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Three Months of Bed Rest Induce a Residual Transcriptomic Signature Resilient to Resistance Exercise Countermeasures

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Three Months of Bed Rest Induce a Residual Transcriptomic Signature Resilient to Resistance Exercise Countermeasures Received: 27 November 2019 | Revised: 19 February 2020 | Accepted: 29 March 2020 DOI: 10.1096/fj.201902976R RESEARCH ARTICLE Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures Rodrigo Fernandez-Gonzalo1 | Per A. Tesch2 | Tommy R. Lundberg1 | Björn A. Alkner3,4 | Eric Rullman1 | Thomas Gustafsson1 1Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Abstract Institutet, and Unit of Clinical Physiology, This study explored the muscle genome-wide response to long-term unloading (84- Karolinska University Hospital, Stockholm, day bed rest) in 21 men. We hypothesized that a part of the bed rest-induced gene Sweden expression signature would be resilient to a concurrent flywheel resistance exercise 2Department of Physiology & Pharmacology, Karolinska Institutet, (RE) countermeasure. Using DNA microarray technology analyzing 35 345 gene- Stockholm, Sweden level probe-sets, we identified 335 annotated probe-sets that were downregulated, 3 Department of Orthopaedics, Region and 315 that were upregulated after bed rest (P < .01). Besides a predictable differen- Jönköping County, Eksjö, Sweden tial expression of genes and pathways related to mitochondria (downregulation; false- 4Department of Biomedical and Clinical Sciences, Linköping University, Linköping, discovery rates (FDR) <1E-04), ubiquitin system (upregulation; FDR = 3E-02), and Sweden skeletal muscle energy metabolism and structure (downregulation; FDR ≤ 3E-03), 84- day bed rest also altered circadian rhythm regulation (upregulation; FDR = 3E-02). Correspondence Rodrigo Fernandez-Gonzalo, Department While most of the bed rest-induced changes were counteracted by RE, 209 transcripts of Laboratory Medicine, Division of were resilient to the exercise countermeasure. Genes upregulated after bed rest were Clinical Physiology, Karolinska Institute, particularly resistant to training (P < .001 vs downregulated, non-reversed genes). and Unit of Clinical Physiology, Karolinska University Hospital, ANA Futura, Specifically, “Translation Factors,” “Proteasome Degradation,” “Cell Cycle,” and Alfred Nobels Allé 8, 141 52 Huddinge, “Nucleotide Metabolism” pathways were not normalized by RE. This study provides Stockholm, Sweden. Email: [email protected] an unbiased high-throughput transcriptomic signature of one of the longest unloading periods in humans to date. Classical disuse-related changes in structural and meta- Funding information bolic genes/pathways were identified, together with a novel upregulation of circadian Swedish National Space Agency; European Space Agency (ESA); Swedish National rhythm transcripts. In the context of previous bed rest campaigns, the latter seemed Center for Research in Sports 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, Abbreviations: BR, bed rest; BRE, bed rest and exercise; DAVID, The Database for Annotation, Visualization and Integrated Discovery; FC, fold change; FDR, false discovery rate; Go-term, gene ontology-term; Kcal, kilocalorie; LIMMA, linear models for microarray data; MEDES, Space Medicine and Physiology clinic, Toulouse, France; NUSE, normalized unscaled standard error; PCA, principal component analysis; RE, resistance exercise; t-SNE, t-distributed stochastic neighbor embedding Eric Rullman and Thomas Gustafsson Joint senior authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology The FASEB Journal. 2020;00:1–12. wileyonlinelibrary.com/journal/fsb2 | 1 2 | FERNANDEZ-GONZALO ET AL. we contend that the human skeletal muscle also displays a residual transcriptomic signature of unloading that is resistant to an established exercise countermeasure. KEYWORDS atrophy, microarray, muscle wasting, unloading 1 | INTRODUCTION paradigm was able to preserve mm. quadriceps mass, and halved the atrophy in m. triceps surae after 90 days of bed rest In response to reduced mechanical stimuli, the skeletal in men.1 We also showed that this protocol was effective in muscle experiences loss of mass and function, increased fa- counteracting some, but not all, of the metabolic alterations tigability and insulin resistance, and a shift toward a faster in muscle triggered by 84-day bed rest.21 However, whether muscle fiber phenotype.1-6 The loss of muscle mass during those positive adaptations induced by RE were due to a re- short periods of disuse or unloading, such