be relevant in liver from hibernating jerboas. PPAR also regulates lipid and energy metabolism by inducing the expression of downstream genes such as fatty-acid binding protein (FABP), a key protein involved in facilitating lipid mobilization. Finally, PPAR protein and downstream gene expression is also relevant to the recruitment and activation of beige-like cells in white adipose tissue (WAT).
A significant increase in PGC-1 protein amount was observed in both euthermic and torpid garden dormouse (GD) fed a high LA (or low ALA) diet compared to GD fed a low LA (or high ALA) diet; however, PGC-1a protein levels in either of the enriched diets were not significantly different from the intermediate LA (or high ALA) diet condition. Additionally, this WAT-specific difference was visible in both euthermic and torpid animals. PGC-1a levels were not different between the aroused and torpid state in WAT, and so the diet-induced changes were seen in both states.
Differences in PGC-1a protein levels induced by a high LA (or low ALA) diet suggest that induction of PPAR downstream targets is possible even though a difference in PPAR protein levels is not seen.
For instance, increased levels of PGC-1a during hibernation in garden dormouse fed a high LA (or low ALA) diet could lead to co-activation of either PPARA or PPARG, downstream activation of the mitochondrial transcription factor A (TFAM) and increased transcription of uncoupling protein-1 (UCP1); ultimately these changes would confer a more robust thermogenic capacity in animals fed a high LA (or low ALA) diet. This result is in line with finding from Logan et al. (2020) reporting increased levels of anti-oxidative and anti-apoptotic factors in the same dormice fed a high LA (or low ALA) diet compared to low or intermediate LA (or high or intermediate ALA) dietary levels during hibernation (euthermia).
Low levels of n-6 PUFAs and/or high amounts of n-3 PUFAs can alter calcium reuptake within the heart and prolong entrance into torpor due to inefficient cardiac maintenance and functioning.

By the way while checking out different oils I accidentally came upon one called perilla, which seems really impressive based on a review.

Perilla frutescens seeds, leaves, and stems contain fixed oil which is useful edible oil. It is an alternative source of polyunsaturated fatty acids (linolenic acid (54%-64%), i.e., omega-3-fatty acids), phenolic compounds (rosmarinic acids, luteolin, chrysoleriol, quercetin, catechin, protocatechuic acid, and apigenin), natural antioxidants, vitamins and minerals. Recent advances prove that compounds purified from Perilla frutescens have been proven to be biologically active against several major diseases to treat depression-related diseases, anxiety, asthma, chest stuffiness, vomiting, coughs, colds, flu, phlegm, tumors, allergies, intoxication, fever, headache, stuffy nose, constipation, abdominal pain, and indigestion. It also acts as an analgesic, anti-abortive agent, sedative such as an antioxidant, antimicrobial, anti-allergic, antidepressant, antiinflammatory, anticancer and neuroprotective activities.
Perilla plant contains a rich amount of omega-3-fatty acids such as alpha-linoleic acid (ALA), linolenic acids, rosmarinic acid, luteolin, chrysoleriol, quercetin, catechin, caffiec acid and ferulic acid. The presence of phytosterols, tocopherols, and polyunsaturated fatty acid (PUFA) has also been reported from Perilla seeds.

Perilla also proved beneficial for CFS people.

The article you brought up about torpor also mentions: The effects of Astaxanthin are similar to Berberine, or to the prescription Metformin.

This is really fascinating considering that another supplement I was testing is Astaxanthin, which turned out to be quite beneficial.
Although its overall effect on POIS is not the greatest, but it has a strong and lasting effect on the reduction of exercise intolerance. I still had muscle fatigue/pain, but the burning pain was considerably reduced and I had practically no bloodshot eyes or sore throat even after exhaustive work. The most exciting finding however is just the right study that may explain how astaxanthin exerts this protective effect and this further strengthens the validity of the previously outlined model.
This also further proves that I have a problem with lactic acid. What I can't understand is that other POISers had a positive experience with lactulose, Lactobacillus probiotics or sauerkraut/sour cabbage which all contribute to an increased lactic acid load. Of course these were mostly detrimental in my case. So does this mean that lactic acid is beneficial in other cases?

