## 7 New Candidate Gravireceptors and Future Perspectives
For example, MLP proteins are strictly connected with the actin cytoskeleton during response to mechanical stimuli together with other important proteins, such as zyxin and paxillin, involved in focal adhesion plaques and stress fibres formation [84]. Under mechanical stimuli, including microgravity, MLP can translocate to the nucleus and bind GATA4, GATA6, AP1, and the serum response factor (SRF) [133]. In long-term microgravity conditions, muscle mass is decreased and the structures of culture myotubes disrupted, an event that, we speculate, would force nuclear localization of MLP. Once in the nucleus, MLP could, however, maintain the vitality of the cells and prepare them for the return to normogravity conditions. On the other hand, sitruins, activated by different compounds like resveratrol, honokiol, physical exercise and calorie restriction, are important for the longevity of cells and for the correct development of several structures from microscopic to macroscopic point of view. Their localization varies from cytoplasm (SIRT1,2), mitochondria (SIRT3,4,5), nucleus (SIRT1,6) to nucleolus (SIRT7). Sirutuins have many targets of interaction, in fact, they share a Sir2 catalytic core domain, but possess different sequences at the amino and carboxyl terminus responsible for different localizations and functions [134; 135]. Sirutuins are also classified for their different activities, such as deacylase at lysine residues and/or mono-ADP-ribosyltransferase on different targets [136; 137]. Mammalian sitruins represent an important bridge between metabolism and epigenetic regulation. For their activity as NAD+-dependent enzymes, sitruins are cellular metabolic sensors, while their deacylase activity represent an efficient way to modulate the epigenetic status of the genome adapting the organism to the environmental changes [138]. Furthermore, sitruins present both short-term effects, such as an increase in mitochondogenesis, O\({}_{2}\) consumption, and an increased metabolism in order to maximize the performance, as well as long-term effects tightly connected with increased lifespan, slowing aging, and inflammation control [139]. An interesting point that would deserve a review per se, is the connection between sitruins, metabolism, and inflammation. In fact, glucose and fatty acid metabolism provides energy to the immune cells for sensing and responding to endogenous and exogenous pathogens [140; 141]. Sirutuins can regulate the inflammatory response in, at least, two ways: 1) by regulating metabolism using NAD+ as a co-factor and 2) by post translational modification of inflammatory-regulating transcription factors such as NF-kB, STAT3, HIF-1\(\alpha\). However, it must be kept in mind that, in the case of inflammation, the role of sitruins is very subtle and not always clear. This is probably due to the plethora of sitruins' targets that complicate the predictivity of the final outcome [142]. Nonetheless, considering that inflammation is activated in microgravity, with an increased production of cytokines such as interferon \(\gamma\) (INF-\(\gamma\)and Interleukin 17 (IL-17) [143], a deeper understanding of how sirtuins regulate inflammation may be worth pursuing. In fact, sirtuins' modulation could be used to decrease inflammation and re-tune the immune response in microgravity or during long-term space travel. Sirtuins, as mentioned above, develop their action in different cell compartments and their expression may change in microgravity or normogravity conditions. Considering the large number of sirtuin targets and the mutations on two lysines residues of MLP in cardiac muscle diseases reported above [130], we can speculate the presence of a pathway of interaction between sirtuins and MLP mechanosensors. Figure 2 depicts the hypothesis in which MLP and Sirtuins may represent two interacting factors for the long-term response and adaptation to microgravity.