Spaceflight increases sarcoplasmic reticulum Ca2+ leak and this cannot be counteracted with BuOE treatment

Abstract

Spending time in a microgravity environment is known to cause significant skeletal muscle atrophy and weakness via muscle unloading, which can be partly attributed to Ca2+ dysregulation. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump is responsible for bringing Ca2+ from the cytosol into its storage site, the sarcoplasmic reticulum (SR), at the expense of ATP. We have recently demonstrated that, in the soleus of space-flown mice, the Ca2+ uptake ability of the SERCA pump is severely impaired and this may be attributed to increases in reactive oxygen/nitrogen species (RONS), to which SERCA is highly susceptible. The purpose of this study was therefore to investigate whether treatment with the antioxidant, Manganese(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+ (BuOE), could attenuate muscle atrophy and SERCA dysfunction. We received soleus muscles from the rodent research 18 mission which had male mice housed on the international space station for 35 days and treated with either saline or BuOE. Spaceflight significantly reduced the soleus:body mass ratio and significantly increased SERCA’s ionophore ratio, a measure of SR Ca2+ leak, and 4-HNE content (marker of RONS), none of which could be rescued by BuOE treatment. In conclusion, we find that spaceflight induces significant soleus muscle atrophy and SR Ca2+ leak that cannot be counteracted with BuOE treatment. Future work should investigate alternative therapeutics that are specifically aimed at increasing SERCA activation or reducing Ca2+ leak.