Androgen receptor upregulation

[KingOfSushi]

Thought I would share this.

I still see the common myth that we need to “reset” or “clean out” androgen receptors

It’s the first concept covered in the video

 

[Fleezy]

Just watched this last night

 

[Steelers_]

It’s a myth no such thing as reset or clean out receptors

 

[Fleezy]

It’s a myth no such thing as reset or clean out receptors

But.. but.. Dave Palumbo..

 

[emeric delczeg]

Thought I would share this.

I still see the common myth that we need to “reset” or “clean out” androgen receptors

It’s the first concept covered in the video

Correct , is no such of think called clean out androgen receptors.

 

[1fst400]

Thought I would share this.

I still see the common myth that we need to “reset” or “clean out” androgen receptors

It’s the first concept covered in the video

“Dirty receptors” .

 

[Ranchhand]

Listened to this episode yesterday, Paul Barnett is putting out some good content. For me right now, he's only second to Scott McNally and all his content. In the last month or so Paul has quickly climbed my list of content providers I like to listen to.

 

[pickapeck]

It's not a question of "cleaning out receptors". That is a myth. The reason why we lose sensitivity late in a cycle or as we blast and cruise is many fold. A major factor is up regulation of excretory enzymes and machinery. The body will modify these steroid entities via sulfonate, glucuranylate hydroxylate and other modifications to allow removal of these entities via hepatic and nephronyl function.

 

[Type-IIx]

I was requested by PM to address the claim that androgen receptor (AR) "resensitization" is a rationale for discontinuing AAS, meaning that supraphysiologic androgen dose (AUC; nmol * h/L) induces tachyphylaxis (desensitization) analogous to opioid/opiate & Opioid Receptors (i.e., κ-, δ-, μ- OR) or clenbuterol & β₂Adrenergic Receptors (B2AR). Since I have some time and think that this is important, I will oblige.

Tachyphylaxis or desensitization is a feature of G-protein-coupled receptors (GPCRs) that AR is not. In the case of opioid/opiate drugs, the μ- OR is a GPCR subject to phosphorylation that recruits β-arrestin, an accessory protein that induces tachyphylaxis, requiring increasing doses to elicit the same efficacy in subsequent doses. Clenbuterol activates the B2AR, a GPCR, thereby stimulating phosphorylation of downstream elements, binding β-arrestin, to regulate signaling pathways involved in muscle growth and decreased fat mass (recomp), as well as increased strength, sprint, power (performance). In the cases of both of these types of drugs, opioids/opiates & B2ARs like clenbuterol, the dose must be increased with subsequent uses in order to elicit comparable effects due to tachyphylaxis.

AR Regulation
AR, by contrast, is not a GPCR, and so is not associated with tachyphylaxis.

AR expression (the number/# of receptor proteins in our bodies) is regulated in several ways:

Broadly speaking, there are four (4) forms of regulation that control the number of receptors in the body. These are:

1. Transcription rate (i.e., up-regulate AR by increased transcriptional AR mRNA synthesis)
2. Translational efficiency (i.e., up-regulate AR by increased AR mRNA synthesis per ribosome)
3. Translational capacity (i.e., up-regulate AR by increased AR mRNA synthesis as a result of increased ribosomal biogenesis [↑ ribosome #])
4. Receptor turnover (i.e., up-regulate AR by decreased degradation/synthesis balance of AR mRNA)

To understand them, let’s quickly review the life-cycle of an individual AR.

? Transcription rate
There is a single gene in the DNA of each cell that codes for the AR. In the transcription process, the DNA code is copied to mRNA. The rate (frequency) of this process can be either increased (promoted) or decreased (repressed) depending on what other proteins are bound to the DNA at the time. Increase or decrease of this rate can be a form of regulation: the more AR mRNA is produced, all else being equal, the more ARs there will be. Bill Roberts.

✖ Translational efficiency
If efficiency is 100%, each mRNA will be used by a ribosome to produce an AR, which is a protein molecule. The process of making protein from the mRNA code is called translation. In practice efficiency will not be 100%. Changes in efficiency of translation can also be a form of regulation. Bill Roberts.

