Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

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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.

Abstract

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.

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Most cited references 76

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Lack of exercise is a major cause of chronic diseases.

Frank Booth, Christian K Roberts, Matthew J. Laye (2012)

Chronic diseases are major killers in the modern era. Physical inactivity is a primary cause of most chronic diseases. The initial third of the article considers: activity and prevention definitions; historical evidence showing physical inactivity is detrimental to health and normal organ functional capacities; cause versus treatment; physical activity and inactivity mechanisms differ; gene-environment interaction (including aerobic training adaptations, personalized medicine, and co-twin physical activity); and specificity of adaptations to type of training. Next, physical activity/exercise is examined as primary prevention against 35 chronic conditions [accelerated biological aging/premature death, low cardiorespiratory fitness (VO2max), sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, nonalcoholic fatty liver disease, coronary heart disease, peripheral artery disease, hypertension, stroke, congestive heart failure, endothelial dysfunction, arterial dyslipidemia, hemostasis, deep vein thrombosis, cognitive dysfunction, depression and anxiety, osteoporosis, osteoarthritis, balance, bone fracture/falls, rheumatoid arthritis, colon cancer, breast cancer, endometrial cancer, gestational diabetes, pre-eclampsia, polycystic ovary syndrome, erectile dysfunction, pain, diverticulitis, constipation, and gallbladder diseases]. The article ends with consideration of deterioration of risk factors in longer-term sedentary groups; clinical consequences of inactive childhood/adolescence; and public policy. In summary, the body rapidly maladapts to insufficient physical activity, and if continued, results in substantial decreases in both total and quality years of life. Taken together, conclusive evidence exists that physical inactivity is one important cause of most chronic diseases. In addition, physical activity primarily prevents, or delays, chronic diseases, implying that chronic disease need not be an inevitable outcome during life. © 2012 American Physiological Society. Compr Physiol 2:1143-1211, 2012.

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The role of exercise and PGC1alpha in inflammation and chronic disease.

Christoph Handschin, Bruce M Spiegelman (2008)

Inadequate physical activity is linked to many chronic diseases. But the mechanisms that tie muscle activity to health are unclear. The transcriptional coactivator PGC1alpha has recently been shown to regulate several exercise-associated aspects of muscle function. We propose that this protein controls muscle plasticity, suppresses a broad inflammatory response and mediates the beneficial effects of exercise.

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Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials.

N. Boule, E Haddad, G P Kenny … (2001)

Exercise is widely perceived to be beneficial for glycemic control and weight loss in patients with type 2 diabetes. However, clinical trials on the effects of exercise in patients with type 2 diabetes have had small sample sizes and conflicting results. To systematically review and quantify the effect of exercise on glycosylated hemoglobin (HbA(1c)) and body mass in patients with type 2 diabetes. Database searches of MEDLINE, EMBASE, Sport Discuss, Health Star, Dissertation Abstracts, and the Cochrane Controlled Trials Register for the period up to and including December 2000. Additional data sources included bibliographies of textbooks and articles identified by the database searches. We selected studies that evaluated the effects of exercise interventions (duration >/=8 weeks) in adults with type 2 diabetes. Fourteen (11 randomized and 3 nonrandomized) controlled trials were included. Studies that included drug cointerventions were excluded. Two reviewers independently extracted baseline and postintervention means and SDs for the intervention and control groups. The characteristics of the exercise interventions and the methodological quality of the trials were also extracted. Twelve aerobic training studies (mean [SD], 3.4 [0.9] times/week for 18 [15] weeks) and 2 resistance training studies (mean [SD], 10 [0.7] exercises, 2.5 [0.7] sets, 13 [0.7] repetitions, 2.5 [0.4] times/week for 15 [10] weeks) were included in the analyses. The weighted mean postintervention HbA(1c) was lower in the exercise groups compared with the control groups (7.65% vs 8.31%; weighted mean difference, -0.66%; P<.001). The difference in postintervention body mass between exercise groups and control groups was not significant (83.02 kg vs 82.48 kg; weighted mean difference, 0.54; P =.76). Exercise training reduces HbA(1c) by an amount that should decrease the risk of diabetic complications, but no significantly greater change in body mass was found when exercise groups were compared with control groups.

