Gene-metabolite network linked to inhibited bioenergetics in association with spaceflight-induced loss of male mouse quadriceps muscle.

Prolonged residence of mice in spaceflight is a scientifically robust and ethically ratified model of muscle atrophy caused by continued unloading. Under the Rodent Research Program of NASA, we assayed the large scale mRNA and metabolomic perturbations in the quadriceps of C57BL/6j male mice that lived in spaceflight (FLT) or on the Ground (Control or CTR) for approximately four weeks. The wet weights of the quadriceps were significantly reduced in FLT mice. Next generation sequencing and untargeted mass spectroscopic assays interrogated the gene-metabolite landscape of the quadriceps. A majority of top ranked differentially suppressed genes in FLT encoded proteins from the myosin or troponin families, suggesting sarcomere alterations in space. Significantly enriched gene-metabolite networks were found linked to sarcomeric integrity, immune fitness, and oxidative stress response; all inhibited in space as per in silico prediction. A significant loss of mitochondrial DNA copy numbers in FLT mice underlined the energy deprivation associated with spaceflight induced stress. This hypothesis was reinforced by the transcriptomic sequencing-metabolomics integrative analysis that showed inhibited networks related to protein, lipid and carbohydrate metabolism, and ATP synthesis and hydrolysis. Finally, we discovered important upstream regulators, which could be targeted for next generation therapeutic intervention for chronic disuse of the musculoskeletal system. This article is protected by copyright. All rights reserved.