This, if it were a mechanism by which androgen regulated AR #, would be marked by mTOR activity (ie, myogenic markers, rpS6 or p70S6K increases in human skeletal muscle cells in vivo).

✓ Translational capacity
By increasing the # of ribosomes, the absolute # of AR produced by translation will increase. This is an important mechanism by which androgens ↑AR # in vivo.

View attachment 181280
The increase to AR # reflects, in part (r = 0.467), increased translational capacity, reflected by an increased muscle total RNA content (Δ μg RNA/mg muscle) that since ribosomal RNA comprises > 85% of cellular RNA, describes an increased ribosome # (suggesting that androgen/T stimulates ribosomal biogenesis):

View attachment 181281View attachment 181282

? Receptor turnover
The final form of potential post-translational regulation is the rate of loss of ARs. If the cell produces x ARs per hour, and their half life is say 7.5 hours, then the number of ARs will be higher than if ARs are produced at that same rate but the half life is say only 3.3 hours. Thus, control of rate of turnover, or change in half-life, can be another means of regulation. Bill Roberts.

Conclusions
1. AR is up-regulated (AR # & density increased) by testosterone/androgen in human skeletal muscle cells in vivo.
2. This up-regulation is known to be a result of increased translational capacity by testosterone/androgen; and not translational efficiency a la mTOR.
3. Regulation of AR is not subject to desensitization; so, by corollary, there is no rationale to support cessation for resensitization.

I'd like to add to this title post, under the subheading Transcription rate:

During nuclear transcription (the primary mechanism of AAS action), AR binding by an androgen/AAS (e.g., T) results in specific conformational changes in the ligand-binding domain of the AR, thereby triggering dissociation of heat shock proteins, dimerization and transport from the cytosol to the cell nucleus where the T-AR dimer complex binds to androgen response elements (AREs).

We know that there are coregulators, proteins that interact with the AR to enhance (coactivators) or reduce (corepressors) transactivation of target genes but that do not significantly alter the basal transcription rate.

Coactivators that have been identified include ARA70 (ARA₇₀), steroid receptor coactivator 1, and RAC3/ACTR. Proteins that enhance AR binding to DNA include RAF. GRIP1 & cJun increase activity.

Corepressors that have been identified include ZBTB7A that recruits NCOR1 and NCOR2 to the AREs on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation

Proteins that decrease AR # include nuclear factor kappa B (NF-κB). CFes & RelA inhibit transactivation and/or transcription.

Although the role of coactivators in androgenic action is clear in sexual & reproductive tissue, their role in AR action in (skeletal) muscle has not been comprehensively demonstrated. There are efforts underway to further investigate anabolic activity with respect to coactivators.

 

[SouthernMuscle]

@Type-IIx

Very much enjoyed reading that, thank you

 

[MouthBreather1982]

It's not a question of "cleaning out receptors". That is a myth. The reason why we lose sensitivity late in a cycle or as we blast and cruise is many fold. A major factor is up regulation of excretory enzymes and machinery. The body will modify these steroid entities via sulfonate, glucuranylate hydroxylate and other modifications to allow removal of these entities via hepatic and nephronyl function.

Are you saying you get used to the ester? I’m not sorry?

 

[MouthBreather1982]

Thanks you have some serious patience sir.

 

[specter]

Been saying this for years but im not as smart or well spoken as Type-IIX and ppl alike so im disregarded, i was speakin with my countrys highest regarded drug and drug abuse specialist, he told me thats what happens with rec drug, the body over time becomes more effecient at removing them hence the need for increase in dosage, offcourse thats simplifying it.

 

[buck]

Seems like the more gear is used the more receptors are made last i checked. But that would make sense as nature tends to like balance.

 

[Sully1234]

I think it @b-boy who posted a few months ago a video of a guy explaining how injectable l-carn up regulates androgen receptors FWIW the video recommended 2--mg a day, every day along with other health benefits.