Gene-Metabolite Network Linked to Inhibited Bioenergetics in Association With Spaceflight-Induced Loss of Male Mouse Quadriceps Muscle
Abstract
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 the National Aeronautics and Space Administration (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 4 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 adenosine triphosphate (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. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 08, 2020
- Source ID
- 10.1002/jbmr.4102
Entities
People
- Aarti Gautam
- Allison Hoke
- Bintu Sowe
- Candace Moyler
- Dana Youssef
- David L Waning
- George Dimitrov
- Melissa A. Kacena
- Michael Savaglio
- Nabarun Chakraborty
- Paul J. Childress
- Raina Kumar
- Rasha Hammamieh
- Stephan Butler
Organizations
- Geneva Foundation
- Indiana University
- National Institutes of Health
- Oak Ridge Institute for Science and Education
- Orthopaedic Trauma Association
- Penn State College of Medicine
- Ralph W. and Grace M. Showalter Research Trust Fund
- Richard L. Roudebush VA Medical Center
- Tufts University School of Medicine
- United States Army
- United States Army Medical Research and Development Command
- United States Department of Defense
- Walter Reed Army Institute of Research