Glycogen Synthase Kinase 3 activation status in soleus and EDL muscles from space‐flown mice aboard the BION‐M1 biosatellite

Background A significant limitation to long‐term spaceflight and space habitation is the deterioration of human musculoskeletal health. It is well known that prolonged exposure to microgravity leads to pronounced muscle and bone loss, with consequences mimicking several major effects observed in human aging (i.e. osteoporosis and sarcopenia). It is therefore critical to elucidate the underlying molecular mechanisms of these processes to develop meaningful intervention strategies. Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase initially defined in its role of regulating glycogen homeostasis, though it's now known to interact with more than 100 target proteins. GSK3 has notably proven to negatively regulate muscle mass by inhibiting hypertrophy‐related mechanisms, myoblast fusion, and muscle regeneration, while also promoting ubiquitin‐mediated protein degradation and muscle inflammation. In this study, we explored GSK3 expression and its serine phosphorylation status, known to control its activation/inactivation, in soleus and extensor digitorum longus (EDL) muscles obtained from the BION‐M1 mission. Methods Male C57BL6/J mice (3 months old) were flown in space for 1 month aboard the BION‐M1 biosatellite (F) and were compared to a ground control (GC, space housing and diet conditions) and a flight control (FC, standard housing conditions) group. Soleus and EDL muscles were extracted and homogenized in protein extraction buffer. Western blotting was used to examine total and phosphorylated (i.e. inactivated) forms of GSK3 (ser21 GSK3α; ser9 GSK3β). Results In the soleus muscle, total GSK3α and GSK3β were reduced in the F group. Though we did not observe any changes in ser21 (GSK3α) or ser9 (GSK3β) phosphorylation, the ratio of phosphorylated:total GSK3β was significantly elevated in the F group compared with GC and FC. We did not observe any differences in soleus phosphorylated:total GSK3α. Further, we did not observe any differences in total, phosphorylated or phosphorylated:total GSK3α/β content in the EDL F group compared to GC and FC. Conclusions Altogether, our data suggest that in response to 1 month of spaceflight, GSK3 is less active in the soleus muscle through changes in expression and phosphorylation. GSK3 may therefore not be involved in the later stages of soleus atrophy in flown mice. This may be explained by a slow‐to‐fast fibre shift in soleus muscle, as GSK3 presence and activity is typically reduced in fast‐twitch muscle fibres compared to slow‐twitch. Future studies with soleus muscles from two other NASA‐flown missions (RR1 and RR9) will be conducted to confirm these effects.

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