Astaxanthin, a xanthophyll carotenoid, accelerates lipid utilization during aerobic exercise. Levels of plasma fatty acids were significantly decreased after exercise in the astaxanthin-fed mice compared with those fed a normal diet. Intermuscular pH was significantly decreased by exercise, and this decrease was inhibited by intake of astaxanthin. Levels of PGC-1a and its downstream proteins (cytochrome c, FNDC5) were significantly elevated in astaxanthin-fed mice compared with mice fed on normal diet. Astaxanthin intake resulted in a PGC-1a elevation in skeletal muscle, which can lead to acceleration of lipid utilization through activation of mitochondrial aerobic metabolism.
When the energy expended during exercise is derived from lipids, a large amount of energy can be continuously obtained via aerobic metabolism. On the other hand, when the energy source is carbohydrate-based, muscular pH will decrease due to increased lactic acid production, which may lead to impaired muscle contraction. Therefore, increased lipid utilization in the mitochondria of skeletal muscle cells is associated with aerobic endurance.
There were no significant differences in body weight, plasma lactate, or blood glucose levels between control and astaxanthin-fed groups. In contrast, plasma non-esterified fatty acids (NEFAs) after exercise were significantly decreased by intake of astaxanthin compared with intake of normal diet. The reduced tendency of plasma NEFA by astaxanthin was also found in sedentary condition.
Levels of circulating NEFA are regulated by a balance between catabolic processes in adipose tissue and fatty acid substrate utilization by the skeletal muscle. Circulating catecholamines such as adrenalin and noradrenalin are increased in response to exercise and stimulate lipolysis of triglycerides in adipose tissues, which causes elevation of circulating fatty acids. In contrast, muscle contraction increases uptake of fatty acids from the circulation into muscle cells, which leads to a decrease in circulating fatty acids. Therefore, we suggest that the reduction of NEFA in astaxanthin-fed group was due to an increase in utilization in muscle when compared to release from adipose tissue.
Astaxanthin also inhibited the decrease in intermuscular pH. During muscle contraction, lactic acid, a major source of protons, is produced rapidly through increased glycolytic metabolism, which causes the pH reduction and inhibits muscle contraction. Because energy consumed in muscle during exercise is mainly supplied by carbohydrates and lipids, astaxanthin-induced lipid utilization can decrease energy obtained from carbohydrates, which may lead to the decrease in lactate/proton production. Indeed, our previous study showed that deposition of muscle glycogen, a major carbohydrate utilized during muscle contraction, during exercise was prevented by intake of astaxanthin, which suggests that glycolytic metabolism is prevented by astaxanthin intake.
Taken together, astaxanthin improves metabolic acidosis through the activation of lipid metabolism.
Elevation of PGC-1a by astaxanthin may induce the acceleration of lipid metabolism during exercise. Indeed, cytochrome c, a component of the mitochondrial electron transport chain and a major PGC-1a-inducible protein, was also upregulated by astaxanthin. In addition, we found an increase in FNDC5, another PGC-1a-inducible protein. FNDC5 is a membrane protein that is cleaved and secreted into the circulation as the newly identified myokine, irisin. It has been shown that FNDC5 induces browning of subcutaneous fat through irisin and mediates metabolic improvement.

We have previously reported that astaxanthin (AX), a dietary carotenoid, directly interacts with peroxisome proliferator-activated receptors PPARA and PPARG, activating PPARA while inhibiting PPARG, and thus reduces lipid accumulation in hepatocytes in vitro. Hepatic PPARA-responsive genes involved in fatty acid uptake and B-oxidation were upregulated, whereas inflammatory genes were downregulated by AX administration. In addition to the previously reported differential regulation of PPARA and PPARG, inhibition of Akt activity and activation of hepatic autophagy reduced hepatic steatosis in mouse livers.

The site you mentioned recommends Sterculia Oil as a management for torpor and obesity. Of course I am quite lean, but given the facts that Sterculia Oil upregulates PPARA and downregulates PPARG makes it worthwhile to check.

They also mention Jiaogulan (sometimes called Southern Ginseng) as a PPARA agonist and it is probably a good supplement to try.
I forgot to mention, but Jiaogulan (Gynostemma pentaphyllum) is a usual constituent of AMPK activator supplements.

Some other thoughts on lactic acid:
The following makes me wonder if LDHC could mean a connection to sexual activity.

LDH undergoes transcriptional regulation by PGC-1a. PGC-1a regulates LDH by decreasing LDH A mRNA transcription and the enzymatic activity of pyruvate to lactate conversion.
A third isoform, LDHC or LDHX, is expressed only in the testis; its gene is likely a duplicate of LDH A and is also located on the eleventh chromosome (11p15.5-p15.3).

There is a strong correlation between estrogenic receptors, lactate metabolism and PGC-1a activity.

