Abstract
Reducing the musculoskeletal deterioration that astronauts experience in microgravity requires countermeasures that can improve the effectiveness of otherwise rigorous and time-expensive exercise regimens in space. The ability of low-intensity vibrations (LIV) to activate force-responsive signaling pathways in cells suggests LIV as a potential countermeasure to improve cell responsiveness to subsequent mechanical challenge. Mechanoresponse of mesenchymal stem cells (MSC), which maintain bone-making osteoblasts, is in part controlled by the “mechanotransducer” protein YAP (Yes-associated protein), which is shuttled into the nucleus in response to cyto-mechanical forces. Here, using YAP nuclear shuttling as a measurement outcome, we tested the effect of 72 h of clinostat-induced simulated microgravity (SMG) and daily LIV application (LIVDT) on the YAP nuclear entry driven by either acute LIV (LIVAT) or Lysophosphohaditic acid (LPA), applied after the 72 h period. We hypothesized that SMG-induced impairment of acute YAP nuclear entry would be alleviated by the daily application of LIVDT. Results showed that while both acute LIVAT and LPA treatments increased nuclear YAP entry by 50 and 87% over the basal levels in SMG-treated MSCs, nuclear YAP levels of all SMG groups were significantly lower than non-SMG controls. LIVDT, applied in parallel to SMG, restored the SMG-driven decrease in basal nuclear YAP to control levels as well as increased the LPA-induced but not LIVAT-induced YAP nuclear entry over SMG only, counterparts. These cell-level observations suggest that daily LIV treatments are a feasible countermeasure for restoring basal nuclear YAP levels and increasing the YAP nuclear shuttling in MSCs under SMG.
Highlights
The musculoskeletal deterioration that astronauts experience on long-term space missions and the resulting increase of traumatic physical injury risk is in part due to the reduction of mechanical loading on the musculoskeleton[1]
We hypothesized that simulated microgravity (SMG)-induced impairment of basal nuclear Yes-associated protein (YAP) levels as well as YAP nuclear entry in response to LIVAT and Lysophosphohaditic acid (LPA) would be alleviated by the daily application of LIVDT
After establishing that LPA induces YAP nuclear entry in mesenchymal stem cell (MSC), we evaluated whether SMG decreases LPA-induced YAP nuclear shuttling and whether LIVDT application alleviates this
Summary
The musculoskeletal deterioration that astronauts experience on long-term space missions and the resulting increase of traumatic physical injury risk is in part due to the reduction of mechanical loading on the musculoskeleton[1]. We hypothesized that SMG-induced impairment of basal nuclear YAP levels as well as YAP nuclear entry in response to LIVAT and LPA would be alleviated by the daily application of LIVDT. While SMG was reported to decrease nuclear TAZ levels[52], the role of SMG on in LIVAT samples compared to controls (Supplementary Fig. 1) As both LIV-induced focal adhesion signaling, initiated by focal adhesion kinase (FAK) phosphorylation at Tyr 397 residue[29], and YAP nuclear entry in response to substrate strain[41] requires intact. Analysis of the cross-sectional area of cell nuclei using DAPI stained images revealed no significant effect on average nuclear size by either SMG or combined SMG + LIVDT treatment compared to control levels
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