Eloading [126]. A recent report recommended that each AKT-dependent and AKT-independent signaling pathways can contribute towards the activation of protein synthesis in rat soleus muscle through 3-day reloading following HU [127]. The use of an inhibitor of phosphotidylinositol-3-kinase (PI3K) for the duration of 3-day reloading resulted in attenuation of both AKT (Ser473) phosphorylation and protein synthesis, as well as the use of an inhibitor of PA production led to a important reduce in both p70S6K (Th389) phosphorylation along with the price of protein synthesis [127]. Therefore, each PI3K/AKT-dependent and AKT-independent (possibly PA-dependent) pathways may be involved in the protein synthesis activation in rat postural muscle in the early stage of recovery from disuse-induced atrophy. A doable role of AMPK, an endogenous mTORC1 inhibitor, in skeletal muscle mass recovery soon after a period of unloading was studied by Egawa et al. (2018) [128]. There was no distinction within the regrowth of soleus muscle mass between wild-type mice and skeletal-muscle-specific dominant-negative AMPK1 (AMPK-DN) mice right after 7 days of reloading; having said that, by the 14th day of recovery, muscle regrowth was considerably greater in AMPK-DN mice [128]. Pansters et al. (2015) elucidated a function of a different damaging Cyclin-Dependent Kinase 5 (CDK5) Proteins site regulator of protein synthesis, GSK-3, through reloading of mouse skeletal muscle [129]. Employing mice lacking muscle GSK-3 (GSK-3 KO), the TIMP Metallopeptidase Inhibitor 3 (TIMP-3) Proteins supplier authors tested a hypothesis that muscle mass recovery following mechanical unloading will be accelerated inside the absence of GSK-3 [129]. Reloading-associated alterations in muscle protein turnover were not affected by the absence of GSK-3; on the other hand, soleus muscle mass and fiber CSA regain in GSK-3 KO mice have been enhanced when compared with wild-type mice after 5-day reloading [129]. Employing constitutively active Ser21/9 GSK-3/ knock-in mice, the identical group of authors have not too long ago reported that phosphorylation of Ser-mediated GSK-3 inactivation is not essential for reloading-induced muscle mass recovery [113]. As a result, these findings suggest that even though GSK-3 activity can suppress soleus mass recovery after disuse atrophy, suppressive actions of GSK-3 usually do not seem to become regulated by Ser9 phosphorylation [113]. In the course of the initial days of reloading, an increase in circulating IGF-1 just isn’t observed [110], even so, as described above, the AKT/mTORC1 signaling pathway is activated and protein synthesis is enhanced. It may be related either with autocrine IGF-1 regulation or mechanosensitive PI3K/AKT-independent signaling mechanisms [130]. Given that mechanosensitive channels have been shown to become involved within the activation of mTORC1 signaling right after eccentric contractions [45] it may be assumed that mechanosensitiveInt. J. Mol. Sci. 2020, 21,11 ofion channels would play a crucial role in the activation of mTORC1 signaling and protein synthesis inside the acute period of reloading. Certainly, it has been not too long ago reported that functional stretched-activated channels are important for full activation of mTORC1 signaling and protein synthesis in rat soleus muscle through an acute reloading (12h) after HU [117]. There is certainly proof that transient receptor possible canonical (TRPC) ion channels are most likely molecular candidates for stretched-activated channels [131,132]. Having said that, it is a debatable point given that it was demonstrated that, beneath physiological conditions, TRPC1 channel might not exhibit mechanosensitive properties [132,133]. Nonetheless, Zhang et al. (2014) showed that TRPC1 protein expression.