We now show that PGC-1a in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-a–dependent (ERRa) manner. Concomitantly, PGC-1a reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene (Myc).
PGC-1a thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise.
However, PGC-1a also drives anabolic processes like lipid and glucose refueling in skeletal muscle. Concomitantly, substrate flux through glycolysis is inhibited by elevated levels of PGC-1a while pentose phosphate pathway activity is increased.
As skeletal muscle is the main site for lactate production, we next assessed the mRNA expression of lactate dehydrogenase (LDH) A, which encodes for the LDH muscle subunit (LDH M) that metabolizes pyruvate to lactate. LDH A mRNA expression in tibialis anterior was decreased by 53.5% in MPGC-1a TG animals (PGC-1a overexpression) compared with control littermates. Consistently, the enzymatic activity of LDH-mediated pyruvate-to-lactate conversion was diminished by 40.1% in skeletal muscle of transgenic animals.
To further characterize the enhanced capacity of muscle for lactate clearance, we determined the mRNA expression of LDH B, which encodes for the LDH heart subunit (LDH H) that drives the conversion of lactate to pyruvate. LDH B mRNA expression in tibialis anterior was significantly elevated in MPGC-1a TG animals by 110.2%. Moreover, the enzymatic activity of LDH to convert lactate to pyruvate was enhanced by 60.7%.
LDH A transcription is regulated by hypoxia inducible factor-1a (HIF-1a) and myelocytomatosis oncogene (Myc).
Overexpression of PGC-1B in differentiated C2C12 myotubes resulted in elevated levels of LDH B, but the effect was less pronounced than with PGC-1a. LDH A levels were reduced, but MCT1 levels were unaltered following overexpression of PGC-1B. Importantly, however, PGC-1B is not induced in skeletal muscle by exercise and might thus be less relevant in mediating altered lactate handling in the adaptation to exercise.
To corroborate the importance of PGC-1a in regulating lactate homeostasis, and especially LDH B expression, we then studied mice with a muscle-specific KO of PGC-1a (MPGC-1a KO). MPGC-1a KO animals fatigued rapidly and accumulated blood lactate to a higher extent than their control littermates in endurance exercise trials.
In MPGC-1a KO mice, LDH A activity was already elevated at the basal state and was not further inducible by exercise. LDH B mRNA levels and activity were lower in MPGC-1a KO animals, and these differences persisted after exercise.
Our study now demonstrates that this adaptation to exercise is directly mediated by the interaction of PGC-1a and ERRa and, moreover, that PGC-1a is required for the elevated LDH B transcription and proper lactate homeostasis during exercise. PGC-1a thus remodels LDH isoenzyme composition distinctly and independently of coactivation of peroxisome proliferator-activated receptor B/D, which recently has been described to drive LDH B transcription via MEF2 activation in a distal enhancer region of LDH B.
In addition, PGC-1a reduces LDH A gene expression, which could potentially counteract the enzymatic activity of LDH B of converting lactate into pyruvate.
Lactate production is important in working muscle to maintain glycolytic fluxes for ATP production. Presumably, the conversion of pyruvate to lactate rapidly regenerates NAD+ from NADH.
Recently, the perception of lactate as a harmful metabolite has drastically waned. During exercise, lactate accumulation and mild lactic acidosis cause vasodilation and dissociation of oxygen from hemoglobin and thus oxygen transport to muscle. In this context, the reduction in blood lactate levels by PGC-1a might be viewed as a performance-limiting factor during strenuous exercise. However, PGC-1a likely overcomes this effect by increasing myoglobin expression and enhancing angiogenesis.
In conclusion, we have demonstrated that PGC-1a and ERRa orchestrate the transcription of LDH B, that PGC-1a reduces the levels of the oncogenic LDH A activator Myc, and that the subsequent shift in LDH composition promotes lactate oxidation in skeletal muscle. Lactate produced during exercise by predominantly glycolytic muscles is thus used as fuel in oxidative muscle fibers that express elevated levels of PGC-1a.

The same factors are also involved in cancer.

PGC-1 and PPARG expression in the tumours was significantly decreased in comparison to normal mucosa. Moreover, the PGC-1 and PPARG mRNA levels positively correlated each other in the normal mucosa and in the tumour tissue with a trend toward significance.
In addition, the increase of the ERa/ERB value in tumour tissue, as compared to adjacent normal mucosa, confirms more and more the protective role exerted by the ERB against colorectal carcinoma development.
In fact, the ERRa seems to emerge as a novel potential modifier of the malignant colorectal tract because the change in the expression of its messenger is associated either with tumour progression or with the different histopathological stages of tumour disease. Our study shows a decline in PGC-1 mRNA levels in human colorectal carcinoma when compared to adjacent normal tissue, and no correlation was found between PGC-1 and other nuclear receptors. Since only the PGC-1 mRNA levels have been investigated in this study, the interaction between PGC-1 and ERRa or between PGC-1 and ERa could also occur in human colorectal cells at protein level. In fact, Schreiber have described that PGC-1 converts ERRa from a factor with little or no transcriptional activity to a potent regulator of gene expression by a physical interaction between the two proteins. Therefore, further investigations are needed to understand whether activation of PGC-1 by specific ligands can also alter the transcriptional regulation of ERa or ERRa.
We observed a decrease of the PPARG mRNA levels in colorectal tumour compartment as compared to adjacent normal mucosa. Although performed on a reduced number of samples, a recent study reports a decrease of the PGC-1 expression from normal to tumour tissues, whereas no changes were observed between these two tissue compartments for PPARG mRNA levels. However, these data seem to be in contrast with the definition of "tumour-suppressor" given to PPARG by some in vivo and in vitro pre-clinical models. The positive correlation between PGC-1 and PPARG expression, that we have found in both tumor tissue and surrounding normal mucosa, suggests that these gene are co-regulated in both tissue types.
« Last Edit: October 29, 2021, 12:38:36 PM by Progecitor »
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Testosterone-PPARs-PGC1a-Irisin axis
« Reply #4 on: November 04, 2021, 05:07:26 PM »
Over-the-Counter Ocular Decongestants in the United States – Mechanisms of Action and Clinical Utility for Management of Ocular Redness
Nasal congestion
Red eyes
Naphazoline eye drops for neurosomatic disorders/neural network disorders are being used but higher concentration like 0.1%, 1 drop in each eye.

Thanks for the pointer. The study you provided is really interesting. I may test Naphazoline, but I am a bit skeptic at the moment. A few months ago I tried synephrine one time and as I remember it resulted in increased eye redness. I haven't got around to test it more thoroughly tough. Synephrine is mainly considered an alpha1 adrenergic agonist. Yohimbine is considered an alpha2 AR antagonist, however I don't believe eye redness was particularly different when I took the supplement. I will recheck it later just to be sure.

Earlier I also said that saffron and berberine were quite good for my eyes. With a bit of searching it turns out that they are both beta2 adrenergic agonists. This is rather indicative I think.

