Exercise and Epigenetic Regulation

General Discussion
#8

This paper has also been posted before but is relevant to this thread as well.

Endurance exercise training enhances local sex steroidogenesis in skeletal muscle.

Abstract

PURPOSE:

Endurance training improves skeletal muscular function including energy metabolism and structure. Sex steroid hormones partly contribute to the exercise-induced muscular adaptations. Recently, we demonstrated that skeletal muscle contains steroidogenic converting enzymes to synthesize sex steroid hormones and an acute endurance exercise activates local steroidogenesis in skeletal muscle. However, whether chronic endurance training leads to enhanced steroidogenesis in skeletal muscle is unknown. Here, we examined changes in steroidogenic enzymes and sex steroid hormones in the skeletal muscle after chronic endurance exercise training.

METHODS:

Eleven male rats were divided into two groups: sedentary (n = 6) and trained (n = 5). Endurance training was performed on a treadmill (30 m·min(-1), 30 min) for 5 d·wk(-1) for 12 wk. The posttraining harvesting was performed 48 h after the last exercise training.

RESULTS:

The mRNA expressions of 3β-HSD, aromatase cytochrome P450, and 5α-reductase in the skeletal muscle of trained rats were significantly higher than those of sedentary rats (P < 0.05). The protein expressions of aromatase cytochrome P450 and 5α-reductase in the skeletal muscle of trained rats were also significantly higher than those of sedentary rats (P < 0.05). The muscular dihydrotestosterone (DHT) concentrations in the skeletal muscle of trained rats were significantly higher than those of sedentary rats (P < 0.01), but there was no change in dehydroepiandrosterone, total testosterone, free testosterone, and estradiol. Furthermore, muscle weight corrected for body weight of trained rats was moderately correlated with the level of muscular DHT concentration in trained rats (r = 0.41, P < 0.05).

CONCLUSIONS:

Endurance exercise training enhances the muscular DHT concentration through 5α-reductase in the skeletal muscle of rats, suggesting that local bioactive androgen metabolism may participate in exercise training-induced skeletal muscular adaptation.

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#9

Another paper showing exercise changes gene methylation patterns not only in skeletal muscles but also in sperm.

Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans.

Abstract

AIM:

DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation.

MATERIALS & METHODS:

Twenty-four men were recruited and assigned to an exercise intervention or control group. Clinical parameters were measured and sperm samples were donated by subjects before and after the 3-month time-period. Mature sperm global and genome-wide DNA methylation was assessed using an ELISA assay and the 450K BeadChip (Illumina).

RESULTS:

Global and genome-wide sperm DNA methylation was altered after 3 months of exercise training. DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson’s disease.

CONCLUSIONS:

Our study provides the first evidence showing exercise training reprograms the sperm methylome. Whether these DNA methylation changes are inherited to future generations warrants attention.

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Agree to disagree
#10

I can keep adding papers to this thread, and no doubt more specific papers can be found that are even more informative for our purposes, but I would like to hear people’s opinion on this - both based on the science but also based on personal experience.

I know there have been many threads about the potential benefits of exercise for us, including recovery stories. It would be good to hear both from (or about) people who have improved and also who have not improved with exercise.

Presumably there are many long-term sufferers who have not improved even with a lot of exercise. It would be good to hear from those - how much exercise they have done, what type, how often, what intensity, etc.

Basically I would like to have a realistic expectation about the possible benefits from embarking on a regular and strenuous exercise regimen. I hope I will be able to do that soon, joint pain permitting.

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#11

The impact of sensory and motor enrichment on the epigenetic control of steroidogenic-related genes in rat hippocampus.

Abstract

In the present study, we analyzed the effects of a short-term environmental enrichment on the mRNA expression and DNA methylation of steroidogenic enzymes in the hippocampus. Thus, young adult (80-day-old) and middle-aged (350-day-old) Wistar female rats were exposed to sensory (SE) or motor (ME) enrichment during 10 days and compared to animals housed under standard conditions. SE was provided by an assortment of objects that included plastic tubes and toys; for ME, rodent wheels were provided. In young adult animals, SE and ME increased the mRNA expression of cytochrome P450 17α-hydroxylase/c17,20-lyase, steroid 5α-reductase type 1 (5αR-1) and 3α-hydroxysteroid dehydrogenase and decreased the methylation levels of 5αR-1 gene. In middle-aged rats, ME and SE upregulated the gene expression of aldosterone synthase and decreased the methylation state of its promoter. These results propose that SE and ME differentially regulate the transcription of neurosteroidogenic enzymes through epigenetic mechanisms in young and aged rats.

