Space Omics and Tissue Response in Astronaut Skeletal Muscle after Short and Long Duration Missions

Abstract

The molecular mechanisms of skeletal muscle adaptation to spaceflight are as yet not fully investigated and well understood. The MUSCLE BIOPSY study analyzed pre and postflight deep calf muscle biopsies (m. soleus) obtained from five male International Space Station (ISS) astronauts. Moderate rates of myofiber atrophy were found in long-duration mission (LDM) astronauts (~180 days in space) performing routine inflight exercise as countermeasure (CM) compared to a short-duration mission (SDM) astronaut (11 days in space, little or no inflight CM) for reference control. Conventional H&E scout histology showed enlarged intramuscular connective tissue gaps between myofiber groups in LDM post vs. preflight. Immunoexpression signals of extracellular matrix (ECM) molecules, collagen 4 and 6, COL4 and 6, and perlecan were reduced while matrix-metalloproteinase, MMP2, biomarker remained unchanged in LDM post vs. preflight suggesting connective tissue remodeling. Large scale proteomics (space omics) identified two canonical protein pathways associated to muscle weakness (necroptosis, GP6 signaling/COL6) in SDM and four key pathways (Fatty acid β-oxidation, integrin-linked kinase ILK, Rho A GTPase RHO, dilated cardiomyopathy signaling) explicitly in LDM. The levels of structural ECM organization proteins COL6A1/A3, fibrillin 1, FBN1, and lumican, LUM, increased in postflight SDM vs. LDM. Proteins from tricarboxylic acid, TCA cycle, mitochondrial respiratory chain, and lipid metabolism mostly recovered in LDM vs. SDM. High levels of calcium signaling proteins, ryanodine receptor 1, RyR1, calsequestrin 1/2, CASQ1/2, annexin A2, ANXA2, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) pump, ATP2A, were signatures of SDM, and decreased levels of oxidative stress peroxiredoxin 1, PRDX1, thioredoxin-dependent peroxide reductase, PRDX3, or superoxide dismutase [Mn] 2, SOD2, signatures of LDM postflight. Results help to better understand the spatiotemporal molecular adaptation of skeletal muscle and provide a large scale database of skeletal muscle from human spaceflight for the better design of effective CM protocols in future human deep space exploration.

Skeletal muscle gene expression dysregulation in long-term spaceflights and aging is clock-dependent

“…The European Space Agency (ESA) and the National Aeronautics and Space Administration (NASA) recently started to use Space omics technology in cells, animals and astronauts in spaceflight [86][87][88] . A number of clock genes with epigenetic modifications was reported through the fundamental Space omics research carried out by the NASA GeneLab project 87 .…”

Roles of Myokines and Muscle-Derived Extracellular Vesicles in Musculoskeletal Deterioration under Disuse Conditions

“…Further studies have shown a decrease in plasma lumican concentrations after 10 days of bed rest [84], while the administration of lumican partially prevents the reduction in muscle mass and muscle fiber cross-sectional area observed in muscles after two weeks of unloading [41], highlighting its role in protecting skeletal muscles. Notably, a recent proteomics analysis of astronauts observed that lumican protein expression in the soleus muscle is elevated after 11 days of spaceflight [85]. However, further verification experiments are needed to confirm the correlation between the elevation of lumican in muscle tissue and its decline in plasma under disuse conditions.…”

Mass Spectrometry-Based Proteomic Technology and Its Application to Study Skeletal Muscle Cell Biology

“…Thus, a detailed understanding of normal muscle function and its cellular regulation including the dynamics of the skeletal muscle proteome, as compared to muscle wasting, is important for diverse biological and biomedical disciplines. This includes crucial aspects of lifestyle biology, health science and clinical medicine, including sports and exercise physiology [39,40], electro-stimulation therapy, research into skeletal muscle plasticity [43,257], disuse-related muscular atrophy and the effects of re-innervation [41,258,259], space flight medicine [260,261], neuromuscular diseases [44,45], frailty-associated muscle aging and biogerontology [47,[262][263][264], forensic medicine [265,266] and the meat industry [267,268]. Important topics in muscle cell biology that are gaining steady interest are the regulation of skeletal muscle mass [269], myokine signaling [270] and muscle-bone-fat crosstalk [271].…”