The present study showed that ET simultaneously with saffron consumption had interactive effects on the increase of PGC1-a gene expression in the hippocampal tissue of rats with AD. It has been reported that exercise activity seems to increase mitochondrial biogenesis in the hippocampus through the beta-adrenergic/cAMP receptor pathway, increased AMP/ATP ratio, increased AMPK, and up-regulation of PGC1-a/FNDC5/BDNF pathway. On the other hand, saffron consumption modulates metabolism, reduces free radicals and MDA and increases SOD and GPX, which all increase the transcription of NRF1 that, in turn, increases PGC1-a and mtDNA expression. Saffron consumption also activates the PKC pathway, protein kinase A, CaM-KII, and cAMP activation, and enhances the expression of MAPK, JNK, and ERK, which lead to increased mitochondrial biogenesis in the hippocampal tissue.
It seems that ET and saffron alone increase PGC1-? gene expression. Also, ET simultaneously with saffron has interactive effects on the increase of PGC1-? gene expression in the hippocampal tissue of rats with AD.

This would suggest that I have a problem with overt vasoconstriction.
The effects on smooth muscle and lipolysis also seem interesting.
The upregulation of cAMP and activation of adenylate cyclase are likely beneficial in my case.
Alpha2 AR agonists may decrease cAMP and adenylate cyclase.

Although blood tests indicated normal potassium levels, but I recently tested a slow release potassium gluconate supplement and it also caused bloodshot eyes. I still need to recheck this, but this may indicate a correlation with beta2 AR agonists.

I am currently testing kanna and it seems to have a mixed effect in my case. For one it looks like it potentiates bloodshot eyes, although not to a great extent. This makes me believe that I really react adversely to opioids, although some further tests are in order to definitely prove this.
However some POISers clearly have a problem with mu-opioid withdrawal. An interesting study in this matter suggests that decreasing cAMP and deactivating adenylate cyclase during withdrawal could be beneficial.
This makes it likely that alpha2 agonists could be beneficial in such a case.
My case seems to be different though and a possible explanation could be opioid induced hyperalgesia (OIH) in contrast to withdrawal.

Many beneficial supplements I take are indicated to increase lipolysis. beta2-adrenergic stimulation also increases it.
Selective B1-adrenergic blockade did not reduce lipolysis; however, a B1- and B2-adrenergic blockade significantly reduced lipolysis. Thus, the increased lipolysis, characteristic of severely burned patients, is caused by stimulation of the B2-adrenergic receptors for catecholamines.

A single bout of low-intensity exercise could increase PGC-1a-b and PGC-1a-c mRNAs via B2-adrenergic receptor (AR) activation, whereas an increase in PGC-1a-a mRNA expression required high-intensity exercise and was independent of B2-AR activation. Among the PGC-1a isoforms, the increase in PGC-1a-b expression was the largest in response to bouts of exercise.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Testosterone-PPARs-PGC1a-Irisin axis
« Reply #5 on: November 17, 2021, 03:59:30 PM »
An updated list of PGC-1a activators. Some of these also increase expression of SIRT1 and/or irisin.

A list of PGC-1a activators (work in progress): CLA, caffeic acid, chlorogenic acid, omija, krill oil, zinc, selenium, saffron, fasting, glucagon, catecholamines, bitter melon, anwulignan (Schisandra and nutmeg), Tongkat Ali, ginger, fingerroot, vitamin D3, fenofibrates, resveratrol, Dihydromyricetin, capsaicin, L-Lysine, arginine, sulforaphane, Cordyceps sinensis, quercetin, epicatechin, HMB, niacin, acetyl-l-carnitine, coenzyme Q10, N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate, alpha-lipoic acid, maca, neohesperidin, melatonin, myricetin, B-aminoisobutyric acid (BAIBA), Acori Tatarinowii Rhizome, capsaicin, Metformin, allantoin (yam, lungwort), AICAR, caffeine, procyanidins (e.g. cocoa), bitter orange, sodium butyrate, scutellarin, Salvianolic acid B (Salvia miltiorrhiza – Danshen), Palmitoyl lactic acid (krill oil), astaxanthin, L-theanine, forskolin, spermidine, Lithium

PGC-1a downregulation (work in progress): biotin, curcumin, oleic acid, palmitic acid, lead acetate, aluminium lactate,
Conditions: diabetes, obesity, neurodegenerative diseases, cardiac pathologies, aging,
Factors: TRPV4 activation, bacterial LPS,
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Testosterone-PPARs-PGC1a-Irisin axis
« Reply #6 on: November 30, 2021, 01:55:07 AM »
Associations with other diseases:
1. Myasthenia Gravis (MG)

Although I am not a case of myasthenia gravis (MG), but interestingly some common factors are possibly involved in both MG and my POIS subtype. At first I didn't think much of this, but then I noticed that MG has been already associated with POIS by members and there could be some comorbidity as well.

MG is more researched than POIS, so I thought it was worth quoting some information to give the issue some perspective.

Beta blockers (e.g. propranolol) can aggravate symptoms in myasthenia gravis or asthma.

Beta blockers and agonists possibly make up another division in POIS subtypes.