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#12

“We have shown that SRD5A2 is absent in 30% of adult human prostatic tissues, owing to methylation of the SRD5A2 promoter, regulated by the DNMT1 family of genes (a process that is enhanced by conditions associated with increased inflammatory mediators), ageing, and obesity.”

Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2

Abstract

Benign prostatic hyperplasia is the most common proliferative abnormality of the prostate. All men experience some prostatic growth as they age, but the rate of growth varies among individuals. Steroid 5α-reductase 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Previous work indicates that one-third of adult prostatic samples do not express SRD5A2, secondary to epigenetic modifications. Here we show that the level of oestradiol is dramatically elevated, concomitant with significant upregulation of oestrogen response genes, in prostatic samples with methylation at the SRD5A2 promoter. The phosphorylation of oestrogen receptor-α in prostatic stroma is upregulated when SRD5A2 expression is absent. We show that tumour necrosis factor (TNF)-α suppresses SRD5A2 mRNA and protein expression, and simultaneously promotes expression of aromatase, the enzyme responsible for conversion of testosterone to oestradiol. Concomitant suppression of SRD5A2 and treatment with TNF-α synergistically upregulate the aromatase levels. The data suggest that, in the absence of prostatic SRD5A2, there is an androgenic to oestrogenic switch. These findings have broad implications for choosing appropriate classes of medications for the management of benign and malignant prostatic diseases.

Keywords: androgenic to oestrogenic switch, prostate, epigenetic silencing, methylation, steroid 5α-reductase 2

Full Text:

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#13

While this paper is not related to exercise, I believe it is a very significant paper.

It shows that NF-kB increases expression of all three SRD5A2s. Nf-kB is stimulated by viral and bacterial infections.

This can potentially explain the reduction of PFS symptoms during episodes of cold/flu that is consistently reported by PFS patients.

This mechanism may also potentially explain the reported positive effects of certain probiotics, although this is widely speculative.

@awor @axolotl @orthogs @Dubya_B @Frustrated @Famajor

NF-κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance.

Abstract

BACKGROUND:

Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy.

METHODS:

Tissue was collected from “Surgical” patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from “Incidental” patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression.

RESULTS:

SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions.

CONCLUSION:

Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016.

Full Text:

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Do we have any theories linking illness with temporary recoveries?
Can someone explain if/how neurosteroids are affected and what it means?
#14

Effects of swim stress on mRNA and protein levels of steroid 5alpha-reductase isozymes in prefrontal cortex of adult male rats

Abstract

The metabolite of progesterone, allopregnanolone, is among the most potent known ligands of the gamma-aminobutyric acid receptor complex (GABA(A)-R) in the central nervous system. This neuroactive steroid is markedly increased in an animal model of acute stress. Allopregnanolone is synthesized from progesterone by steroidogenic enzymes 5alpha-reductase (5alpha-R) and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), with the former being the rate-limiting enzyme in this reaction sequence. In this paper, a quantitative RT-PCR method coupled to laser-induced fluorescence capillary electrophoresis (LIF-CE) and Western blot were used to measure both mRNA and protein levels of 5alpha-R type 1 (5alpha-R1) and 5alpha-R type 2 (5alpha-R2) isozymes in prefrontal cortex of male rats after acute swim stress situations. Our results demonstrate that both 5alpha-R isozymes are significantly higher in prefrontal cortex of male rats after acute swim stress in comparison with control rats. These data may open up a new research line that could improve our understanding of the role of 5alpha-R isozymes in processes that accompany stress situations.

