Mechanisms behind skeletal muscle and immune system alterations during spaceflight

Whether in a space mission to Mars or during a long-term hospitalization, humans exposed to microgravity/severe inactivity suffer from skeletal muscle an immune function alterations.

These consequences have been reported during bed rest studies, the gold-standard spaceflight analog and a condition resembling long-term hospitalized patients.

Yet, despite a rather deep understanding of the unloading-induced muscular and immune phenotypic changes, the potential interactions between these systems and the regulatory mechanisms driving those alterations are only starting to be unraveled.

My group has recently conducted one of the most comprehensive bed rest transcriptomic studies to date, where we report that as little as 3 minutes per week of muscle activation through exercise was enough to offset the majority, but not all of the 3-month bed rest-induced muscle transcriptomic alterations.

These data indicate that while bed rest-induced RNA changes play a significant role directing the phenotypic alterations triggered by microgravity, there must be other regulatory mechanism(s) controlling the molecular machinery during unloading. One such mechanisms could be long non-coding RNA (lncRNA).

Indeed, the role of lncRNAs in the transcriptomic regulation of skeletal muscle and the immune system is starting to emerge. However, lncRNA’s role during unloading in humans has not yet been described.

Importantly, bed rest is the only human model offering the necessary level of environmental control to study lncRNAs.In an attempt to optimize unloading countermeasures, researchers have suggested that intermittent bouts of artificial gravity (AG) using short-arm human centrifugation, could add another level of protection against bed rest-induced alterations.An important topic for the space agencies is to define the individual trajectory of microgravity-induced tissue and organ changes, as well as the mechanisms explaining such individual responses.

This enterprise is a difficult one given multiple methodological constrains, like the common lack of a sound control group or the very limited number of observations that can be recorded during space or bedrest studies.The overall PURPOSES I will pursue with my project plan are:To discover lncRNAs with a role on microgravity-induced changes on skeletal muscle and the immune system, andto describe their mechanisms of action using cellular modelsTo depict if AG with concurrent exercise is an effective and suitable countermeasure to offset unloading-induced muscular and immune alterationsTo investigate individual variability after a period of microgravity in skeletal muscle related outcomesTo investigate the crosstalk between skeletal muscle and immune system under individual and combined space stressors (i.e., radiation, microgravity, stress) in miceMy working HYPOTHESIS is that there are key lncRNAs directing immune and skeletal muscle unloading-induced changes, which respond to some extent (normalized expression), to AG and exercise.

I predict these experiments will discover a group of unloading-specific lncRNAs important for immune system and skeletal muscle integrity, whose mechanisms of action can be defined using cellular models.

In addition, I believe there is real individual variability in the response to microgravity in humans that, if it can be predicted, could be used to improve health management of astronauts and to optimize individual programs to counteract the negative effects of unloading during space missions.

Finally, I hypothesize that space stressors (microgravity, radiation, stress) induce an infiltration of immune cells into the muscle in mice, which could jeopardize the normal and healthy response of muscle upon injury or exercise.Part of the activities described in this proposal have secured funding (4.5 Mkr) from the Swedish National Space Agency.

Access to the bed rest campaigns during 2022-2023 to conduct the activities described here has been granted by the European Space Agency.