Beta 2 adrenergic agonists are beneficial in some cases of MG.
The diagnosis of myasthenia gravis (MG) was finally confirmed by direct measurement of diaphragmatic strength using magnetic nerve stimulation providing clear cut evidence of significant fatigable weakness and the demonstration of muscle-specific kinase (MuSK) serum antibodies using a novel cell-based assay. Review of the literature suggested a possible impairment of excitation–contraction coupling with malfunction of a signaling protein downstream to the AchR, without an accompanying impairment of electrical transmission. This postulated mechanism, resulting in a disturbance of calcium signaling, explained the unusual features in this patient's illness and led to treatment with salbutamol and ephedrine and to significant symptomatic improvement not achieved by any other treatment.

The same factors seem to be involved in my case!
Numerous reports demonstrate that the loss of PKA compartmentalization significantly disrupts PKA signaling and leads to many physiological dysfunctions, for example, in memory, immune response and cytoskeletal dynamics.
This study demonstrated that gravin undergoes subcellular redistribution following treatment with ionomycin or thapsigargin, both from extracellular Ca2+ influx and from intracellular store release. Although the mechanism behind calcium mediated redistribution of gravin has yet to be fully elucidated, previous work indicates the involvement of Ca2+/calmodulin.
Since gravin interacts with a diverse array of signaling molecules including PKA, PKC, PDE4, B2-adrenergic receptor (B2AR), cyclin D and others, subcellular translocation of this AKAP would likely affect signaling events involving these binding partners.
PKA, for instance, is known to require spatial compartmentalization by AKAPs. Thus, loss of cortically-localized gravin/PKA would likely affect PKA signaling by reducing activity at the plasma membrane or directing PKA signaling to another subcellular compartment. B2AR signaling is known to be regulated by gravin expression and redistribution in a variety of contexts and thus receptor mediated events leading to gravin redistribution would most certainly impact a wide range of B2AR dependent physiological activities known to be linked to gravin. Finally, reports that PDE4 binds to gravin and that this complex regulates cortical cAMP levels suggest that receptor mediated relocalization of gravin could impact cAMP dependent signaling broadly by altering dynamic control of [cAMP].
Our data supports the hypothesis that receptor mediated signaling events involving calcium and/or PKC can alter cAMP-dependent signaling through the spatial regulation of gravin and anchored PKA. This finding suggests that gravin facilitates a novel cross-talk mechanism in which cAMP-dependent signaling pathways are altered by calcium and PKC, and lays the groundwork for future studies of gravin spatiotemporal dynamics in regulating cAMP-dependent signaling events.
Ca2+ elevation and purinergic receptor activation induces gravin relocalization.

SIRT1 is downregulated in MG!
Myasthenia gravis (MG) is an autoimmune disease associated with autoantibody production that leads to skeletal muscle weakness. By integrating the datasets, we identified 143 hypermethylation-low expression genes and 91 hypomethylation-high expression genes. Then we constructed PPI network and ceRNA networks by these genes. Phosphatase and tensin homolog (PTEN) and Abelson tyrosine-protein kinase (ABL)1 were critical genes in both PPI networks and ceRNA networks. And potential MG associated lncRNAs were selected by comprehensive analysis of the critical genes and ceRNA networks. In the hypermethylation-low expression genes associated ceRNA network, sirtuin (SIRT)1 was the most important gene and the lncRNA HLA complex (HC) P5 had the highest connection degree. Meanwhile, PTEN was the most important gene and the lncRNA LINC00173 had the highest connection degree in the hypomethylation-high expression genes associated ceRNA network.
As an autoimmune disease, MG is caused by both genetic and external factors. Genetics can influence disease susceptibility, which can be modulated by external factors such as infection or diet that lead to chromatin modification. Infections can induce the production of antibodies that act as autoantibodies against AChR; in fact, exacerbation of MG is often associated with infection. Thus, aberrant antigen processing and presentation may contribute to the pathogenesis of MG. IFN-g level was shown to be elevated in MG patients.
The top 5 hub genes in the PPI network of hypermethylation-low expression genes were VHL, ZBTB16, WSB1, TRIM4, and RNF144b. ZBTB16, also known as promyelocytic leukemia zinc finger (PLZF), is a transcription factor that promotes the recruitment of effector T helper cells during the development of innate lymphocyte lineages and is also essential for the development of osteoblasts and spermatogonia. ZBTB16 may contribute to abnormal T cell development in MG, and ZBTB16 methylation is a potential mechanism of MG pathogenesis.
SIRT1 has been linked to immune-related diseases such as tumors and autoimmune diseases and was decreased in the PBMCs of multiple sclerosis patients during relapses. The lncRNAs HCP5, OIP5-AS1, and LINC00894 were the most important lncRNAs in the ceRNA network. HCP5 is associated with several autoimmune diseases including psoriatic arthritis, systemic lupus erythematosus, and Graves’ disease; and OIP5-AS1 was found to play a critical role in the ceRNA network of multiple sclerosis.

Irisin is elevated in MG!?
Serum irisin levels were significantly elevated in Myasthenia gravis (MG) patients compared with HCs. Furthermore, serum irisin levels were associated with the myasthenia gravis activities of daily living score in ocular myasthenia gravis (OMG) patients, but there was no relationship to be considered of any relevant value in generalized myasthenia gravis (GMG) patients. Acetylcholine receptor antibody–positive MG patients had higher serum irisin levels compared with HCs. Thymoma, endotracheal intubation, or intensive care unit treatments subsequently were not found to have effect on serum levels of irisin, but tendencies of increase were observed in negative ones.

