The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms
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Abstract
Abstract Decline in mitochondrial function associates with decreased muscle mass and strength in multiple conditions, including sarcopenia and type 2 diabetes. Optimal treatment could include improving mitochondrial function, however, there are limited and equivocal data regarding the molecular cues controlling muscle mitochondrial plasticity. Here we uncover the mitochondrial-mRNA-stabilizing protein SLIRP, in complex with LRPPRC, as a PGC-1α target that regulates mitochondrial structure, respiration, and mitochondrially-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracted mitochondrial defects induced by loss of LRPPRC/SLIRP, despite sustained low mitochondrially-encoded-mRNA pools, via increased mitoribosome translation capacity. In humans, exercise training robustly increased muscle SLIRP and LRPPRC protein content across exercise modalities and sexes, yet this increase was less prominent in subjects with type 2 diabetes. Our work identifies a mechanism of post-transcriptional mitochondrial regulation in skeletal muscle through mitochondrial mRNA stabilization. It emphasizes exercise as an effective approach to alleviate mitochondrial defects by possibly increasing mitoribosome capacity.
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- Authors
- Pham, T. C. P., Raun, S. H., Havula, E., Henriquez-Olguín, C., Rubalcava-Gracia, D., Frank, E., Fritzen, A. M., Jannig, P. R., Andersen, N. R., Kruse, R., Ali, M. S., Irazoki, A., Halling, J. F., Ringholm, S., Needham, E. J., Hansen, S., Lemminger, A. K., Schjerling, P., Petersen, M. H., de Almeida, M. E., Jensen, T. E., Kiens, B., Hostrup, M., Larsen, S., Ørtenblad, N., Højlund, K., Kjær, M., Ruas, J. L., Trifunovic, A., Wojtaszewski, J. F. P., Nielsen, J., Qvortrup, K., Pilegaard, H., Richter, E. A., & Sylow, L.
- Affiliations
- University of Copenhagen (DK)
- University of Helsinki (FI)
- Karolinska Institutet (SE)
- Odense University Hospital (DK)
- The University of Sydney (AU)
- University of Southern Denmark (DK)
- Corresponding author
- Sylow, Lykke
- ORCID
- Pham, Tang Cam Phung
- Raun, Steffen Henning
- Havula, Essi
- Henriquez-Olguín, Carlos
- Rubalcava-Gracia, Diana
- Fritzen, Andreas Mæchel
- Jannig, Paulo R.
- Andersen, Nicoline Resen
- Kruse, Rikke
- Ali, Mona Sadek
- Irazoki, Andrea
- Halling, Jens Frey
- Ringholm, Stine
- Needham, Elise J.
- Hansen, Solvejg
- Lemminger, Anders Krogh
- Schjerling, Peter
- Petersen, Maria Houborg
- de Almeida, Martin Eisemann
- Jensen, Thomas Elbenhardt
- Kiens, Bente
- Hostrup, Morten
- Larsen, Steen
- Ørtenblad, Niels
- Højlund, Kurt
- Kjær, Michael
- Ruas, Jorge L.
- Trifunovic, Aleksandra
- Wojtaszewski, Jørgen Frank Pind
- Nielsen, Joachim
- Qvortrup, Klaus
- Pilegaard, Henriette
- Richter, Erik Arne
- Sylow, Lykke
- Venue
- Nature Communications
- Published
- 2024-11-13
- Volume
- 15
- Issue
- 1
- Pages
- 9826-9826
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11561311
- OpenAlex
- W4404311279
- Cited by
- 19
- References
- 16
- Citations by year
- 2026: 10 · 2025: 9
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Työväentutkimus Vuosikirja (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by-nc-nd)
- Funders
- Novo Nordisk Fonden (NNF16OC0023418, NNF18OC0032082, NNF20OC0063577)
- EC | Horizon 2020 Framework Programme (801199)
- Lundbeckfonden (R380-2021-1451)
- Det Frie Forskningsråd (2030-00007A)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- LRPPRC, skeletal muscle mitochondria, mitochondrial respiration, exercise training, PGC-1α, mitochondrial quality control, post-transcriptional regulation, type 2 diabetes, sarcopenia, mitochondrial plasticity
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, RNA, Mitochondrial, Animals, DNA, Mitochondrial, Drosophila, Drosophila melanogaster, Female, Humans, Male, Mitochondria, Muscle, Neoplasm Proteins, Physical Conditioning, Animal, RNA, Messenger, Exercise, RNA-Binding Proteins, Muscle, Skeletal, RNA Stability, Mitochondrial Proteins, Mice
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