Catabolic signaling pathways after a steroid cycle: Akt / mTOR / FOXO and myostatin

There is no magic PCT, a deep and beautiful way of saying that you will always lose after a cycle, no matter what you do!

The loss of muscle mass after a steroid cycle is inevitable, and this is due to a drastic change in the post-cycle hormonal environment. Many users question whether the gains can be maintained in any way, but the truth is that in general they cannot, because just as these gains were achieved through the use of supraphysiological doses of androgenic steroids, the losses after a cycle are due to suspension the use of anabolic hormones, with the aggravation of the production of endogenous testosterone is suppressed, due to the inhibition of the HPT (hypothalamus-pituitary-testicular) axis caused by the use of androgenic steroids.

The idea of ​​the present article is to show which are the intracellular signaling pathways involved in the loss of muscle mass after the use of steroids, and to show that this signaling is independent of the nutritional or training status, and suffers little influence from the glucorticoids (cortisol), but it is directly related to fluctuations in androgen levels and low testosterone levels after the steroid cycle. Not only that, the alteration of gene expression related to the signaling pathways responsible for hypertrophy (Akt / mTOR / FOXO) and muscle atrophy are dependent on androgen levels.

The activation of the PI3-kinase pathway (PI3k) can induce skeletal muscle hypertrophy, defined as an increase in skeletal muscle mass. In mammals, skeletal muscle hypertrophy occurs as a result of an increase in the size, rather than the number (hyperplasia), of the skeletal muscle fibers. This pathway is activated by insulin-like growth factor 1 (IGF-1) and insulin. Pro-hypertrophy activity of IGF-1 comes predominantly through its ability to activate the PI3K / Akt signaling pathway. Akt is a serinatreonine kinase protein that can induce protein synthesis (via the mTOR pathway) and block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the ubiquitin ligases E3 MuRF1 and MAFbx (also called atrogin-1) , through phosphorylation and inhibiting nuclear translocation of the FOXO family (also called "forkhead") of transcription factors (proteins that modulate gene expression). Once phosphorylated by Akt, foxes are excluded from the nucleus, and over-regulation of genes related to MuRF1 and atrogin1 atrophy is blocked. IGF1 / PI3K / Akt signaling can also dominantly inhibit the effects of a secreted protein called "myostatin", which is a member of the TGF-beta (transforming growth factor-beta) protein family. Elimination or inhibition of myostatin causes an increase in the size of skeletal muscle, because myostatin acts to inhibit the differentiation of myoblasts (precursor cell of muscle fibers) and to block the Akt pathway. Thus, by blocking myostatin, activation of the PI3K / Akt pathway stimulates protein differentiation and synthesis by this distinct mechanism. As mentioned, myostatin also decreases the expression of the Akt / mTOR / p70S6k protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes [1].

After a cycle of steroids, there is a situation of temporary hypogonadism (low testosterone) induced by the use of androgenic steroids. Low endogenous testosterone production, known as hypogonadism, is commonly associated with conditions that induce loss of muscle mass. Akt signaling can control skeletal muscle mass by regulating mTOR protein synthesis and regulating protein degradation by the FOXO transcription factor (acts on the cell nucleus by altering the gene expression of the genes responsible for muscle atrophy), and this path has been previously identified as an androgen signaling target. In experiments on rats, the removal of androgens induced by castration induces the loss of muscle mass through the suppression of myofibrillar protein synthesis and is associated with the suppression of activation of the Akt / mTOR pathway. There was also subsequent activation of atrophy-related pathways through PRAS40, and GSK3β. This suppression of mTOR was independent of AMPK signaling (AMPK acts as a cellular sensor of energy balance and inhibits protein synthesis by inhibiting mTOR). Foxo atrogin1 / MAFbx, MuRF1 and REDD1 transcription targets were induced by androgen withdrawal. Androgen administration (nandrolone) was able to reverse all these changes in the gastrocnemius muscle [2]. These genes (atrogin1, MuRF1) are upregulated in several models of atrophy and cachexia. They target certain substrates of degradation proteins via the ubiquitin / proteasome pathway. IGF-1 can block the transcriptional upregulation of MuRF1 and atrogin1 via the PI3K / Akt / Foxo pathway (Akt inhibits the Foxo transcription factor) [3].

Myostatin is an important negative regulator of skeletal muscle growth, while androgens are strong positive effectors. In order to investigate the possible interaction between myostatin and androgen pathways, a study looked at testosterone deprivation (castration) in the levator ani muscle of rats, which led to muscle growth stopping in young male rats, and atrophy in some adults, however, both processes have been reversed by testosterone supplementation. After castration, a significant increase in regulation of the active myostatin protein (and its pro-peptides) was found, while subsequent testosterone treatment reduced myostatin protein levels to normal values ​​in both young and adult rats. Likewise, a suppression of testosterone induced by myostatin mRNA levels was observed in castrated adults, but not in young animals. Altogether, androgens appear to have a strong negative impact on the expression of myostatin [4]. From this study we can speculate that a reduction in the levels of testosterone or steroids after the steroid cycle leads to an over-regulation of the myostatin gene, which ends up being responsible for part of the loss of muscle mass after the use of steroids.

From all this we can conclude the loss of muscle mass after a cycle of androgenic steroids is directly associated with low testosterone and the aggressive reduction of androgen levels. A drop in androgen levels induces the loss of muscle mass through the suppression of myofibrillar protein synthesis and is associated with the suppression of activation of the Akt / mTOR pathway. This suppression of mTOR after using androgenic steroids is independent of AMPK signaling. Foxo atrogin1, MuRF1 and REDD1 transcription targets (related to muscle atrophy) are induced by the reduction of androgens after steroid use. Low testosterone also leads to an overloading of the myostatin gene, which inhibits activation of the Akt / mTOR / p70S6k protein synthesis pathway, which mediates both myoblast differentiation and myotube hypertrophy.

Reducing the dose and low post-cycle testosterone lead to catabolism, that's it!


[1] PI3 kinase regulation of skeletal muscle hypertrophy and atrophy.
Glass DJ

Molecular Cell Biology, Alberts et al. 5th edition.

Signaling in Muscle Atrophy and Hypertrophy
Marco Sandri

HYPERTROPHY: insulin, IGF-1, testosterone, myostatin and the mTOR pathway (DUDU)

[2] Testosterone regulation of Akt / mTORC1 / FoxO3a signaling in skeletal muscle.
White JP, Gao S, Puppa MJ, Sato S, Welle SL, Carson JA.

[3] Signaling pathways perturbing muscle mass.
Glass DJ

Signaling pathways during diet and exercise, in BULK and CUTTING: mTOR, AMPK, PGC-1alfa, FOXO (DUDU)

[4] Androgens negatively regulate myostatin expression in an androgen-dependent skeletal muscle.
Mendler L, Baka Z, Kovács-Simon A, Dux L.

Myostatin reduces Akt / TORC1 / p70S6K signaling, inhibiting myoblast differentiation and myotube size.
Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ.

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