MMPs can cause myocardial interstitial fibrosis and loss of contractile function by degrading matrix components and increasing abnormal collagen synthesis (Cabral-Pacheco et al. 2020). Therefore, mTORC1 may become an important regulator and potential new target of androgen hormone metabolism signal/cardiac hypertrophy. Partial inactivation of mTOR caused by genes or drugs can inhibit pathological hypertrophy of the myocardium maintaining the heart’s adaptability to stress overload (Oeing et al. 2020). Treatment with bicalutamide decreased the phosphorylation of all three mTOR substrates, although with some minor differences (Figure 1B). Since PSA is a known target gene of AR, the results suggest that AR activity is depressed by bicalutamide in this experimental condition. Bicalutamide slightly decreased the protein level of AR, but completely blocked PSA production at both doses and time points (Figure 1A). Bicalutamide is a non-steroidal anti-androgen which competitively blocks the binding of testosterone or dihydrotestosterone to AR (10). The data were expressed as induction of cell death, i.e. the net increase due to treatment. The cell death reading (measured in O.D. units) was then normalized against the MTT reading. More importantly, our results suggested that rapamycin alleviated the dysregulation of MMP-9/TIMP-1 balance while improving Testosterone-induced OVX SHR cardiac hypertrophy. In the present study, the high expression of MMP-9 and the low expression of TIMP-1 displayed imbalance in the Testosterone-induced cardiac hypertrophy of OVX SHR. The specific knockout of rheb1 gene in mice under pressure overload can inhibit the expression of mTORC1 and reduce the occurrence of myocardial hypertrophy and myocardial fibrosis (Wu et al. 2013). Testosterone-induced ovariectomy SHR cardiac hypertrophy may be related to the expression of mTORC1/S6K1/4EBP1/eIF4E. Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Effect of glucose deprivation on induction of cell death in high testosterone- or… Effect of concomitant glucose deprivation and bicalutamide treatment on cell growth and cell… AR signaling and expression of mTOR regulators. AR signaling and expression of… The research team identified the next priority as determining whether the same abnormal nerve cell overactivity occurs in human SBMA patients. Additionally, genes responsible for activating nerve cells, especially glutamate receptors, were abnormally overactive in SBMA mice in the first week of life and caused motor neurons to become overactive. In this context, future studies of mTOR signaling as a possible therapeutic target using non-coding RNAs are warranted. Hence, the hypertrophic response by mTOR activation is important for overall muscle maintenance in aged muscle. Related to this, reduced mTOR signaling has been shown to regulate longevity in human and model organisms (Powers et al., 2006; Bjedov et al., 2010; Robida-Stubbs et al., 2012; Passtoors et al., 2013) and reduce age-related pathologies (Johnson et al., 2013a). Sarcopenia has been defined as an age-related continuous decline in muscle mass, quality, and strength (Sakuma et al., 2014). In addition, follistatin, an inhibitor of myostatin, activates Akt/mTOR/p70S6K1/S6 signaling in muscle growth, which exists independently of myostatin-driven mechanisms (Winbanks et al., 2012), supporting the disconnection between myostatin and mTOR signaling. However, on the other hand, several studies suggested that mTOR signaling and myostatin signaling could separately regulate muscle growth. Hence, the studies suggested that myostatin attenuates protein synthesis in muscle by coordinating the crosstalk between myostatin-mediated and mTOR signaling. The knockdown of rictor itself inhibits muscle cell differentiation, and does not affect myostatin-induced pSmad2 and muscle differentiation. The depletion of raptor increases myostatin-induced Smad2 phosphorylation, followed by further inhibition of myostatin-induced muscle differentiation. Supporting the negative regulation of myostatin in mTORC1 signaling, genetic deletion of myostatin elevates the activities and the expression levels of Akt, p70S6K1, and S6 (Lipina et al., 2010). The deletion of myostatin in mice results in muscle hyperplasia and hypertrophy, and more than doubles skeletal muscle (McPherron et al., 1997). In conclusion, this study demonstrates that the regulation of mTOR/S6K1/4E-BP1 signaling pathway may be one of the important mechanisms for the occurrence of myocardial hypertrophy in testosterone-induced OVX SHR. Secondly, it was confirmed that mTORC1/S6K1/4E-BP1 signaling pathway is an important pathway for testosterone-induced myocardial hypertrophy in postmenopausal hypertensive female rats. On the other hand, changes in the expression levels of the S6K1 and 4E-BP1 protein confirmed that rapamycin did block mTOR signaling transduction in the heart tissue. In addition, we found that rapamycin, an mTORC1 inhibitor, can delay the occurrence of myocardial hypertrophy in testosterone-induced SHR after ovariectomy on the basis of antihypertensive therapy. A major finding in our study is that testosterone-mediated changes in the expression level of myocardial mTOR/S6K1/4EBP1/eIF4E signaling pathway play a critical role in the pathogenesis and development of cardiac hypertrophy in SHR after ovariectomy. (A) mTOR inhibitor rapamycin abolished the effects of testosterone-induced OVX SHR myocardial hypertrophy.
