## 7 New Candidate Gravireceptors and Future Perspectives  
A series of experiments have been developed in order to establish the presence and the role of gravity-specific mechanosensors. Some of them were conducted on the International Space Station (ISS), while the majority have been performed by simulating microgravity using machineries such as RPM (Random Positioning Machine) or RCCS (Rotary Cell Culture System). Therefore, RPM or RCCS represent the major source of information about the biological effects of microgravity. Here, we propose exploring two novel possible candidate protein families for gravity sensing and for microgravity adaptation, the LIM protein family (especially MLP) for their important role in mechanosensing in muscle, and SIRTUINS for their important role as protein and histones deacylases, for their ability to control cellular adaptation to external stresses and for their role upon physical activity. Muscle LIM protein (MLP) belongs to a family of cysteine-rich proteins first observed in cardiac and skeletal muscle [125]. The LIM domain is a cysteine-histidine-rich, zinc-coordinating domain, \begin{table}
\begin{tabular}{c c c c c} \hline \hline  & \multicolumn{4}{c}{**MICROGRAVITY**} \\ \hline
**PROTEIN** & **TISSUE** & **SM/ISS** & **Cytosol/Nucleus Shuttling** & **References** \\ \hline FOX proteins & Several Tissues & SM/RCCS & No Data Available & [119] \\ \hline \multirow{2}{*}{KLF4} & Several Tissues & \multirow{2}{*}{SM/RCCS} & \multirow{2}{*}{No Data Available} & [118] \\  & (Pluripotent Stem Cells) & & & \\ \hline MHC & Muscle & SM & No Data Available & [13] \\ \hline PTHrP & Lung and Bone & SM/ISS & No Data Available & [33; 80; 113] \\ \hline \multirow{2}{*}{TRPC6} & Several Tissues & \multirow{2}{*}{SM/RFM} & \multirow{2}{*}{No Data Available} & [120] \\  & (Intervertebral Discs) & & & \\ \hline YAP/TAZ & Several cells & SM/ISS & YES & [121; 122; 123] \\ \hline \hline \end{tabular}
\end{table} 
Table 2: List of Mechanosensors in Microgravity conditions and cytosol/nucleus shuttling. SM, Simulated Microgravity. ISS, International Space Station. RPM, Random Positioning Machine. RCCS, Rotary Cell Culture System. consisting of two zinc fingers [126; 127] and conferring specific protein-protein interaction. In particular, MLP cooperates with several proteins, such as titin and telethonin, in order to form anchorage blocks and to maintain the structure of the muscle fibres. MLP is tightly bound to the Z-disk, especially at the periphery where it seals with sarcolemma, cooperating in maintaining the structure and the correct function of contractile apparatus [128; 129]. Interestingly, about 10 missense mutations have been reported for MLP. These mutations fall within the first 100 aminoacids and include the first LIM domain and the nuclear localization signal (NLS) [130]. Moreover, two mutations involve two lysines (K) at position 42 and 69. Several MLP mutations have been associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Lysine 69 is localized in the NLS and the mutation K69R prevents MLP from entering the nucleus [63]. Interestingly, K69 is predicted to be acetylated, therefore, some of the alterations observed in DCM and HCM patients could be due to an aberrant acetylation in the K69R mutant. Another important aspect is that MLP is strictly connected with autophagy, especially in skeletal muscle [131]. Autophagy is an important process that causes the degradation of damaged organelles and proteins in order to promote cellular survival. Unfolded or damaged proteins and damaged organelles are collected in vesicles composed by a double membranous layer, called autophagosomes, which, after fusing with lysosomes, are degraded into their principal units [132]. Less is known about the involvement of these factors in microgravity conditions, but several pieces of evidence led us to speculate a role of these proteins in weightlessness conditions.