#15

Expression of steroid 5α‐reductase isozymes in prostate of adult rats after environmental stress

Abstract

The elevated incidence of prostate cancer and benign prostatic hypertrophy is a cause of increasing public health concern in the Western world. The normal and pathological growth of the prostate are both dependent on stimulation by dihydrotestosterone, which is synthesized from circulating testosterone by two 5α‐reductase (5α‐R) isozymes, 5α‐reductase type 1 (5α‐R1) and 5α‐reductase type 2 (5α‐R2). Both isozymes have been implicated in prostate disease. We used quantitative RT‐PCR and immunohistochemistry, respectively, to quantify mRNA and protein levels of 5α‐R isozymes in the ventral prostate of adult rats under environmental stress conditions analogous to those found in some common workplace situations, i.e. artificial light, excessive heat, and the sensation of immobility in a small space. Transcription and expression levels of both 5α‐R isozymes were significantly higher in environmentally stressed rats than in unstressed rats. Increased 5α‐R isozyme levels may play a role in the development or maintenance of prostate disease. Further research is warranted to explore these effects of environmental stress on human health and their implications for environmental and occupational health policies.

Full Text
https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.12052

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#16

Effects of environmental stress on mRNA and protein expression levels of steroid 5alpha-Reductase isozymes in adult rat brain.

Abstract

Environmental stress conditions are important factors in human health and should be considered in the development of appropriate health policies, since they have been associated with psychological disorders and even with death. A link between stress and changes in 3alpha,5alpha-reduced neurosteroids has been reported. Steroid 5alpha-Reductase (5alpha-R) is the rate-limiting enzyme in the biosynthesis of 3alpha,5alpha-reduced neurosteroids. Using reverse transcription-polymerase chain reaction and immunohistochemistry, 5alpha-R isozymes (5alpha-R1 and 5alpha-R2) mRNA and protein levels were detected in prefrontal cortex of male and female rats after they underwent environmental stresses, i.e., excessive heat, artificial light, and the sensation of immobility in a small space, similar to those found in common workplace situations. Results showed significantly higher 5alpha-R2 mRNA and protein levels in environmentally-stressed versus control rats. Interestingly, a sexual dimorphism in 5alpha-R1 mRNA and protein levels was observed after environmental stress, with an increase in males and a decrease in females. This fact might explain gender differences in the incidence of some type of minor depression.

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#17

Great thread, Sibelio. Bookmarked for future reference.

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#18

S…should I travel to Wuhan?

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#19

@Sibelio I really thank you for all of your findings I’m to much of a dumb ass these days to even comprehend this stuff but thanks for doing research

1 Like
#20

Thanks for the papers.

I´ve not really been exercising for the last 2 months actually, just some pushups here and there. After a lifetime of chronic exercising. Been really sedentary, and even though I have been improving my condition, I feel like no exercise hasn’t really been serving me well. I’m thinking about starting up again, but not like I was doing in the past. I used to do a 2-split, 6 days a week, high reps; 20-30 reps, 3 sets, and 3 exercises each time. It always left me feeling exhausted, irritable and with worse brain fog/head pressure. Seemed like it increased a stress/estrogenic response, and I tried “forcing” it through hoping it would get better, but it never did and I just decided I’m not going lift more weights for a while.

But yeah, I think movement is crucial, and I think I will try doing less but heavier, accompanied by more walking outside to get sun/daylight. Maybe just 1 exercise pr day, 3 sets of 10.
For example:
Day 1: Dips 3x10. Walking.
Day 2: Barbell rows 3x10. Walking.
Day 3: Sumodeadlift 3x5-8. Walking.
Repeat.

I think for me at this point, a stronger “androgenic stimulus” is needed to really activate more androgen receptors or increase their expression… this is what my intuition tells me, and a sedentary/mostly housebound lifestyle is not cutting it. Exercise clearly increases 5-ar levels and DHT, but does this equal increased AR expression? I would guess it does… My current theory is that retinoic acid is somehow attached to the AR, or a retinoic acid receptor nearby, effectively antagonizing/inhibiting DHT from attaching to the AR and expressing it. So it wouldn’t matter if I just increased DHT through whatever means, if it doesn’t actually bind to the AR… but if RA and DHT competes for the same receptors, then increased DHT would perhaps increase the “pressure” on RA at the AR, and eventually if the “androgenic stimulus” is strong enough, force RA off of the receptors and remove it from the body.

Well, I might be wrong on this lol, but this what I’m thinking now anyway.


Down-regulation of androgen receptor expression and inhibition of lacrimal gland cell proliferation by retinoic acid.

