Long non-coding RNAs Kcnq1ot1 and Lncpint are involved in skeletal muscle atrophy induced by the space exposome

Long non-coding RNAs (lncRNAs) play an important role in the regulation of skeletal muscle transcriptional processes, but their involvement in spaceflight- or inactivity-induced muscle atrophy remains poorly understood. To address this gap we simulated the space environment by combining microgravity, irradiation and stress in a mouse model. This simulation resulted in the differential expression (threshold set at P < 0.01) of 6191 protein-coding genes (3525 downregulated and 2666 upregulated compared to controls) and 465 lncRNAs, of which 27% were downregulated and 73% upregulated compared to controls. Particularly several previously identified lncRNAs involved in muscle regulation were affected, including H19 (log fold change, logFC: -2.0), Gm29773 (logFC: -1.4), Pvt1 (logFC: 0.63), Kcnq1ot1 (logFC: 0.31) and Lncpint (logFC: 0.86). To determine whether similar changes occurred in humans, we examined the expression of lncRNAs during long-term (3 months) head-down tilt bed rest, a model for microgravity-induced muscle atrophy. We found that Kcnq1ot1 and Lncpint (human homologues KCNQ1OT1 and LINC-PINT) were upregulated in response to simulated microgravity. In addition KCNQ1OT1 was increased in a human 3-D in vitro model of muscle atrophy. These results are the first to demonstrate the involvement of lncRNAs in spaceflight- and severe inactivity-induced muscle atrophy, in particular KCNQ1OT1 and LINC-PINT. Our study provides novel insights into the contribution of lncRNAs to muscle atrophy caused by the space exposome and has broader implications for understanding and combating muscle atrophy in clinical scenarios of prolonged inactivity. Future research can build on these findings to investigate the therapeutic potential of lncRNAs in muscle atrophy. KEY POINTS: The combination of unloading, irradiation and stress led to a significant reduction in skeletal muscle mass and marked transcriptional responses (6191 differentially expressed genes) in the skeletal muscle of mice. The simulated space exposome led to the differential expression of 465 long non-coding RNAs (lncRNAs) in mouse skeletal muscle. Two lncRNAs upregulated in mice - Kcnq1ot1 and Lncpint - were also upregulated in human muscle after 3 months of bed rest (human homologues KCNQ1OT1 and LINC-PINT). KCNQ1OT1, but not LINC-PINT, was upregulated in a human 3-D in vitro model of muscle atrophy. This study offers fundamental insights into the role of lncRNAs in muscle atrophy induced by the space exposome. These findings have broader implications for understanding and mitigating muscle atrophy in clinical settings, such as prolonged inactivity.