## 7 New Candidate Gravireceptors and Future Perspectives
Following this model, in normogravity conditions, muscle cell homeostasis is maintained by MLP, that can sense the mechanical cues, including gravity, and by sirtuins that amplify these signals into biological adaptation. In normogravity conditions (Figure 2A) in skeletal and cardiac muscle, there might be an interplay between MPL and sirtuins, as is suggested by mlp-KO or mlp-overexpressing transgenic mice [144]. MLP resides in the sarcomere and has a cytoplasmatic localization ensuring the correct maintenance of the tissue. MLP can sense mechanical stimuli at the level of Z-disc, while sirtuins cooperate by  
Figure 2: Schematic representation of the possible interaction in post-mitotic cells between the mechanosensor muscle LIM protein (MLP) and sirtuins in normogravity (**A**) and microgravity (**B**) condition. (**A**): Gravity is sensed by MLP that, in muscle cells, resides and contributes to Z-disc maintenance. MLP function is influenced by its interaction with sirtuins that, in turn, controls MLP acylation status. On the other hand, sirtuins integrate other external signals, such as nutrients availability and Reactive Oxygen Species (ROS) levels, to MLP function. Overall, such continuous interaction contributes to the physiology of post mitotic tissues, such as skeletal and cardiac muscle. (**B**): Reduction or absence of gravity (microgravity) alters Z-disc architecture and MLP localization. MLP may migrate from cytosol to the nucleus. The cytosolic interaction between MLP and sirtuins is lost or reduced. However, in surviving myocytes, nuclear MLP can still interact with nuclear sirtuins forming a complex that can, together with other transcription factors, maintain myocytes vitality while in microgravity and re-activate differentiation once gravity is restored. sensing metabolic changes, such as ROS level, nutritional changes, or stresses, ions, etc., integrating the adaptive response with mechanical signalling. Additionally, cytosolic sirtiuins can perform post-translational modifications (deacylation and/or ADP-ribosylation) on MLP in order to adapt its function and intracellular localization, including the translocation to the nucleus for a muscle-specific gene expression. Under microgravity conditions (Figure 2B), MLP detaches from the Z-disk and migrates to the nucleus with opposite effects. In the cytosol, the architecture of the Z-disk is weakened and the interactions with the cytosolic sirtiuins is lost; however, once in the nucleus, MLP can interact with nuclear sirtiuins, thereby acquiring new properties as part of transcription complexes for muscle-specific gene and thus contributing to maintain muscle cell integrity. To this effect, once normogravity is restored, nuclear MLP can be used by the muscle cell to increase Myoblast determination protein (MyoD) and myogenin expression to activate myocyte differentiation to then translocate back to the cytosol to the Z-disk of the forming sarcomere. This hypothesis accommodates a number of new experimental data and suggests an important role for sirtiuins. It is known that sirtiuins can be activated by caloric restriction or by natural or synthetic activators, such as SRT1720, resveratrol, honokiol, etc., and in this way they can protect cells, ensuring their vitality and homeostasis through their short- and long-terms effects (Figure 2B). This aspect could be instrumental in protecting skeletal/cardiac muscle cell structure and function by using one or several sittuin activators during persistent microgravity conditions. Analogously, sirtiuins' activators might be used in normogravity to accelerate muscle repair in various human pathological conditions, such as myocardium in dilated cardiomyopathy with myofibrilolysis [145] and skeletal muscle in cachexia. In conclusion, it would be interesting to investigate if sirtiuins can deacetylate MLP on lysine 42 and/or 69 in its cytoplasmic or nuclear localization in order to obtain more information on the possible interplay between these two classes of molecules.