In contrast to testosterone, DHT did not prevent the induction of AR by rapamycin (Figure 4C). Another experiment was carried out to determine whether dihydrotestosterone (DHT) has the same effect on rapamycin induction of AR as testosterone. The increase of PSA and KLK2 at 0.03 and 1 nM testosterone paralleled the increase of AR expression. The data suggest that AR expression is up-regulated when mTOR is depressed, but this loop was operative only in a low testosterone condition. However, at 5 nM testosterone, the induction of AR by rapamycin was no longer evident. Up to this point, the results indicated that AR positively regulates mTOR activity in both low and high testosterone conditions.
In addition, both the association of mTOR with eIF3F and S6K1 activity are increased in fed conditions after exercise, which provides an explanation for the enhanced muscle protein synthesis (Song et al., 2017). These results implied that an unknown upstream mediator beyond IGFR might regulate Akt/mTOR signaling in skeletal muscle hypertrophy. Understanding of the role of mTOR in muscle growth and hypertrophy has progressed recently from the evidence of several loss-of-function animal models, although it is relatively well-understood as being similar to the mechanism of the function of mTOR in cell growth regulation.
The analysis of these effects showed that the mRNA expression levels of ANP, β-MHC and MMP-9 reduction were greater in the high-dose rapamycin group compared to the low-dose and the medium-dose group and did not change in the chlorthalidone group (Fig. 5B, C and D). However, it was difficult to restore the area of myocardial cells to the level of WKY rats under the protection of estrogen (Fig. 4A and C). Induction of E alone reduced the area of myocardial cells isolated from OVX SHR. Induction of estrogen alone reduced the mRNA expression levels of Anp, Bmhc and MMP-1 in myocardial tissue isolated from OVX SHR, while Timp1 was significantly decreased (Fig. 2B, C, D and E). E, estrogen; eIF4E, eukaryotic translation initiation factor 4E; mTOR, mammalian rapamycin receptor; OVX, ovariectomized; S6K1, ribosomal protein S6 kinase; T, testosterone; WKY, Wistar Kyoto; 4EBP1, 4E-binding protein 1. There was also no statistical difference in the area of myocardial cells between the sham-operated group and the OVX group (Fig. 4A and C). The mRNA levels of mTOR, 40S ribosomal protein S6K1, eukaryotic initiation factor 4EBP1 in myocardial tissue were quantitatively analyzed by qPCR.
The SBP and DBP levels did not change significantly in the OVX group (Fig. 1A and B). Plasma E and T levels in OVX group were significantly lower than those in WKY and sham group (Table 1). Heart weight (HW) and HW/tibial length (TL) were significantly increased after OVX in SHR. In contrast, the cell types of WKY and sham-operated group belonged to pre-estrus or estrus (Supplementary Fig. 1, see section on supplementary materials given at the end of this article). The cell types in the OVX group were estrous interphase I and estrous interphase II, which proved that the establishment of postmenopausal animal model was successful. After formaldehyde fixation, paraffin sectioning and deparaffinization, the myocardial tissue was stained with wheat germ agglutinin solution and the nucleus was counterstained with DAPI. ECL chemiluminescence liquid developed luminescence, gel imaging system took pictures, and Image Pro Plus image analysis system analyzed protein bands.
What are the advantages offered by this kind of signaling interaction? An intriguing observation of the present study is that the mTOR → AR signal is sensitive only to testosterone, but not to DHT. Cinar et al. (6), on the other hand, concluded that the up-regulation of AR by rapamycin is at the translational level. Since AR is known to activate multiple kinases through non-genotropic mechanisms (16, 17), inhibiting AR activity may result in increasing TSC2 stability.
However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. The outcome is predictable because the low testosterone-acclimated cells are able to up-regulate AR protein and activity, and are therefore better equipped for survival in a stress situation. The data of the scrambled siRNA control cells presented in Figure 2B show that the phosphorylation of p70S6K and S6 was increased by testosterone stimulation (lane 1 vs. lane 3). These results indicated that the mTOR pathway plays a key role in testosterone-induced OVX SHR myocardial hypertrophy. Finally, the relationship between the total elevated levels of these proteins (mTOR, S6K1 and 4E-BP1) induced by testosterone and their phosphorylated form remains unclear and requires further investigation. First, this study effectively identified the mTOR signaling pathway as a potential target of testosterone-induced OVX SHR cardiac hypertrophy, but it did not explore mTOR upstream regulatory molecules.
Compared with OVX + E group, the levels of SBP and DBP in OVX + E + T group increased at the end of the 30th day. After testosterone intervention, the OVX female rats exhibited significant increments in the HW/TL, HW/body weight (BW) and area of cardiomyocytes accompanied by a significant increase in the serum testosterone levels. The levels of Mtor, S6k1, 4Ebp1 and eIF4E were reduced in myocardial tissue of OVX + E group compared to those of OVX group (Fig. 3D, E, F, G and H). Plasma estrogen levels were increased after ovariectomy with SHR with E supplementation (Table 1).
In addition, myostatin blocks differentiation-inducing genes, such as myogenin and myoD (Trendelenburg et al., 2009), suggesting that myostatin regulates muscle differentiation by modulating both the programs of differentiation and atrophy. The binding of myostatin to the type II activin receptor IIb leads to interaction with the type I receptor ALK4 or ALK5, which results in the phosphorylation and activation of the transcription factors Smad2 and Smad3(Sartori et al., 2014). Myostatin regulates the number of muscle fibers during development and the growth of muscle fibers postnatally (Lee, 2007). In this section, it will be discussed the crosstalk between mTOR and two major muscle atrophy-inducing signals such as myostatin and glucocorticoids.

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