Increasing PGC-1a is probably beneficial in MG.
These results implied that Qiangji Jianli Decoction may provide a potential therapeutic strategy through promoting mitochondrial biogenesis to alleviate myasthenia gravis via activating the AMPK/PGC-1a signaling pathway.

2. COVID-19

The same factors are also involved in COVID-19, so a comparison is in order.

Alpha adrenergic antagonists (blockers) are possibly beneficial in COVID-19 infection.
Here, we analyzed a large cohort of patients hospitalized at Veterans Health Administration (VA) hospitals, in whom a1-AR antagonists are commonly used to treat unrelated diseases such as benign prostatic hyperplasia (BPH), post-traumatic stress disorder (PTSD), or arterial hypertension.
Having an active prescription for any a1-AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 18%) and death within 28 days of admission (relative risk reduction 17%). In a subset of patients on doxazosin specifically, an inhibitor of all three alpha-1 adrenergic receptors, we observed a relative risk reduction for death of 74% compared to matched controls not on any a1-AR antagonist at the time of admission. These findings suggest that use of a1-AR antagonists may reduce mortality in COVID-19.
While dexamethasone and other immunosuppressive strategies have shown some promise in improving outcomes in patients with severe COVID-19, they have not shown benefit (and may be detrimental) when given to patients with less advanced disease.
Catecholamines (adrenaline, noradrenaline, and dopamine) are monoamine hormones that signal through adrenergic receptors (ARs) expressed on tissues including cells of the immune system. Cells of the innate and adaptive immune system (phagocytes, lymphocytes) are capable of producing catecholamines de novo and signal in an autocrine/paracrine self-regulatory fashion. Beyond their well-established role in neurotransmission and physiological fight-or-flight responses, catecholamines have been shown to amplify immune responses and enhance acute inflammatory injury in vitro and in vivo by increasing cytokine production in immune cells (e.g., IL-6, TNF-a, MIP-2). In animal models of hyperinflammation, prophylactic treatment with an alpha-1 adrenergic receptor (a1-AR) antagonist that inhibits all three receptor subtypes (a1A-,a1D-, and a1B-AR) can prevent cytokine storm and death by blocking deleterious catecholamine signaling and immune responses.
Importantly, a1-AR antagonists are immunomodulatory, but not immunosuppressive drugs.

Beta adrenergic antagonists (blockers) are possibly beneficial in COVID-19 infection.
A combined Dutch/German study investigated 1134 patients recently hospitalised because of Covid-19 infection and extracted information from their electronic medical records.
Treatment with ACEIs or ARBs did not influence the major outcome, while beta-blocker treatment significantly reduced the risk of major outcome. In contrast, calcium channel blocker (CCB) treatment worsened the major outcomes. There was also a statistically non-significant trend for diuretic treatment to worsen the major outcomes. Hypertension was the most important comorbidity in the German part of the study.
A previous study suggested a modestly lower likelihood of a positive test for Covid-19 among patients taking beta-blockers. Another recent paper suggested that non-selective beta-blockers blunt the excessive inflammatory burst commonly reported in severe Covid-19 infected patients.

Table 1 lists the many beneficial effects of beta blockers in COVID-19.

Irisin is possibly beneficial in COVID-19, while SIRT1 is detrimental!?
The cell line showed the expression of multiple genes related to severe COVID-19, such as FURIN, ADAM10, TLR3, KDM5B, SIRT1 and TRIB3.
Our data showed that irisin treatment decreased the levels of FURIN, ADAM10, TLR3, KDM5B and SIRT1 mRNA expression, and increased the levels of TRIB3 transcript by 3-fold. These results come together with the beneficial results that irisin has shown in a recent study published by our group, in which irisin improved uncoupling protein 1 (UCP1) production, reduced lipid profile and oxidative stress, while not altering leptin, adiponectin, peroxisome proliferator-activated receptor gamma (PPARG) and FNDC5 levels.
FURIN cleaves SARS-CoV-2 spike (S) glycoprotein, the key protein used to infect mammal cells; ADAM10 is correlated with ACE2 cleavage regulation in human airway epithelia; TLR3 plays an important role in the innate response to SARS-CoV or MERS-CoV infection and regulates ACE2 cleavage; KDM5B regulates positively ACE2; in more than 57% addressed studies, researchers found that SIRT1 was upregulated in the lung of patients with severe COVID-19 comorbidities; all these genes favor the viral infection and can be potential targets for preventing SARS-CoV-2 spread. On the other hand, TRIB3 gene has been linked to fatty acid synthesis control and insulin resistance, in addition to regulating plasma levels of triglycerides and HDL cholesterol in humans and was previously reported to decrease virus infection and replication; so TRIB3 can be considered a therapeutic target for COVID-19.
Irisin is found in human blood at concentrations of 3–5 ng/ml; circulates at ~3.6 ng/ml in sedentary individuals; this level is increased to ~4.3 ng/ml in individuals undergoing aerobic interval training. The involvement of irisin in viral infection is poorly understood; however, a cross-sectional study of patients with HIV demonstrated that irisin levels correlated negatively with body fat and positively with fat-free mass and strength parameters. In another scenario, researchers verified that FNDC5 overexpression or irisin supplementation could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis.
Although alveolar cells do not express irisin, previous studies using exogenous irisin indicated that these cells benefit from irisin in case the pulmonary tissue is damaged; the administration of irisin in mice subjected to ischemia demonstrated that inflammation in the lungs was reduced, there was evident tissue repair, and hypoxemia and proinflammatory cytokines were decreased.

