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Cited by 120Cardiovascular and exercise physiologyMuscle Physiology and DisordersAdipose Tissue and Metabolism

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Time Course Analysis Reveals Gene-Specific Transcript and Protein Kinetics of Adaptation to Short-Term Aerobic Exercise Training in Human Skeletal Muscle

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Egan, Brendan, O’Connor, Paul L., Zierath, Juleen R., O’Gorman, Donal J.·2013·PLoS ONE
DOI 10.1371/journal.pone.0074098PMC PMC3771935
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Abstract

Repeated bouts of episodic myofibrillar contraction associated with exercise training are potent stimuli for physiological adaptation. However, the time course of adaptation and the continuity between alterations in mRNA expression and protein content are not well described in human skeletal muscle. Eight healthy, sedentary males cycled for 60 min at 80% of peak oxygen consumption (VO2peak) each day for fourteen consecutive days, resulting in an increase in VO2peak of 17.5±3.8%. Skeletal muscle biopsies were taken at baseline, and on the morning following (+16 h after exercise) the first, third, seventh, tenth and fourteenth training sessions. Markers of mitochondrial adaptation (Cyt c and COXIV expression, and citrate synthase activity) were increased within the first week of training, but the mtDNA/nDNA ratio was unchanged by two weeks of training. Accumulation of PGC-1α and ERRα protein during training suggests a regulatory role for these factors in adaptations of mitochondrial and metabolic gene expression. A subset of genes were transiently increased after one training session, but returned to baseline levels thereafter, which is supportive of the concept of transcriptional capacity being particularly sensitive to the onset of a new level of contractile activity. Thus, gene-specific temporal patterns of induction of mRNA expression and protein content are described. Our results illustrate the phenomenology of skeletal muscle plasticity and support the notion that transcript level adjustments, coupled to accumulation of encoded protein, underlie the modulation of skeletal muscle metabolism and phenotype by regular exercise.