"Androgens and retinoids are known to be involved in control of lacrimal gland function. Because retinoids generally antagonize androgen function it was the purpose of this study to investigate interactions of retinoic acid and androgens in rabbit lacrimal acinar cells in culture by determining effects of retinoic acid on androgen receptor (AR) mRNA expression, AR protein levels and androgen-stimulated cell proliferation. Experiments were conducted using primary rabbit lacrimal acinar cells and a transformed rabbit lacrimal acinar cell line. Exposure of primary lacrimal acinar cells in culture to 10(-10)-10(-6)M all-trans retinoic acid for 4-24hr causes an approximately 50% decrease in AR mRNA expression.
…


“RA and androgen responsive elements (RARE and ARE) were mapped to the hTGP promoter by chromatin immunoprecipitation (ChIP), which also indicated that the active ARE and RARE sites were adjacent, suggesting that the antagonistic effect of androgen and RA is related to the relative position of binding sites.”
…
Retinoic Acid Inhibits Androgen-Stimulated Up-Regulation of Androgen Receptor Expression in Lacrimal Glands of Orchiectomized Rats
…

For me, the things I clearly feel the most dopaminergic/androgenic from doing is: approaching girls, and camping in nature (but I also feel worse and crash from them). Lifting weights doesn’t come close to those, but there is probably a cumulative positive effect in the long-term from doing the right type of training. I´ll ponder this a little more, but the high rep, high lactic acid/time under tension training definitely makes me worse.

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#21

Just speaking from experience, I had experience sexual improvements when I’ve had the flu but not colds. Over the past decade, there have been two times where I basically panicked and had a revival in sexual functioning for a couple days. One of the times I thought I was going to be fired and had to wait for about an hour before speaking to somebody about it, but it was completely an overreaction and it was a non-issue. Definitely not worth it, but it did bring this back partially. For whatever that is worth.

1 Like
#22

DNA methylation is a reversible biological signal

Abstract

The pattern of DNA methylation plays an important role in regulating different genome functions. To test the hypothesis that DNA methylation is a reversible biochemical process, we purified a DNA demethylase from human cells that catalyzes the cleavage of a methyl residue from 5-methyl cytosine and its release as methanol. We show that similar to DNA methyltransferase, DNA demethylase shows CpG dinucleotide specificity, can demethylate mdCpdG sites in different sequence contexts, and demethylates both fully methylated and hemimethylated DNA. Thus, contrary to the commonly accepted model, DNA methylation is a reversible signal, similar to other physiological biochemical modifications.

Full text
https://www.pnas.org/content/96/11/6107

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#23

This paper was already posted elsewhere but I think it is nice to have it in this thread as well.

Dihydrotestosterone is elevated following sprint exercise in healthy young men

Abstract

Dihydrotestosterone (DHT) exerts both functional and signaling effects extending beyond the effects of testosterone in rodent skeletal muscle. As a primer for investigating the role of DHT in human skeletal muscle function, this study aimed to determine whether circulating DHT is acutely elevated in men following a bout of repeat sprint exercise and to establish the importance of training status and sprint performance to this response. Fourteen healthy active young men (V̇o2max 61.0 ± 8.1 ml·kg body mass−1·min−1) performed a bout of repeat sprint cycle exercise at a target workload based on an incremental work-rate maximum (10 × 30 s at 150% Wmax with 90-s recovery). Venous blood samples were collected preexercise and 5 and 60 min after exercise. Five minutes after exercise, there were significant elevations in total testosterone (TT; P < 0.001), free testosterone (FT; P < 0.001), and DHT ( P = 0.004), which returned to baseline after 1 h. Changes in DHT with exercise (5 min postexercise − preexercise) correlated significantly with changes in TT ( r = 0.870; P < 0.001) and FT ( r = 0.914; P < 0.001). Sprinting cadence correlated with changes in FT ( r = 0.697; P = 0.006), DHT ( r = 0.625; P = 0.017), and TT ( r = 0.603; P = 0.022), and habitual training volume correlated with the change in TT ( r = 0.569, P = 0.034). In conclusion, our data demonstrate that DHT is acutely elevated following sprint cycle exercise and that this response is influenced by cycling cadence. The importance of DHT in the context of exercise training and sports performance remains to be determined.

Full Text:

#24

Effect of exercise on serum sex hormones in men: a 12-month randomized clinical trial.

