## 1 Microgravity Effects in Different Tissues
Structural muscle damages underlying the above condition and associated with microgravity are characterized by less dense Z and C bands (loss of proteins for the anchorage of actin and myosin filaments, respectively), myofibril and actin/myosin filaments decrease with Sarcomere disorganization, sarcoplasmic reticulum and sarclemma disorganization, and several lesions of endomysium [12]. Usually, these pathological conditions are reversible upon return in normogravity conditions. Although 15% of the skeletal/cardiac muscle mass is lost during prolonged spaceflight, the contractile mass is recovered after a variable period of returning to normogravity conditions [15]. Nevertheless, unloading causes severe conditions, such as microcirculatory changes and interstitial oedema [11] with a consequent decrease in force, mass, and power in muscle contraction [16; 17; 18]. In humans, the most important muscles involved in microgravity-associated changes are the gastrocnemius, knee extensor, soleus, and tibialis; muscles that are in contact with the ground and suffer the effects of the free fall in microgravity conditions [19]. It is worth noting that bone tissue is also affected by microgravity. Bone tissue is characterized, on average, by a 1%-2% mass loss for every month spent in weightlessness with a substantial decrease in mineral density (osteoporosis). These changes appear to be site-specific because they are especially evident in the weight-bearing bones [20]. This clinically relevant situation reflects microscopic/molecular changes with a decrease in the master genes of bone differentiation, such as RUNX2, and an increase in adipose tissue markers, such as PPAR, leptin, adipsin, and Glut4. These molecular changes are responsible for the increase in bone fragility and the decrease in bone elasticity, as demonstrated by computed tomography (QCT), speed of sound relevation (SOS), and broadband ultrasound attenuation (BUA). [PERSON] et al. measured the levels of the factors that are involved with bone formation (osteocalcin, alkaline phosphatases, precollagen type I) and the markers of bone resorption like galactosyl hydroxylysine, pyridinoline, and deoxypyridinoline [21], reporting an increase in the markers of bone resorption and a decrease in the markers involved in bone formation. Bone is composed mainly by osteocytes, the differentiated form of osteoblasts, by osteoclast and mesenchymal stem cells (MSCs). MSCs can differentiate in several tissue types, such as fat, muscle, bone, cartilage, and marrow stroma [22], according to the stiffness of their extracellular environment and on the basis of several molecules and stimuli that come from the organism [23]. Several studies have revealed that microgravity causes adipogenesis, while mechanical stimuli can cause bone formation [24]. [PERSON] et al. have demonstrated that osteocytes are involved in bone loss in microgravity conditions [25]. In fact, after a two-week flight, osteocytes apoptosis occurs with an increase in the activity of osteoclasts, responsible for bone resorption and with an increase in their activity in microgravity conditions [26; 27]. Nevertheless, bone tissue is also characterized by a recovery after spaceflight, although this process may be longer than the mission duration [28]. Furthermore, weight bearing bones like femurs are more affected by microgravity than less weight bearing bones, like vertebrae [29; 30], causing a different recovery strictly related to the bone type. After landing, in fact, many adaptations occur, like a normalized bone tissue resorption and an increased bone formation [28]. Several parameters of bone tissue are often compared in normogravity and microgravity conditions in order to obtain an overview of these different situations, such as the crystallinity index, mineral maturity, carbonation, and the mineralization index, but its results are very important to consider, especially the collagen quality because collagen represents the most important organic component of bone matrix.