PGC-1a increases TRIB3! This is also a very comprehensive study about PGC-1a.
Hence, in healthy individuals, in response to a high-fat diet, SIRT1 may stimulate FA oxidation through PPARA–PGC-1a–lipin-1.
In particular, the expression of Ucp2 and the prolactin receptor gene (Prlr), both of which significantly influence B-cell function, were downregulated by SIRT1 overexpression.
Overexpression of PGC-1a in cultures of primary rat skeletal muscle cells induces increased expression of the mammalian tribbles homolog TRIB3, an inhibitor of AKT signaling, highlighting the potential of PGC-1a to cause insulin resistance. Moreover, PGC-1?/? mice are protected against high-fat diet induced insulin resistance. Acute disruption of hepatic PGC-1 expression enhances insulin sensitivity, in part reflecting reduced expression of TRIB3. The observation that, in liver, TRIB3 is a target for PPARA and that knockdown of hepatic TRIB3 expression improves glucose tolerance, whereas hepatic overexpression of TRIB3 reverses the insulin-sensitive phenotype of PGC-1-deficient mice has led to the suggestion that TRIB3 inhibitors may have a potential role in the treatment of T2DM. However, more recently, chronic reduction of hepatic PGC-1a expression has been shown to impair hepatic insulin sensitivity.

Association between COVID-19, MG and supplements:

COVID-19 course in MG is rather unpredictable.
The risk of COVID-19 in MG patients seems to be no higher than that of the general population, regardless of immunosuppressive therapies. In our cohort, COVID-19 barely affected MG course.

Most patients with MG hospitalized for COVID-19 had severe courses of the disease: 87% were admitted in the intensive care unit, 73% needed mechanical ventilation, and 30% died. Immunoglobulin use and the plasma exchange procedure were safe. Immunosuppressive therapy seems to be associated with better outcomes, as it might play a protective role.

A total of 91 patients with myasthenia gravis were included at the time of interim analysis. Myasthenia gravis worsening or crisis requiring rescue therapy (eg, intravenous immunoglobulin, plasma exchange, or steroids) in the setting of COVID-19 was reported in 36 (40%) of 91 patients. Complete recovery or discharge to home was reported in 39 (43%) patients, whereas 22 (24%) patients died due to COVID-19.
Current data, which might be biased toward poor outcomes reporting, show that patients with myasthenia gravis who are infected with severe acute respiratory syndrome coronavirus 2 are frequently admitted to hospital, have disease exacerbations, and have a higher mortality than the general population with COVID-19.

Clinical responses of MG patients during SARS-CoV-2 infection are unpredictable and challenging for clinicians. From the pathogenetic point of view, it has been hypothesized that Treg/Th17 imbalance in the course of SARS-CoV-2 could amplify or trigger the excessive autoimmune response. Though there is no direct evidence for the involvement of proinflammatory cytokines and chemokines in lung pathology, the change of laboratory parameters, including elevated serum cytokine, chemokine level in infected patients correlating with the severity of the disease and adverse outcome, confirmed a possible role for hyper-inflammatory responses in COVID-19.

As the most important predictors of severe COVID-19 in MG patients we identified unsatisfied condition of MG with lower FVC, previous long-term corticosteroid treatment especially in higher doses, older age, the presence of cancer, and recent rituximab treatment.

NAC increases SIRT1 and B-adrenergic signaling, so does it adversely affect COVID-19 course, even though it proved beneficial in small cohort studies?!
The expressions of MnSOD, SIRT1, and FOXO3a were examined at both transcriptional and protein levels. The expression levels of MnSOD, SIRT1, and FOXO3a reduced significantly in the PM2.5 group as compared to the control group. However, their expression levels were increased after NAC intervention. These results suggested that SIRT1 exerted a protective effect against PM2.5-induced respiratory oxidative damage by regulating the expression of FOXO3a. NAC can activate SIRT1 and exert an anti-oxidative role in PM2.5-induced oxidative injury.

Conclusions: like pyruvate, the antioxidant NAC potentiated B-adrenergic inotropism of stunned myocardium. Unlike pyruvate, NAC did not increase cellular energy reserves, thus effectively limiting its potentiation of B-adrenergic stimulation. Thus, pyruvate's potentiation of B-adrenergic stimulation in stunned myocardium is most likely the result of the combined effects of its antioxidant and energetic properties.

Overall, our study demonstrated that NAC therapy provided a significant improvement in oxygenation parameters and reduction in CRP, NEWS2 scale, and length of hospitalization in hospitalized patients with COVID-19.

Melatonin may exacerbate MG.
The use of melatonin in patients with MG, whether ocular or generalized, may trigger exacerbations of the disease, probably due to an upregulation of adaptative immune response and an interaction with treatment involving corticosteroids and other immunosuppressants.

Melatonin is supposedly beneficial in COVID-19.
Compared with the control group, the clinical symptoms such as cough, dyspnea, and fatigue, as well as the level of CRP and the pulmonary involvement in the intervention group had significantly improved.
Adjuvant use of melatonin has a potential to improve clinical symptoms of COVID-19 patients and contribute to a faster return of patients to baseline health.

