Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures

Abstract

This study explored the muscle genome‐wide response to long‐term unloading (84‐day bed rest) in 21 men. We hypothesized that a part of the bed rest‐induced gene expression signature would be resilient to a concurrent flywheel resistance exercise (RE) countermeasure. Using DNA microarray technology analyzing 35 345 gene‐level probe‐sets, we identified 335 annotated probe‐sets that were downregulated, and 315 that were upregulated after bed rest (P < .01). Besides a predictable differential expression of genes and pathways related to mitochondria (downregulation; false‐discovery rates (FDR) <1E‐04), ubiquitin system (upregulation; FDR = 3E‐02), and skeletal muscle energy metabolism and structure (downregulation; FDR ≤ 3E‐03), 84‐day bed rest also altered circadian rhythm regulation (upregulation; FDR = 3E‐02). While most of the bed rest‐induced changes were counteracted by RE, 209 transcripts were resilient to the exercise countermeasure. Genes upregulated after bed rest were particularly resistant to training (P < .001 vs downregulated, non‐reversed genes). Specifically, “Translation Factors,” “Proteasome Degradation,” “Cell Cycle,” and “Nucleotide Metabolism” pathways were not normalized by RE. This study provides an unbiased high‐throughput transcriptomic signature of one of the longest unloading periods in humans to date. Classical disuse‐related changes in structural and metabolic genes/pathways were identified, together with a novel upregulation of circadian rhythm transcripts. In the context of previous bed rest campaigns, the latter seemed to be related to the duration of unloading, suggesting the transcriptomic machinery continues to adapt throughout extended disuse periods. Despite that the RE training offset most of the bed rest‐induced muscle‐phenotypic and transcriptomic alterations, we contend that the human skeletal muscle also displays a residual transcriptomic signature of unloading that is resistant to an established exercise countermeasure.

Comparative Transcriptomics Identifies Neuronal and Metabolic Adaptations to Hypergravity and Microgravity in Caenorhabditis elegans

“…Corroborating previous spaceflight studies in worms (Adenle et al, 2009; and rodents (Blaber et al, 2017;Kuznetsov et al, 2019), across spaceflight missions we found consistently upregulated genes associated with altered rates of cell cycle, DNA modification, and actin cytoskeleton/ Genes enriched for ubiquitin-dependent protein degradation were also consistently upregulated by spaceflight conditions, consistent with observations in space-flown rodent liver (Blaber et al, 2017) and skeletal muscle tissue (Nikawa et al, 2004), and human skeletal muscle using ground-based spaceflight analogs (bedrest/immobilization; Fernandez-Gonzalo et al, 2020;Reich et al, 2010). Although counter to earlier reports of unaltered bulk protein degradation in space-flown C. elegans (Etheridge et al, 2011), low-level increases in ubiquitin-proteasome mediated breakdown could be protective against cytotoxic increases in protein aggregates, as occurs during simulated microgravity (Aleshcheva et al, 2013) and animal aging (Melentijevic et al, 2017), a pathophysiological analog of microgravity.…”

Simulated Space Environmental Factors of Weightlessness, Noise and Low Air Pressure Differentially Affect the Circadian Rhythm and Gut Microbiome

“…Head-down bed rest leads to changes in circadian/diel rhythms of physiological, metabolic and locomotion [39][40][41][42][43]. At the molecular level, upregulation of genes involved in circadian rhythm was found during and after 84 days of head-down tilt bed rest [12].…”

“…It has also been demonstrated that the circadian rhythms of diverse organisms display signi cant changes in space [6][7][8][9][10]. Among different space environmental factors, the effects of microgravity and lighting conditions on circadian rhythms have been extensively investigated [9,[11][12][13][14][15]. However, the potential effects of other factors, such as noise and low atmospheric pressure, on circadian rhythms remain elusive.…”

PGC-1α-Targeted Therapeutic Approaches to Enhance Muscle Recovery in Aging

“…Interestingly, these skeletal muscle facets are dysregulated features in aging and following disuse and recovery in humans and rodents [ 6 , 10 , 31 , 32 , 33 , 34 ]. Moreover, PGC-1α expression has been observed to be lower with advanced age [ 35 , 36 , 37 , 38 , 39 ], during atrophy-inducing conditions [ 24 ], during disuse [ 40 , 41 , 42 , 43 ], and in recovery from disuse [ 44 , 45 ]. Interestingly, PGC-1α overexpression in rodent muscle can prevent disuse-induced atrophy [ 24 , 46 , 47 ].…”