Abstract

PURPOSE:

The effect of exercise on androgens in middle-aged to older men is poorly understood, and it could have implications for several aspects of health. This analysis was conducted to examine the effects of long-term aerobic exercise on serum sex hormones in middle-aged to older men.

METHODS:

One hundred two sedentary men, ages 40-75 yr, were randomly assigned to a 12-month exercise intervention or a control group (no change in activity). The combined facility- and home-based exercise program consisted of moderate/vigorous-intensity aerobic activity for 60 min.d(-1), 6 d.wk(-1). Serum concentrations of testosterone, free testosterone, dihydrotestosterone (DHT), 3alpha-androstanediol glucuronide (3alpha-Diol-G), estradiol, free estradiol, and sex hormone-binding globulin (SHBG) were measured at baseline, 3, and 12 months.

RESULTS:

Exercisers trained a mean of 370 min.wk(-1) (102% of goal), with only two dropouts. Cardiopulmonary fitness (.VO(2max)) increased 10.8% in exercisers and decreased by 1.8% in controls (P < 0.001). DHT increased 14.5% in exercisers versus 1.7% in controls at 3 months (P = 0.04); at 12 months, it remained 8.6% above baseline in exercisers versus a 3.1% decrease in controls (P = 0.03). SHBG increased 14.3% in exercisers versus 5.7% in controls at 3 months (P = 0.04); at 12 months, it remained 8.9% above baseline in exercisers versus 4.0% in controls (P = 0.13). There were significant trends toward increasing DHT and SHBG, with greater increases in .VO(2max) at 3 and 12 months in exercisers. No statistically significant differences were observed for testosterone, free testosterone, 3alpha-Diol-G, estradiol, or free estradiol in exercisers versus controls.

CONCLUSIONS:

A year-long, moderate-intensity aerobic exercise program increased DHT and SHBG, but it had no effect on other androgens in middle-aged to older men.

Full text:

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#25

Increased Muscular 5α-Dihydrotestosterone in Response to Resistance Training Relates to Skeletal Muscle Mass and Glucose Metabolism in Type 2 Diabetic Rats

Abstract

Regular resistance exercise induces skeletal muscle hypertrophy and improvement of glycemic control in type 2 diabetes patients. Administration of dehydroepiandrosterone (DHEA), a sex steroid hormone precursor, increases 5α-dihydrotestosterone (DHT) synthesis and is associated with improvements in fasting blood glucose level and skeletal muscle hypertrophy. Therefore, the aim of this study was to investigate whether increase in muscle DHT levels, induced by chronic resistance exercise, can contribute to skeletal muscle hypertrophy and concomitant improvement of muscular glucose metabolism in type 2 diabetic rats. Male 20-week-old type 2 diabetic rats (OLETF) were randomly divided into 3 groups: sedentary control, resistance training (3 times a week on alternate days for 8 weeks), or resistance training with continuous infusion of a 5α-reductase inhibitor (n = 8 each group). Age-matched, healthy nondiabetic Long-Evans Tokushima Otsuka (LETO) rats (n = 8) were used as controls. The results indicated that OLETF rats showed significant decrease in muscular DHEA, free testosterone, DHT levels, and protein expression of steroidogenic enzymes, with loss of skeletal muscle mass and hyperglycemia, compared to that of LETO rats. However, 8-week resistance training in OLETF rats significantly increased the levels of muscle sex steroid hormones and protein expression of steroidogenic enzymes with a concomitant increase in skeletal muscle mass, improved fasting glucose level, and insulin sensitivity index. Moreover, resistance training accelerated glucose transporter-4 (GLUT-4) translocation and protein kinase B and C-ζ/λ phosphorylation. Administering the 5α-reductase inhibitor in resistance-trained OLETF rats resulted in suppression of the exercise-induced effects on skeletal muscle mass, fasting glucose level, insulin sensitivity index, and GLUT-4 signaling, with a decline in muscular DHT levels. These findings suggest that resistance training-induced elevation of muscular DHT levels may contribute to improvement of hyperglycemia and skeletal muscle hypertrophy in type 2 diabetic rats.

Full Text:

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#26

Since being without my gym due to COVID-19, my libido is down and penis does not want to get hard so easily.

Weight training is good stuff, and I can’t wait till I can resume. This situation sucks. I underestimated the benefits of heavy lifts.

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#27

What about people that can’t exercize because muscolar, tendons, joints and ligments deteroration?