Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

Nicolas J. Pillon; Brendan M. Gabriel; Lucile Dollet; Jonathon A. B. Smith; Laura Sardón Puig; Javier Botella; David J. Bishop; Anna Krook; Juleen R. Zierath

doi:10.1038/s41467-019-13869-w

Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

Nicolas J. Pillon, Brendan M. Gabriel, Lucile Dollet, Jonathon A. B. Smith, Laura Sardón Puig, Javier Botella, David J. Bishop, Anna Krook, Juleen R. Zierath^* (Corresponding Author)

^*Corresponding author for this work

Medical Sciences

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Abstract

The molecular mechanisms underlying the response to exercise and inactivity are not fully understood. We propose an innovative approach to profile the skeletal muscle transcriptome to exercise and inactivity using 66 published datasets. Data collected from human studies of aerobic and resistance exercise, including acute and chronic exercise training, were integrated using meta-analysis methods (www.metamex.eu). Here we use gene ontology and pathway analyses to reveal selective pathways activated by inactivity, aerobic versus resistance and acute versus chronic exercise training. We identify NR4A3 as one of the most exercise- and inactivity-responsive genes, and establish a role for this nuclear receptor in mediating the metabolic responses to exercise-like stimuli in vitro. The meta-analysis (MetaMEx) also highlights the differential response to exercise in individuals with metabolic impairments. MetaMEx provides the most extensive dataset of skeletal muscle transcriptional responses to different modes of exercise and an online interface to readily interrogate the database. The pathways that underlie the effects of exercise on metabolism remain incompletely described. Here, the authors perform a meta-analysis of transcriptomic data from 66 published datasets of human skeletal muscle. They identify pathways selectively activated by inactivity, aerobic or resistance exercise, and characterize NR4A3 as one of the genes responsive to inactivity.

Original language	English
Article number	470
Number of pages	15
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-019-13869-w
Publication status	Published - 24 Jan 2020

Bibliographical note

The authors are supported by grants from the Novo Nordisk Foundation (NNF14OC0011493, NNF17OC0030088 and NNF14OC0009941), Swedish Diabetes Foundation (DIA2018-357, DIA2018-336), Swedish Research Council (2015-00165, 2018-02389), the Strategic Research Program in Diabetes at Karolinska Institutet (2009-1068), the Stockholm County Council (SLL20150517, SLL20170159), the Swedish Research Council for Sport Science (P2018-0097), and the EFSD European Research Programme on New Targets for Type 2 Diabetes supported by an educational research grant from MSD. L.D. was supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet. B.M.G. was supported by a fellowship from the Wenner-Gren Foundation (Sweden). N.J.P. was supported by an Individual Fellowship from the Marie Skłodowska-Curie Actions (European Commission, 704978, 675610) and grants from the Sigurd och Elsa Goljes Minne and Lars Hiertas Minne Foundations (Sweden). D.J.B. was supported by the ANZ Mason Foundation and Australian Research Council Discovery Program (ARC DP140104165). Additional support was received from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900) (to J.R.Z.). We thank Dr. Nanjiang Shu from National Bioinformatics Infrastructure Sweden (NBIS) for setting up the web-server. We also thank EGI federated cloud for providing the computer resource for hosting the web-server. We acknowledge the Beta Cell in-vivo Imaging/Extracellular Flux Analysis core facility supported by the Strategic Research Program (SRP) in Diabetes for the usage of the Seahorse flux analyzer. Open access funding provided by Karolinska Institute.

