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PreprintCited by 19Mitochondrial Function and PathologyAdipose Tissue and MetabolismMuscle Physiology and Disorders

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The mitochondrial mRNA stabilizing protein, SLIRP, regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms

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Pham, Tang Cam Phung, Raun, Steffen Henning, Havula, Essi, Henriquez-Olguín, Carlos, Rubalcava-Gracia, Diana, Frank, Emma, Fritzen, Andreas Mæchel, Jannig, Paulo R., Andersen, Nicoline Resen, Kruse, Rikke, Ali, Mona Sadek, 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·2023·Nature Communications
DOI 10.1101/2023.10.30.564600PMC PMC11561311

Preprint — published as 10.1038/s41467-024-54183-4 · Paper page

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Abstract

Summary and graphical 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. Abstract Figure:

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Metadata

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., 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
Venue
Nature Communications
Publisher
openRxiv
Published
2023-10-30
Volume
15
Issue
1
Pages
9826-9826
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2023.10.30.564600
PMC
PMC11561311
OpenAlex
W4404311279
Cited by
19
References
1
Citations by year
2026: 10 · 2025: 9
FWCI
2.58
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
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
  • European Commission (801199, HORIZON2020)
  • University of Sydney
  • Lundbeckfonden (R380‐2021‐1451)
  • Novo Nordisk (NNF20OC0063577, NNF16OC0023418, NNF22OC0074110, NNF18OC0032082)
  • Danmarks Frie Forskningsfond (0169-00013B, 2030-00007A, 4181-00078)
  • Augustinus Fonden
  • Faculty of Health and Medical Sciences, University of Western Australia
  • Novo Nordisk Fonden (NNF22OC0074110, NNF22OC0074481, NNF20OC0063577, NNF16OC0023418, NNF18OC0032082)
  • Universitätsklinikum Köln
  • H. Lundbeck A/S
  • Bispebjerg Hospital
  • Horizon 2020 Framework Programme (801199)
  • Det Sundhedsvidenskabelige Fakultet, Københavns Universitet
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology (medical) › 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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