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Figure 1 Study design for time course analysis of exercise training-induced changes in skeletal muscle gene expression. Each subject performed fourteen consecutive days of exercise training on a stationary cycle ergometer with one session each day for 60-training 80%VO2peak. Skeletal muscle biopsies were taken at baseline (day 0), and on the morning following the first, third, seventh, tenth and fourteenth training sessions. In order to monitor exercise intensity, oxygen uptake was measured for 5 min at three time points (15–20 min, 35–40 min and 55–60 min) during each training session.
Figure 1 Study design for time course analysis of exercise training-induced changes in skeletal muscle gene expression. Each subject performed fourteen consecutive days of exercise training on a stationary cycle ergometer with one session each day for 60-training 80%VO2peak. Skeletal muscle biopsies were taken at baseline (day 0), and on the morning following the first, third, seventh, tenth and fourteenth training sessions. In order to monitor exercise intensity, oxygen uptake was measured for 5 min at three time points (15–20 min, 35–40 min and 55–60 min) during each training session.CC BY · PubMed Central
Figure 2 Representative immunoblots for proteins of interest. Protein extracts from skeletal muscle biopsies prior to training (BL, baseline) and after 1, 3, 7, 10 and 14 days of aerobic exercise training were resolved by SDS-PAGE and subjected to immunoblot directed against the protein of interest indicated. Approximate location of molecular weight markers (RPN 800E; GE Healthcare/Amersham) is also indicated. See Table S1 in File S1 for full list of abbreviations.
Figure 2 Representative immunoblots for proteins of interest. Protein extracts from skeletal muscle biopsies prior to training (BL, baseline) and after 1, 3, 7, 10 and 14 days of aerobic exercise training were resolved by SDS-PAGE and subjected to immunoblot directed against the protein of interest indicated. Approximate location of molecular weight markers (RPN 800E; GE Healthcare/Amersham) is also indicated. See Table S1 in File S1 for full list of abbreviations.CC BY · PubMed Central
Figure 3 Effect of exercise training on maximal oxygen uptake (A&B), and markers of mitochondrial adaptation (C-H). Aerobic capacity was determined prior to training (Baseline) and 72 h after the last training session (After training). A, average group improvement in aerobic capacity in response to exercise training. B, individual changes in aerobic capacity expressed as percentage increase from Baseline. C, relative copy number of mtDNA and nDNA was determined by qPCR directed toward non-coding DNA fragments in the mitochondrial and nuclear genomes. D, maximal enzymatic activity of citrate synthase. E, relative mRNA expression of COXIV. F, protein content of COXIV. G, relative mRNA expression of cytochrome c. H, protein content of cytochrome c. mRNA expression was normalized to the housekeeping gene GAPDH. Values are mean ± SEM, n = 7–8. * trend for a significant difference compared to Baseline (P<0.1), ** significantly different from Baseline (P<0.05), *** significantly different from Baseline (P<0.005).
Figure 3 Effect of exercise training on maximal oxygen uptake (A&B), and markers of mitochondrial adaptation (C-H). Aerobic capacity was determined prior to training (Baseline) and 72 h after the last training session (After training). A, average group improvement in aerobic capacity in response to exercise training. B, individual changes in aerobic capacity expressed as percentage increase from Baseline. C, relative copy number of mtDNA and nDNA was determined by qPCR directed toward non-coding DNA fragments in the mitochondrial and nuclear genomes. D, maximal enzymatic activity of citrate synthase. E, relative mRNA expression of COXIV. F, protein content of COXIV. G, relative mRNA expression of cytochrome c. H, protein content of cytochrome c. mRNA expression was normalized to the housekeeping gene GAPDH. Values are mean ± SEM, n = 7–8. * trend for a significant difference compared to Baseline (P<0.1), ** significantly different from Baseline (P<0.05), *** significantly different from Baseline (P<0.005).CC BY · PubMed Central
Figure 4 Training-induced alterations in gene expression of members of the PGC-1 family of transcriptional coactivators. A, relative mRNA expression of PGC-1α. B, protein content of PGC-1α. C, relative mRNA expression of PGC-1β. D, relative mRNA expression of PRC. mRNA expression was normalized to the housekeeping gene GAPDH. Values are mean ± SEM, n = 7–8. * trend for a significant difference compared to Baseline (P<0.1), ** significantly different from Baseline (P<0.05), *** significantly different from Baseline (P<0.005).
Figure 4 Training-induced alterations in gene expression of members of the PGC-1 family of transcriptional coactivators. A, relative mRNA expression of PGC-1α. B, protein content of PGC-1α. C, relative mRNA expression of PGC-1β. D, relative mRNA expression of PRC. mRNA expression was normalized to the housekeeping gene GAPDH. Values are mean ± SEM, n = 7–8. * trend for a significant difference compared to Baseline (P<0.1), ** significantly different from Baseline (P<0.05), *** significantly different from Baseline (P<0.005).CC BY · PubMed Central
Figure 5 Training-induced alterations in the expression of selected transcriptional regulators of skeletal muscle gene expression. A, relative mRNA expression of NRF-2. B, protein content of NRF-2. C, relative mRNA expression of ERRα. D, protein content of ERRα. E, relative mRNA expression of Tfam. F, protein content of Tfam. G, protein content of Mfn2. H, protein content of DRP-1. mRNA expression was normalized to the housekeeping gene GAPDH. Values are mean ± SEM, n = 7–8. * trend for a significant difference compared to Baseline (P<0.1), ** significantly different from Baseline (P<0.05), *** significantly different from Baseline (P<0.005).
Figure 5 Training-induced alterations in the expression of selected transcriptional regulators of skeletal muscle gene expression. A, relative mRNA expression of NRF-2. B, protein content of NRF-2. C, relative mRNA expression of ERRα. D, protein content of ERRα. E, relative mRNA expression of Tfam. F, protein content of Tfam. G, protein content of Mfn2. H, protein content of DRP-1. mRNA expression was normalized to the housekeeping gene GAPDH. Values are mean ± SEM, n = 7–8. * trend for a significant difference compared to Baseline (P<0.1), ** significantly different from Baseline (P<0.05), *** significantly different from Baseline (P<0.005).CC BY · PubMed Central
Figure 6 Training-induced alterations in gene expression of selected metabolic targets. A, relative mRNA expression of PDK4. B, protein content of PDK4. C, relative mRNA expression of HKII. D, protein content of HKII. E, relative mRNA expression of GLUT4. F, protein content of GLUT4. mRNA expression was normalized to the housekeeping gene GAPDH. Values are mean ± SEM, n = 7–8. * trend for a significant difference compared to Baseline (P<0.1), ** significantly different from Baseline (P<0.05), *** significantly different from Baseline (P<0.005).
Figure 6 Training-induced alterations in gene expression of selected metabolic targets. A, relative mRNA expression of PDK4. B, protein content of PDK4. C, relative mRNA expression of HKII. D, protein content of HKII. E, relative mRNA expression of GLUT4. F, protein content of GLUT4. mRNA expression was normalized to the housekeeping gene GAPDH. Values are mean ± SEM, n = 7–8. * trend for a significant difference compared to Baseline (P<0.1), ** significantly different from Baseline (P<0.05), *** significantly different from Baseline (P<0.005).CC BY · PubMed Central

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Metadata

Authors
Egan, B., O’Connor, P. L., Zierath, J. R., & O’Gorman, D. J.
Affiliations
  • University College Dublin (IE)
  • Dublin City University (IE)
  • Karolinska Institutet (SE)
Corresponding author
O’Gorman, Donal J.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-09-12
Volume
8
Issue
9
Pages
e74098
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0074098
PMC
PMC3771935
OpenAlex
W2020255277
Cited by
120
References
61
Citations by year
2026: 4 · 2025: 3 · 2024: 7 · 2023: 11 · 2022: 10 · 2021: 14 · 2020: 7 · 2019: 12 · 2018: 10 · 2017: 8 · 2016: 20 · 2015: 8 · 2014: 5 · 2013: 1
FWCI
26.79
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Irish Research Council for Science, Engineering and Technology
  • Dublin City University
  • European Foundation for the Study of Diabetes
  • Irish Research Council
  • Karolinska Institutet
  • Novo Nordisk
  • Vetenskapsrådet
Topics
  • Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Keywords
aerobic exercise training, skeletal muscle adaptation, temporal gene expression, mRNA expression, protein content, mitochondrial biogenesis, PGC-1α, estrogen-related receptor alpha, citrate synthase, cytochrome c, cytochrome c oxidase subunit IV, mtDNA/nDNA ratio, skeletal muscle plasticity, human skeletal muscle
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adaptation, Physiological, Adult, Carrier Proteins, Gene Expression Regulation, Humans, Kinetics, Male, Mitochondria, Oxygen Consumption, Time Factors, Transcription Factors, Transcription, Genetic, Biomarkers, Exercise, RNA-Binding Proteins, Muscle, Skeletal, Proteome, Young Adult, Transcriptome

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