Modulation of mTOR and autophagy in hibernating hamster lung and the application of the potential mechanism to improve the recellularization process of decellularized lung scaffolds

Abstract

During hibernation, hamsters cycle through periods of deep cooling (torpor) and re-warming (arousal). Reversible lung remodeling was previously observed through hibernation, where smooth muscle actin (SMA) expression was increased during torpor and normalized at arousal, sustaining lung structure throughout torpor. In the present research, the activation of mTOR (mammalian target of rapamycin) which is known to have an important role in remodeling and SMA protein expression was studied in hamster lung. Further, lung serotonin level known to modulate mTOR pathway was investigated. To determine if an increase of serotonin in lung tissue could be affecting SMA expression, cell number and cell matrix adhesion molecules, the effect of serotonin on Human Bronchial Smooth Muscle Cells (HBSMC) was investigated. Further, the potential application of serotonin in recellularization of decellularized rat lungs was studied in vitro. In hibernating hamster, mTOR, p-Akt and p-S6 levels decreased during torpor phase but were all upregulated during early arousal. Autophagy increased during torpor and reached maximum value during arousal. Serotonin treatment of HBSMC increased cell number and protein synthesis including SMA expression. It activated mTOR while increasing the expression of adhesion molecules, integrin α1, β1 and β-sarcoglycan in cells. Further, serotonin increased cell attachment to decellularized lung matrix, supporting ECM structure. Aberrations in proteostasis have negative effects on cellular growth and metabolism. This research provides new information on regulation of proteostasis in hibernating hamster lung with potential implications on regenerative medicine. It accordingly, further introduces a new approach to more efficient recellularization of lung scaffolds ex vivo.

Molecular Basis of White Adipose Tissue Remodeling That Precedes and Coincides With Hibernation in the Syrian Hamster, a Food-Storing Hibernator

“…Amino acids such as leucine can activate mTORC1 in an insulin-independent manner (Roh et al, 2003); leucine directly binds sestrin2 and suppresses its inhibitory effect on mTORC1 (Wolfson et al, 2016). Alternatively, serotonin may activate mTORC1 and PPARs in peripheral tissues of Syrian hamster during hibernation (Talaei et al, 2011; Talaei, 2014), because serotonin is reported to be an endogenous ligand for PPAR-γ (Waku et al, 2010) and the activation of serotonin receptor promotes lipogenesis in WAT of mice (Oh et al, 2015). Moreover, previous studies suggest that melatonin transduces photoperiodic stimulation to a neuroendocrine signal and could therefore control sexual activity, body mass, and hibernation in Syrian hamsters (Bartness and Wade, 1984; Vanecek et al, 1984; Pitrosky et al, 2003), which might be an upstream machinery of iWAT remodeling during the pre-HIB.…”

In Vivo Autophagy Up-Regulation of Small Intestine Enterocytes in Chinese Soft-Shelled Turtles during Hibernation

“…Hibernation is a way that some animals, including Chinese soft-shelled turtles, cope with unfavorable ecological conditions by dramatically reducing their body activity [4,5], metabolic rate [6], and physiological parameters such as body temperature and heart and respiratory rate compared to nonhibernation [7,8]. Hibernation is an energy-limiting period [6], as during this period the animals are sedentary, and the demand for oxygen is reduced severely, thus eliminating the need for food during cold seasons [2,9]; although, animals face different kinds of challenges in these critical situations. However, animal bodies have developed different physiological defense mechanisms against any stressor that could enter into the animals along with nutrients in the digestive system [10].…”

Body Protein Sparing in Hibernators: A Source for Biomedical Innovation

“…These findings suggest that the resistance to atrophy in small deep hibernators might be attained primarily by relatively constant or decreased proteolysis (see below) in combination with oscillatory anabolic activity (e.g., p -mTOR) during arousals. This response is not restricted to skeletal muscle, as both cardiac (Wu and Storey, 2012 ) and smooth muscle (Talaei, 2014 ) also show increases in mTOR activity upon arousal from torpor. Muscle preservation during torpor in thirteen-lined ground squirrels may also involve an increase in the percentage of satellite cells favoring growth processes (Brooks et al, 2015 ).…”