## 6 Mechanosensing in Microgravity  
Despite the body of evidence regarding the negative effects of microgravity on muscle, bone, cardiac tissue, nervous system, and immunity, we still need to identify the molecular players and pathways responsible for mechanosensing in microgravity. Table 2 reports the most important proteins involved in mechanosensing process in simulated microgravity conditions.  
For example, the first system that sense the alteration of gravity, such as microgravity, is the vestibular system in which several changes occur in order to adapt to this new condition. The first mechanism actuated by these structures is to regulate the mass of otoconia and the innervation of sensory epithelium in order to resist to microgravity. This situation is very important for the development of axons and for the projection of the gravity sensors to the brain and spinal cord in which this mechanical signal is interpreted and analysed [112]. The principal aim of this system is to adapt itself to the microgravity conditions in order to establish a new homeostasis and a new balance.  
As mentioned above, bone density is also modified by microgravity. Under microgravity conditions, mesenchymal (MSC) cells, which can differentiate in several tissues, such as bone, cartilage, fat, etc., have the trend to differentiate in adipose tissue with the expression of several genes like glut4, adipsin etc. These conditions alter the development of canaliculi that in this way cannot sense the mechanical force that characterizes life on Earth suffering for the free fall in which the body is exposed.  
Microgravity also causes several changes in the lungs. Parathyroid hormone-related protein (PTHrP) is essential for the correct development of the lungs [80] and bone tissue [113]. In the lungs, this mechanosensor stimulates the correct alveolar development. In simulated microgravity conditions, the PTHrP signalling pathway is repressed and the concentration of mechanosensor results is very low [33; 114]. Furthermore, under microgravity, important cytoskeletal changes occur, involving Rho GTPases. In normogravity, cells show a physiological distribution in cytoskeletal components, while in microgravity, microtubules organization is altered with a perinuclear distribution and an altered radial pattern, which is responsible for an incorrect segregation of chromosomes during mitosis. Microgravity also causes a different polymerization and distribution of actin stress fibres and a different pattern of distribution of intermediate filaments. These effects are attributable to a decrease of Rho activity. Several studies conducted by [PERSON] et al. demonstrated that RhoA is strictly connected with the formation of FAs, stress fibres, and with intracellular tension Rac1, another member of the Ras superfamily of small GTP-binding proteins that control actin polymer formation [115]. Moreover, FAs also serve as mechanosensors in arterial remodelling in a rat model subjected to a 4-week hindlimb unweighted (HU) [116].  
Nevertheless, cells in microgravity conditions tend to adapt in order to revert this condition and to restore the physiological characteristics that occur in normogravity [117]. Microgravity also causes a transition in myosin heavy chain (MHC) isoforms, with a decrease in the expression of slow type I MHC and an increased expression of fast type IIx MHCin rodents and in humans [13].  
As mentioned above, less is known about the connection between mechanosensing and microgravity, but [PERSON] et al. demonstrated an upregulation of Kruppel-like factor-4 KLF4 in mammary tissue [118]. This factor is strictly connected with the reprogramming of somatic cells into pluripotent stem cells thanks to the downregulation of DNA methylation. Forkhead box (FOX) proteins are also dysregulated during microgravity with various consequences on proliferation, differentiation, and longevity [119].