Recently, a randomized controlled study reported that low doses of melatonin significantly improved symptoms in hospitalized COVID-19 patients, leading to more rapid discharge with no side effects, while significantly decreasing levels of CRP, proinflammatory cytokines, and modulating dysregulated genes governing cellular and humoral immunity.

Melatonin mostly inhibits SIRT1, however in some cases it may actually increase it.
Additionally, melatonin treatment down-regulated SIRT1 and up-regulated acetylated-p53. Sirtinol (a known SIRT1 inhibitor) and SIRT1 siRNA further enhanced the antitumor activity of melatonin, while SRT1720 (a known SIRT1 activator) attenuated the antitumor activity of melatonin.

Here, we challenged our hypothesis that melatonin will impart antiproliferative response against prostate cancer (PCa) via inhibiting Sirt1. We demonstrated that melatonin significantly inhibited Sirt1 protein and activity in vitro in multiple human PCa cell lines, and melatonin-mediated Sirt1 inhibition was accompanied with a significant decrease in the proliferative potential of PCa cells, but not of normal cells. Our data identified melatonin as a novel inhibitor of Sirt1 and suggest that melatonin can inhibit PCa growth via Sirt1 inhibition.

Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling.

These data indicate that melatonin per se is capable of relaxing vascular smooth muscle and that low doses of melatonin impair alpha-1 and alpha-2 adrenergic responses without changes in the beta adrenergic response of vascular smooth muscle.

The ratio of pAMPK to AMPK and the protein levels of SIRT1 and cytosolic PGC-1 in the diabetic control group group were declined compared to those in the NC group. These markers were significantly increased in the vitamin D3 group.

The mean expression of the PGC1-a gene was increased amongst the ulcerative colitis (UC) patients treated with Zinc (Zn) supplement. However, in the control group, no any changes have been recorded for this gene. The mean expression of the SIRT1 gene was increased amongst the UC patients treated with Zn supplement. However, in the control group, no any changes have been recorded for this gene. In cell culture experiments and colitis animal models, Zn administration improves intestinal barrier function and reduces expression of proinflammatory cytokines. The study findings revealed that the expression of both SIRT1 and PGC1-a genes were significantly increased after Zn supplementation.
In a similar survey, Khazdouz et al. reported that Selenium (Se) supplement caused some changes in the SIRT1 and PGC1-a genes in UC patients. They reported that the SIRT1 gene expression in the Se group was significantly increased compared to the placebo. An increase in the expression of the PGC-1a gene in the Se group was not statistically significant. It seems that Se supplementation caused a significant decrease in the inflammatory response of the colon by a significant increase in the expression of the SIRT1 gene. Researches established that SIRT1 can regulation of intestinal inflammation and tissue homeostasis in UC model.

Of course these facts don't make for an easy interpretation, but anyone with an active COVID-19 infection should be still careful with SIRT1 activators and beta adrenergic agonists even if they are potentially beneficial in some cases of POIS.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: Testosterone-PPARs-PGC1a-Irisin axis
« Reply #7 on: December 01, 2021, 04:13:42 PM »
I tested negatiwe for MG but i hawe all symptomes.
I found out that there is a nonserologic MG..


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Re: Testosterone-PPARs-PGC1a-Irisin axis
« Reply #8 on: December 02, 2021, 11:56:21 AM »
I tested negatiwe for MG but i hawe all symptomes.
I found out that there is a nonserologic MG..

Hi Hopeoneday!

So I don't have either diabetes or MG, but I was wondering if the common link to POIS could be a kind of irisin resistance which had been already mentioned in the first post. The source of the metabolic stress could be different, however some of the symptoms and inflammatory pathway would still overlap. In my case PPARA agonists so far have been proven to be useful, although I couldn't test some important ones like fenofibrate or palmitoylethanolamide (PEA). I am also unsure if increasing irisin would be beneficial in such a case. Some supplements specifically indicated to raise irisin are saffron, DHM and garlic oil. Saffron has proven beneficial, but it has too many health effects to conclude anything. I have already ordered some Dihydromyricetin (DHM) [marketed for the management of hangover and considered a potent exercise mimetic] to see if it is any good. Sirt1 downregulation may be an effect of irisin resistance as seen in MG. Boosting Sirt1 also works for me. MACA and resveratrol can increase Sirt1 just to mention a few beneficial ones.
By the way I would be interested to know if you have ever tried resveratrol with any success.

Excerpt of the irisin resistance theory:
We hypothesize that the increased irisin levels in T2DM with hypertriglyceridemia in our study might have represented irisin resistance, reflecting a compensatory result to counterbalance the increasing needs for irisin (similar to the increased insulin levels in insulin resistance) and to improve metabolic features.
Importantly, we report for the first time here that fenofibrate treatment administered to T2DM patients with hypertriglyceridemia for 8 weeks resulted in a significant decrease in serum irisin levels, although fenofibrate was reported to increase irisin gene expression in diet-induced male obese mice. We hypothesize that the PPARA agonist fenofibrate could induce the increase of UCP1 and browning of WAT by activating PPARA and that the increased UCP1 levels and browning programme might compensatively inhibit the FNDC5 expression and then reduce the irisin levels.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.