Protein synthesis, as for other anabolic processes, is controlled and coordinated by the mTOR (mammalian Target Of Rapamycin) complex via a complex versatile and interconnected signal pathway network [27,28]. Briefly, two requirements are essential for mTOR activation; the first one concerns growth signals due to the binding of growth factors (mainly IGF-1, Insulin, but also GH) to its corresponding membrane receptor, and the second involves nutrients availability. Growth factors activate the PI3K/Akt signal pathway [29], one of the requirements for mTOR activation. In turn, this signal produces a translocation of GluT4 transporters to the membrane, increasing the transport of glucose inside the cell. With regard to amino acids, there are several transport mechanisms for the different families (not shown in Figure 2 for clarity). Although a well-balanced and proportional intracellular mixture is essential for protein synthesis, leucine is particularly important. Leucine acts as a trigger-sensor for the activation of the mTOR pathway because of its high affinity towards Sestrin2 [30]. Sestrins are stress-inducible metabolic proteins that protect organisms against various noxious stimuli, including DNA damage, oxidative stress, starvation, endoplasmic reticulum stress, and hypoxia. Furthermore, Sestrin-2 regulates the metabolism mainly by the activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of the mammalian target of rapamycin complex 1 (mTORC1) [12]. Thus, Sestrin2 is usually linked to another protein, GATOR2, as a Sestrin2-GATOR2 complex that remains inactive the mTOR. The formation of the Leu–Sestrin2 complex promotes the release and subsequent conversion of GATOR2 to GATOR1, as an active effector of the mTOR pathway [31,32]. This displacement of the Sestrin2-GATOR2 so as to release GATOR1, and some other factors, allows for the translocation of mTOR to the periphery of the lysosomal membrane, and the full activation of the phosphorylation of key proteins for anabolic processes (mostly SREBP for lipid synthesis [33] and S6K1 plus 4E-BP1 for protein synthesis [34]).

Proteolysis of the myocyte proteins is stimulated by some transcription factors (FoxO and NFκB) related to oxidative stress, a usual condition in CKD as previously discussed (Figure 1). Extracellular and intracellular ROS generated by NOX membrane reactions or mitochondrial respiration induce: (i) the expression of atrogenic genes, mostly atrogin-1 and MuRF1 [35]. They act as ubiquitin ligases and increase the protein degradation rate via the ubiquitin-proteasome system [36,37], including (ii) the formation of Sestrin2, which is a member of the family of defense-proteins that protect cells against the ROS damage that is able to bind to GATOR2 and block protein synthesis by maintaining mTOR as an inactive form. In that way, oxidative stress accelerates protein degradation and inhibits protein synthesis, so that the equilibrium between both processes is broken, and the muscular proteostasis is lost. From an overall point of view, oxidative stress induces Sestrin2 expression, and this led to the necessity of higher levels of Leu for GATOR1 release and mTOR activation. In turn, Leu availability to the myocyte is diminished due to the partial loss of vascularization described in Section 2. Altogether, the anabolic threshold in the CKD patient is higher than in healthy people, as the higher levels of Sestrin2 plus the lower supply of Leu through the blood cannot trigger the same degree of mTOR activation.