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Cited by 135Cardiovascular and exercise physiologyGenetics and Physical PerformanceExercise and Physiological Responses

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Modulation of extracellular matrix genes reflects the magnitude of physiological adaptation to aerobic exercise training in humans

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Timmons, James A, Jansson, Eva, Fischer, Helene, Gustafsson, Thomas, Greenhaff, Paul L, Ridden, John, Rachman, Jonathan, Sundberg, Carl Johan·2005·BMC Biology
DOI 10.1186/1741-7007-3-19PMC PMC1224855
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Abstract

Background: Regular exercise reduces cardiovascular and metabolic disease partly through improved aerobic fitness. The determinants of exercise-induced gains in aerobic fitness in humans are not known. We have demonstrated that over 500 genes are activated in response to endurance-exercise training, including modulation of muscle extracellular matrix (ECM) genes. Real-time quantitative PCR, which is essential for the characterization of lower abundance genes, was used to examine 15 ECM genes potentially relevant for endurance-exercise adaptation. Twenty-four sedentary male subjects undertook six weeks of high-intensity aerobic cycle training with muscle biopsies being obtained both before and 24 h after training. Subjects were ranked based on improvement in aerobic fitness, and two cohorts were formed (n = 8 per group): the high-responder group (HRG; peak rate of oxygen consumption increased by +0.71 ± 0.1 L min -1 ; p < 0.0001) while the low-responder group (LRG; peak rate of oxygen consumption did not change, +0.17 ± 0.1 L min -1 , ns). ECM genes profiled included the angiopoietin 1 and related genes ( angiopoietin 2 , tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1) and 2 ( TIE2 ), vascular endothelial growth factor ( VEGF ) and related receptors ( VEGF receptor 1, VEGF receptor 2 and neuropilin-1 ), thrombospondin-4 , α2-macroglobulin and transforming growth factor β2 . Results: neuropilin-1 (800%; p < 0.001) and VEGF receptor 2 (300%; p < 0.01) transcript abundance increased only in the HRG, whereas levels of VEGF receptor 1 mRNA actually declined in the LRG (p < 0.05). TIE1 and TIE2 mRNA levels were unaltered in the LRG, whereas transcription levels of both genes were increased by 2.5-fold in the HRG (p < 0.01). Levels of thrombospondin-4 (900%; p < 0.001) and α2-macroglobulin (300%, p < 0.05) mRNA increased substantially in the HRG. In contrast, the amount of transforming growth factor β2 transcript increased only in the HRG (330%; p < 0.01), whereas it remained unchanged in the LRG (-80%). Conclusion: We demonstrate for the first time that aerobic training activates angiopoietin 1 and TIE2 genes in human muscle, but only when aerobic capacity adapts to exercise-training. The fourfold-greater increase in aerobic fitness and markedly differing gene expression profile in the HRG indicates that these ECM genes may be critical for physiological adaptation to exercise in humans. In addition, we show that, without careful demonstration of physiological adaptation, conclusions derived from gene expression profiling of human skeletal muscle following exercise may be of limited value. We propose that future studies should (a) investigate the mechanisms that underlie the apparent link between physiological adaptation and gene expression and (b) use the genes profiled in this paper as candidates for population genetic studies.

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Crossref · 10.1186/1741-7007-3-19

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Figure 1 Change in Vascular endothelial growth factor-related gene expression following endurance training. Values are -fold changes in human skeletal muscle gene expression (mean ± SE) following six weeks of aerobic training. Gene expression was determined using real-time quantitative PCR. Following six weeks training (n = 24), the eight highest and eight lowest responders to exercise training were identified using the sum of (a) the percent improvement in maximal aerobic capacity, (b) the percent reduction in submaximal heart rate during 15 min fixed-workload, submaximal cycling and (c) the percent improvement in work done during a 15 min maximal cycling test. This ranking was carried out before any genomic analysis was carried out. The training responses were evaluated by two-way ANOVA and Bonferoni post-hoc tests. * indicates p < 0.05, ** indicates p < 0.01 and *** indicates p < 0.001.
Figure 1 Change in Vascular endothelial growth factor-related gene expression following endurance training. Values are -fold changes in human skeletal muscle gene expression (mean ± SE) following six weeks of aerobic training. Gene expression was determined using real-time quantitative PCR. Following six weeks training (n = 24), the eight highest and eight lowest responders to exercise training were identified using the sum of (a) the percent improvement in maximal aerobic capacity, (b) the percent reduction in submaximal heart rate during 15 min fixed-workload, submaximal cycling and (c) the percent improvement in work done during a 15 min maximal cycling test. This ranking was carried out before any genomic analysis was carried out. The training responses were evaluated by two-way ANOVA and Bonferoni post-hoc tests. * indicates p < 0.05, ** indicates p < 0.01 and *** indicates p < 0.001.CC BY · PubMed Central
Figure 2 Changes in Angiopoietin-related gene expression following endurance training. Values are -fold changes in human skeletal muscle gene expression (mean ± SE) following six weeks of aerobic training, as described in Fig. 1. * indicates p < 0.05, ** indicates p < 0.01 and *** indicates p < 0.001.
Figure 2 Changes in Angiopoietin-related gene expression following endurance training. Values are -fold changes in human skeletal muscle gene expression (mean ± SE) following six weeks of aerobic training, as described in Fig. 1. * indicates p < 0.05, ** indicates p < 0.01 and *** indicates p < 0.001.CC BY · PubMed Central
Figure 3 Change in extracellular-matrix-related gene expression following endurance training. Values are -fold changes in human skeletal muscle gene expression (mean ± SE) following six weeks of aerobic training, as described in Fig. 1. * indicates p < 0.05, ** indicates p < 0.01 and *** indicates p < 0.001.
Figure 3 Change in extracellular-matrix-related gene expression following endurance training. Values are -fold changes in human skeletal muscle gene expression (mean ± SE) following six weeks of aerobic training, as described in Fig. 1. * indicates p < 0.05, ** indicates p < 0.01 and *** indicates p < 0.001.CC BY · PubMed Central

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Authors
Timmons, J. A., Jansson, E., Fischer, H., Gustafsson, T., Greenhaff, P. L., Ridden, J., Rachman, J., & Sundberg, C. J.
Affiliations
  • Karolinska Institutet (SE)
  • University of Nottingham (GB)
  • AstraZeneca (United Kingdom) (GB)
Corresponding author
Timmons, James A
ORCID
Venue
BMC Biology
Publisher
Springer Science and Business Media LLC
Published
2005-09-02
Volume
3
Issue
1
Pages
19-19
ISSN
1741-7007 (ISSN-L)
DOI
10.1186/1741-7007-3-19
PMC
PMC1224855
OpenAlex
W1527271891
Cited by
135
References
55
Citations by year
2026: 3 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 6 · 2018: 9 · 2017: 3 · 2016: 9 · 2015: 5 · 2014: 8 · 2013: 10 · 2012: 7
FWCI
17.01
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Medical Research Council
Topics
  • Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
  • Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
Keywords
aerobic exercise training, endurance training, exercise-induced gene expression, extracellular matrix genes, cardiorespiratory fitness, high responders, low responders, VEGF receptor 2, neuropilin-1, Tie1, Tie2, angiopoietin-1, angiopoietin-2, thrombospondin-4, alpha2-macroglobulin, transforming growth factor-beta2
MeSH terms
Acclimatization, Aerobiosis, Extracellular Matrix, Gene Expression Regulation, Humans, Oxygen Consumption, Physical Fitness, Exercise, Extracellular Matrix Proteins, Gene Expression Profiling, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A

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