High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content
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Abstract
Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible, inexpensive therapeutic intervention that can improve mitochondrial bioenergetics and quality of life. By combining multiple omics techniques with biochemical and in silico normalisation, we removed the bias arising from the training-induced increase in mitochondrial content to unearth an intricate and previously undemonstrated network of differentially prioritised mitochondrial adaptations. We show that changes in hundreds of transcripts, proteins, and lipids are not stoichiometrically linked to the overall increase in mitochondrial content. Our findings suggest enhancing electron flow to oxidative phosphorylation (OXPHOS) is more important to improve ATP generation than increasing the abundance of the OXPHOS machinery, and do not support the hypothesis that training-induced supercomplex formation enhances mitochondrial bioenergetics. Our study provides an analytical approach allowing unbiased and in-depth investigations of training-induced mitochondrial adaptations, challenging our current understanding, and calling for careful reinterpretation of previous findings.
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HIIT over 6 weeks improved muscle mitochondrial respiration, prompting substantial ATP regeneration by mitochondrial OXPHOS in young human skeletal muscle tissue.
“HIIT over 6 weeks improved muscle mitochondrial respiration, prompting substantial ATP regeneration by mitochondrial OXPHOS in young human skeletal muscle tissue [69].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [69]
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Mass-spectrometry-based proteomics reveals mitochondrial supercomplexome plasticity
González-Franquesa, A., Stocks, B., Chubanava, S., Hattel, H. B., Moreno‐Justicia, R., Peijs, L., Treebak, J. T., Zierath, J. R., & Deshmukh, A. S. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109180 · Cited by 51 · see citing works
Assessment of mitochondrial respiratory chain enzymes in cells and tissues
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Mitochondrial increase in volume density with exercise training: More, larger or better?
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Flagged first, then by citations
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Cited by
Sorted by citations
Exercise Metabolism and Adaptation in Skeletal Muscle
Smith, J. A. B., Murach, K. A., Dyar, K. A., & Zierath, J. R. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00606-x · Cited by 342 · see citing works
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Exercise Induces Tissue-Specific Adaptations to Enhance Cardiometabolic Health
Ashcroft, S. P., Stocks, B., Egan, B., & Zierath, J. R. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.008 · Cited by 149 · see citing works
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Self-citationExerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis
Wang, J., Jia, D., Zhang, Z., & Wang, D. (2025) · Metabolites · doi:10.3390/metabo15010059 · Cited by 23 · see citing works
Targeting skeletal muscle mitochondrial health in obesity
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Small peptides: Could they have a big role in metabolism and the response to exercise?
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Self-citation
- Authors
- Granata, C., Caruana, N. J., Botella, J., Jamnick, N. A., Huynh, K., Kuang, J., Janssen, H. A., Reljic, B., Mellett, N. A., Laskowski, A., Stait, T. L., Frazier, A. E., Coughlan, M. T., Meikle, P. J., Thorburn, D. R., Stroud, D. A., & Bishop, D. J.
- Affiliations
- Deutsches Diabetes-Zentrum e.V. (DE)
- The University of Melbourne (AU)
- Victoria University (AU)
- Deakin University (AU)
- Baker Heart and Diabetes Institute (AU)
- Monash University (AU)
- Royal Children's Hospital (AU)
- Corresponding author
- Granata, Cesare
- Stroud, David A.
- Bishop, David J.
- ORCID
- Venue
- Nature Communications
- Published
- 2021-12-03
- Volume
- 12
- Issue
- 1
- Pages
- 7056-7056
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8642543
- OpenAlex
- W3215897669
- Cited by
- 93
- References
- 100
- Citations by year
- 2026: 10 · 2025: 22 · 2024: 19 · 2023: 22 · 2022: 20
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Victoria University Research Repository (Victoria University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Own your potential (DEAKIN) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- high-intensity training, mitochondrial proteome, skeletal muscle, mitochondrial content, electron transport chain, oxidative phosphorylation, supercomplex formation, mitochondrial bioenergetics, exercise adaptation, mitochondrial lipid metabolism, transcriptome, proteome, multi-omics integration
- MeSH terms
- High-Intensity Interval Training, Adaptation, Physiological, Adenosine Triphosphate, Adolescent, Adult, Biopsy, Electron Transport, Energy Metabolism, Humans, Male, Mitochondria, Oxidative Phosphorylation, Quality of Life, Muscle, Skeletal, Proteome, Young Adult, Healthy Volunteers
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