as during recovery versal effect on the specific molecular pathways controlling from injury or illness, is characterized by a rapid increase muscle integrity during unloading, or to an activation of dif- in protein breakdown,7,8 along with reduced muscle protein ferent pathways, or a combination, remains to be elucidated. synthesis.9 In contrast, knowledge about the physiological It follows that the potential existence of groups of genes that and molecular basis for muscle loss during prolonged disuse are not reversed by the countermeasure employed might be periods warrants further research, since this has mainly been of particular interest, since these could provide mechanistic characterized in cross-sectional studies. insight into disuse-related changes that are resilient to current Hitherto attempts to provide mechanistic information on interventions employed to combat muscle loss. the molecular programs governing unloading-induced mus- The main purpose of the current study was to analyze the cle deconditioning have included the exploration of tran- genome-wide muscle transcriptome response to long-term scriptome changes in muscle after short-term bed rest or bed rest with or without RE. We hypothesized that pathways unilateral lower limb suspension/cast immobilization, rang- related to metabolism, cell structure, and protein synthesis ing from 24 hours to 21 days,10-17 or longer periods of bed would be downregulated, while molecular routes direct- rest (60 days).18,19 A common disuse signature, regardless of ing protein breakdown would be upregulated by 84 days of the differences in methods and/or study duration, is a marked bed rest. In addition, while we hypothesized that RE would downregulation of gene networks related to both energy me- restore the majority of the transcriptional signature of bed tabolism and structural components, together with an upreg- rest, we specifically sought to explore the potential existence ulation of the ubiquitin-proteasome pathway.10-12,14,15,17-19 of genes that would be resilient to the countermeasure em- In addition, we recently identified the MEF2 family of tran- ployed. Finally, we used an exon usage analysis to determine scription factors, in particular MEF2C, as potential master splice events induced by long-term bed rest. regulators of skeletal muscle alterations to short-term un- loading (21-day bed rest),15 while microRNAs seemed to play a negligible role.16 In contrast, the molecular basis of 2 | MATERIALS AND METHODS long-term disuse atrophy have remained scantly research. Thus, although unloading models, in particular bed rest, in- 2.1 | General design duce robust muscle atrophy solely due to lack of mechani- cal stimuli, it is plausible that the transcriptomic information Twenty-one healthy men (age range 26-41 years) were ran- gathered from long-term bed rest could further our under- domly assigned to performed 90-day bed rest with (bed rest standing of more complex and multifactorial muscle wasting and exercise, BRE; n = 9) or without (BR; n = 12) concur- conditions.20 Indeed, additional mechanistic information on rent iso-inertial RE every third day targeting the quadriceps the driving forces behind disuse-induced muscle loss would muscle group (ie, supine squat; four sets of seven maximal allow for better characterization of nutritional/pharmacolog- concentric-eccentric repetitions) and the calf muscles (ie, ical and/or exercise countermeasures to prevent, or at least calf press; 4 sets of 14 concentric-eccentric repetitions) attenuate, muscle loss during long-term lack of mechanical employing flywheel technology. Muscle biopsies from m. stimuli such as during extended disease episodes. vastus lateralis were obtained from all subjects before and One of the most efficient strategies to preserve muscle in- after 84 days of bed rest. The muscle specimens were used tegrity during unloaded conditions is high-intensity resistance to conduct a DNA microarray analysis. We and others have exercise (RE). The use of an iso-inertial flywheel exercise previously reported on functional, structural, and metabolic FERNANDEZ-GONZALO ET AL. | 3 muscle adaptations during the same bed rest project,1,3,6,21-23 force, power, work, joint angle, and angular velocity were as well as tendon24 and bone properties,25,26 and vascular recorded.1 alterations.27 2.5 | Skeletal muscle biopsies 2.2 | Subjects Before (PRE) and after (POST) 84-day bed rest, yet prior to Specialized personnel from the Institute for Space Medicine re-ambulation, muscle biopsies were obtained from m. vas- and Physiology clinic
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