Recovery from 6-month spaceflight at the International Space Station: muscle-related stress into a pro-inflammatory setting

Abstract

The Sarcolab pilot study of 2 crewmembers, investigated before and after a 6-mo International Space Station mission, has demonstrated the substantial muscle wasting and weakness, along with disruption of muscle’s oxidative metabolism. The present work aimed at evaluating the pro/anti-inflammatory status in the same 2 crewmembers (A, B). Blood circulating (c-)microRNAs (miRs), c-proteasome, c-mitochondrial DNA, and cytokines were assessed by real-time quantitative PCR or ELISA tests. Time series analysis was performed (i.e., before flight and after landing) at 1 and 15 d of recovery (R+1 and R+15, respectively). C-biomarkers were compared with an age-matched control population and with 2-dimensional proteomic analysis of the 2 crewmembers’ muscle biopsies. Striking differences were observed between the 2 crewmembers at R+1, in terms of inflamma-miRs (c-miRs-21-5p, -126-3p, and -146a-5p), muscle specific (myo)-miR-206, c-proteasome, and IL-6/leptin, thus making the 2 astronauts dissimilar to each other. Final recovery levels of c-proteasome, c-inflamma-miRs, and c-myo-miR-206 were not reverted to the baseline values in crewmember A. In both crewmembers, myo-miR-206 changed significantly after recovery. Muscle biopsy of astronaut A showed an impressive 80% increase of α-1-antitrypsin, a target of miR-126-3p. These results point to a strong stress response induced by spaceflight involving muscle tissue and the proinflammatory setting, where inflamma-miRs and myo-miR-206 mediate the systemic recovery phase after landing.—Capri, M., Morsiani, C., Santoro, A., Moriggi, M., Conte, M., Martucci, M., Bellavista, E., Fabbri, C., Giampieri, E., Albracht, K., Flück, M., Ruoss, S., Brocca, L., Canepari, M., Longa, E., Di Giulio, I., Bottinelli, R., Cerretelli, P., Salvioli, S., Gelfi, C., Franceschi, C., Narici, M., Rittweger, J. Recovery from 6-month spaceflight at the International Space Station: muscle-related stress into a proinflammatory setting. It is known that short- and long-term spaceflights are associated with physiologic and biologic changes of the human body (1–3). Currently, long-term orbiting flights are regularly performed to serve the International Space Station (ISS) missions, and deep space missions (e.g., to the moon or Mars) are thought to be feasible soon (4). Among the many bodily effects, those related to the skeletal-muscle apparatus and brain appear to be particularly relevant in terms of possible health risks and difficulty to revert the changes after landing (5). Many of the space-related changes are detrimental to the body, and it has been suggested that microgravity could be seen as a model of ageing (6). Access to astronauts is quite limited, which is a considerable impediment to the generation of knowledge in space medicine. Luckily, the possibility of measuring advanced blood biomarkers, such as microRNAs (miRs), and pro- and anti-inflammatory cytokines offer the intriguing opportunity of easily monitoring crew health concerning the physiologic and stress-associated challenges of spaceflight. In addition, circulating (c-)markers are promising tools for the evaluation of healthy and unhealthy ageing trajectories (7). Thus, blood is an informative tissue in which the presence and the concentration of markers may indicate not only tissue/organ injuries or suffering status but also epigenetic changes that may propagate in all the body, especially in the case of c-miRs. In fact, many of these molecules are able to modulate inflammatory signaling pathways, in particular the inflamma-miRs (miR-21-5p, -126-3p, -146a-5p), which were found to be increased or dysregulated in the blood with ageing or pathologic conditions (8). The Sarcolab pilot study has studied the neuromuscular adaptations to long-term space flight in 2 crewmembers before and after a 6-mo ISS mission and has demonstrated substantial muscle wasting and weakness, along with disruption of muscle’s oxidative metabolism, as a result of spaceflight (9). The muscle atrophy observed with spaceflight has some analogy with the age-associated loss of muscle mass (sarcopenia) (10). In both conditions, the loss of muscle mass could contribute to the increase of c-markers networking with the stress response and proinflammatory status as well as inflammageing along with life span (11–13). Further support for such a view is provided by the recent observation that body core temperature is increased in space in a way that is independent of impeded heat dissipation and which seems to be linked with an inflammatory response (14). The driving hypothesis is that spaceflight, as a prolonged stressor, and recovery may favor a proinflammatory status, increasing the molecular “garbage,” such as misplaced molecules (15), which in turn may favor the inflammatory stress conditions. To this purpose, the present work attempts to evaluate the pro- and anti-inflammatory status in the 2 crewmembers (A and B) who spent ∼6 mo in space. Blood c-miRs, c-proteasome, c-mitochondrial DNA (mtDNA), and cytokines were evaluated before flight and after 1 and 15 d of recovery and correlated with muscle proteomic analysis. All data were acquired taking into account the main question: How similar are the 2 crewmembers’ responses to spaceflight and recovery after 1 and 15 d from landing?