Keywords

molecular medicine
translational research
Humans
Exercise/physiology
Gene Expression Profiling
Gene Regulatory Networks
Receptors, Steroid/genetics
Resistance Training
Adaptation, Physiological/genetics
Receptors, Thyroid Hormone/genetics
DNA-Binding Proteins/genetics
Muscle, Skeletal/physiology
Gene Ontology
Sedentary Behavior

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Cite this

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title = "Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity",

abstract = "The molecular mechanisms underlying the response to exercise and inactivity are not fully understood. We propose an innovative approach to profile the skeletal muscle transcriptome to exercise and inactivity using 66 published datasets. Data collected from human studies of aerobic and resistance exercise, including acute and chronic exercise training, were integrated using meta-analysis methods (www.metamex.eu). Here we use gene ontology and pathway analyses to reveal selective pathways activated by inactivity, aerobic versus resistance and acute versus chronic exercise training. We identify NR4A3 as one of the most exercise- and inactivity-responsive genes, and establish a role for this nuclear receptor in mediating the metabolic responses to exercise-like stimuli in vitro. The meta-analysis (MetaMEx) also highlights the differential response to exercise in individuals with metabolic impairments. MetaMEx provides the most extensive dataset of skeletal muscle transcriptional responses to different modes of exercise and an online interface to readily interrogate the database. The pathways that underlie the effects of exercise on metabolism remain incompletely described. Here, the authors perform a meta-analysis of transcriptomic data from 66 published datasets of human skeletal muscle. They identify pathways selectively activated by inactivity, aerobic or resistance exercise, and characterize NR4A3 as one of the genes responsive to inactivity.",

keywords = "molecular medicine, translational research, Humans, Exercise/physiology, Gene Expression Profiling, Gene Regulatory Networks, Receptors, Steroid/genetics, Resistance Training, Adaptation, Physiological/genetics, Receptors, Thyroid Hormone/genetics, DNA-Binding Proteins/genetics, Muscle, Skeletal/physiology, Gene Ontology, Sedentary Behavior",

author = "Pillon, {Nicolas J.} and Gabriel, {Brendan M.} and Lucile Dollet and Smith, {Jonathon A. B.} and Puig, {Laura Sard{\'o}n} and Javier Botella and Bishop, {David J.} and Anna Krook and Zierath, {Juleen R.}",

note = "The authors are supported by grants from the Novo Nordisk Foundation (NNF14OC0011493, NNF17OC0030088 and NNF14OC0009941), Swedish Diabetes Foundation (DIA2018-357, DIA2018-336), Swedish Research Council (2015-00165, 2018-02389), the Strategic Research Program in Diabetes at Karolinska Institutet (2009-1068), the Stockholm County Council (SLL20150517, SLL20170159), the Swedish Research Council for Sport Science (P2018-0097), and the EFSD European Research Programme on New Targets for Type 2 Diabetes supported by an educational research grant from MSD. L.D. was supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet. B.M.G. was supported by a fellowship from the Wenner-Gren Foundation (Sweden). N.J.P. was supported by an Individual Fellowship from the Marie Sk{\l}odowska-Curie Actions (European Commission, 704978, 675610) and grants from the Sigurd och Elsa Goljes Minne and Lars Hiertas Minne Foundations (Sweden). D.J.B. was supported by the ANZ Mason Foundation and Australian Research Council Discovery Program (ARC DP140104165). Additional support was received from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900) (to J.R.Z.). We thank Dr. Nanjiang Shu from National Bioinformatics Infrastructure Sweden (NBIS) for setting up the web-server. We also thank EGI federated cloud for providing the computer resource for hosting the web-server. We acknowledge the Beta Cell in-vivo Imaging/Extracellular Flux Analysis core facility supported by the Strategic Research Program (SRP) in Diabetes for the usage of the Seahorse flux analyzer. Open access funding provided by Karolinska Institute. ",

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AU - Gabriel, Brendan M.

AU - Dollet, Lucile

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AU - Puig, Laura Sardón

AU - Botella, Javier

AU - Bishop, David J.

AU - Krook, Anna

AU - Zierath, Juleen R.

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KW - Receptors, Thyroid Hormone/genetics

KW - DNA-Binding Proteins/genetics

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Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

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Brendan Gabriel

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Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

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Brendan Gabriel

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