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

Abstract

The circadian clock regulates cellular and molecular processes in mammals across all tissues including skeletal muscle, one of the largest organs in the human body. Dysregulated circadian rhythms are characteristic of aging and crewed spaceflight, associated with, for example, musculoskeletal atrophy. Molecular insights into spaceflight-related alterations of circadian regulation in skeletal muscle are still missing. Here, we investigated potential functional consequences of clock disruptions on skeletal muscle using published omics datasets obtained from spaceflights and other clock-altering, external (fasting and exercise), or internal (aging) conditions on Earth. Our analysis identified alterations of the clock network and skeletal muscle-associated pathways, as a result of spaceflight duration in mice, which resembles aging-related gene expression changes observed in humans on Earth (e.g., ATF4 downregulation, associated with muscle atrophy). Furthermore, according to our results, external factors such as exercise or fasting lead to molecular changes in the core-clock network, which may compensate for the circadian disruption observed during spaceflights. Thus, maintaining circadian functioning is crucial to ameliorate unphysiological alterations and musculoskeletal atrophy reported among astronauts.

Spaceflight alters host-gut microbiota interactions

“…These genes can feedback to inhibit Clock/Npas2 and Bmal1 as part of a feedback loop 94,95 , and also regulate other the clock controlled genes such as DBP, HLF and TEF, significantly downregulated, and Nfil3 (E4BP4), significantly upregulated after 56 days of spaceflight. These spaceflight-associated changes in core clock genes, such as upregulation of Bmal1, Arntl and Npas2, largely agree with those found in murine muscle tissue after longer-term spaceflight which were characterised as similar to age-related gene expression on earth 96 .…”

Circadian regulation in aging: Implications for spaceflight and life on earth

“…Miller MJ et al showed that Atf4 is an essential mediator of skeletal muscle aging, and its loss in mice exhibited significant protection from age‐related decline in skeletal muscle strength (Miller et al, 2023 ). In a recent study from our group, we reported clock regulated expression of Atf4 in human and mice skeletal muscle (Malhan et al, 2023 ). A cross‐sectional study performed on elderly women identified a specific polymorphism in ACTN3 (R577X), which contributes to a higher risk of developing sarcopenia (Romero‐Blanco et al, 2021 ).…”

“…Thus, investigating the circadian clock and its misalignments in Space is of major relevance to get a deeper understanding of the potential key roles in many functional impairments in human physiology on the ground and in spaceflight. A recent comprehensive bioinformatics and computational analysis using 1179 mammalian skeletal muscle samples from 28 published genomics and proteomics datasets, by our group showed common gene expression changes in the circadian clock and skeletal muscle associated pathways due to aging on Earth and long‐term spaceflight in mammalian skeletal muscle (Malhan et al, 2023 ).…”

“…Aging phenotype results from alterations in telomere length, epigenetic regulation, and mitochondrial function, along with dysregulations in nine other processes (proteostasis, macroautophagy, cellular senescence, stem cell exhaustion, intercellular communication, chronic inflammation, dysbiosis, genomic instability, and nutrient‐sensing), which are altogether referred to as the hallmarks of aging (López‐Otín et al, 2023 ). Interestingly, recent studies associate aging to spaceflight with contradictory conclusions (Biolo et al, 2003 ; Cannavo et al, 2022 ; Garrett‐Bakelman et al, 2019 ; Honda et al, 2012 ; Ma et al, 2015 ; Malhan et al, 2023 ; Nwanaji‐Enwerem et al, 2020 ; Otsuka et al, 2019 ; 2022 ; Wang, 1999 ), while some of the studies report an anti‐aging impact of spaceflight, others observed progressive aging due to spaceflight. Whether the anti‐aging impact of spaceflight correlates with the “twin paradox” (Gron, 2006 ) based on the theory of relativity coined by Albert Einstein, which proposes that an individual in Space ages slower compared to his/her biological twin on Earth, remains to be shown.…”

The effect of low birth weight as an intrauterine exposure on the early onset of sarcopenia through possible molecular pathways

“… 89 Therefore, clock gene disruption is associated with ageing. 90 Even though the connection between telomere length and sarcopenia is not fully elucidated, shorter telomere length is linked to decreased grip strength—a sarcopenia marker. 91 Furthermore, epigenetic mechanisms such as histone alterations, including acetylation and methylation, play a role in regulating CLOCK transcription factor expression.…”