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Author and article information

Contributors

Juleen R. Zierath:

ORCID: http://orcid.org/0000-0001-6891-7497

Juleen.Zierath@ki.se

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 24 January 2020

Publication date PMC-release: 24 January 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 470

Affiliations

[1 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Physiology and Pharmacology, , Karolinska Institutet, ; Stockholm, Sweden

[2 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Molecular Medicine and Surgery, , Karolinska Institutet, ; Stockholm, Sweden

[3 ]ISNI 0000 0001 0396 9544, GRID grid.1019.9, Institute for Health and Sport, , Victoria University, ; Melbourne, Australia

[4 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Novo Nordisk Foundation Center for Basic Metabolic Research, , University of Copenhagen, ; Copenhagen, Denmark

Author information

Nicolas J. Pillon http://orcid.org/0000-0003-1107-9490

Brendan M. Gabriel http://orcid.org/0000-0001-6878-8779

Jonathon A. B. Smith http://orcid.org/0000-0003-2452-1655

Laura Sardón Puig http://orcid.org/0000-0002-0481-4023

Javier Botella http://orcid.org/0000-0001-9722-8519

David J. Bishop http://orcid.org/0000-0002-6956-9188

Anna Krook http://orcid.org/0000-0002-0891-0258

Juleen R. Zierath http://orcid.org/0000-0001-6891-7497

Article

Publisher ID: 13869

DOI: 10.1038/s41467-019-13869-w

PMC ID: 6981202

PubMed ID: 31980607

SO-VID: ba40f2d5-b99c-4082-ba7c-c81688d3cdc8

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 2 May 2019

Date accepted : 29 November 2019

Funding

Funded by: FundRef https://doi.org/10.13039/100011264, EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013));

Award ID: 704978

Award ID: 675610

Award ID: 704978

Award Recipient : Nicolas J. Pillon Juleen R. Zierath

Funded by: Grants from the Sigurd och Elsa Goljes Minne and Lars Hiertas Minne Foundations (Sweden).

Funded by: BMG was supported by a fellowship from the Wenner-Gren Foundation (Sweden).

Funded by: L.D. was supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet.

Funded by: ANZ Mason Foundation and Australian Research Council Discovery Program (ARC DP140104165)

Funded by: FundRef https://doi.org/10.13039/501100004359, Vetenskapsrådet (Swedish Research Council);

Award ID: 2018-02389

Award ID: 2015-00165

Award Recipient : Anna Krook Juleen R. Zierath

Funded by: FundRef https://doi.org/10.13039/501100001648, European Foundation for the Study of Diabetes (EFSD);

Funded by: Strategic Research Program in Diabetes at Karolinska Institutet (2009-1068). Swedish Diabetes Foundation (DIA2018-336)

Funded by: FundRef https://doi.org/10.13039/501100009708, Novo Nordisk Fonden (Novo Nordisk Foundation);

Award ID: NNF14OC0011493

Award ID: NNF17OC0030088

Award ID: NNF14OC0009941

Award ID: NNF18CC0034900

Award Recipient : Juleen R. Zierath

Funded by: EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))

Funded by: FundRef https://doi.org/10.13039/501100004348, Stockholms Läns Landsting (Stockholm County Council);

Award ID: SLL20150517

Award ID: SLL20170159

Award Recipient : Juleen R. Zierath

Funded by: Swedish Diabetes Foundation (DIA 2018-357) Strategic Research Program in Diabetes at Karolinska Institutet (2009-1068) Swedish Research Council for Sport Science (P2018-0097)

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Keywords: translational research,molecular medicine

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Keywords: translational research, molecular medicine

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Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

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Vascular Biology

Most cited references 76

Lack of exercise is a major cause of chronic diseases.

The role of exercise and PGC1alpha in inflammation and chronic disease.

Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials.

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Cited by 137

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