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

Tang Cam Phung Pham; Steffen Henning Raun; Essi Havula; Carlos Henriquez-Olguín; Diana Rubalcava-Gracia; Emma Frank; Andreas Mæchel Fritzen; Paulo R Jannig; Nicoline Resen Andersen; Rikke Kruse; Mona Sadek Ali; Andrea Irazoki; Jens Frey Halling; Stine Ringholm; Elise J Needham; Solvejg Hansen; Anders Krogh Lemminger; Peter Schjerling; Maria Houborg Petersen; Martin Eisemann de Almeida; Thomas Elbenhardt Jensen; Bente Kiens; Morten Hostrup; Steen Larsen; Niels Ørtenblad; Kurt Højlund; Michael Kjær; Jorge L Ruas; Aleksandra Trifunovic; Jørgen Frank Pind Wojtaszewski; Joachim Nielsen; Klaus Qvortrup; Henriette Pilegaard; Erik Arne Richter; Lykke Sylow

doi:10.1038/s41467-024-54183-4

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

Tang Cam Phung Pham, Steffen Henning Raun, Essi Havula, Carlos Henriquez-Olguín, Diana Rubalcava-Gracia, Emma Frank, Andreas Mæchel Fritzen, Paulo R Jannig, Nicoline Resen Andersen, Rikke Kruse, Mona Sadek Ali, Andrea Irazoki, Jens Frey Halling, Stine Ringholm, Elise J Needham, Solvejg Hansen, Anders Krogh Lemminger, Peter Schjerling, Maria Houborg Petersen, Martin Eisemann de AlmeidaThomas Elbenhardt Jensen, Bente Kiens, Morten Hostrup, Steen Larsen, Niels Ørtenblad, Kurt Højlund, Michael Kjær, Jorge L Ruas, Aleksandra Trifunovic, Jørgen Frank Pind Wojtaszewski, Joachim Nielsen, Klaus Qvortrup, Henriette Pilegaard, Erik Arne Richter, Lykke Sylow^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

Original language	English
Article number	9826
Journal	Nature Communications
Volume	15
Number of pages	21
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-024-54183-4
Publication status	Published - 13. Nov 2024

Keywords

Animals
Humans
Muscle, Skeletal/metabolism
RNA-Binding Proteins/metabolism
Male
RNA, Messenger/metabolism
Female
Mitochondria, Muscle/metabolism
Physical Conditioning, Animal
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Mitochondrial Proteins/metabolism
DNA, Mitochondrial/genetics
Mice
Drosophila melanogaster/genetics
RNA Stability
RNA, Mitochondrial/metabolism
Exercise/physiology
Drosophila/metabolism
Neoplasm Proteins

Documents & Links

10.1038/s41467-024-54183-4Licence: CC BY-NC-ND

Open access versionFinal published version, 6.31 MBLicence: CC BY-NC-ND

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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., ... Sylow, L. (2024). The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms. Nature Communications, 15, Article 9826. https://doi.org/10.1038/s41467-024-54183-4

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

abstract = "Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.",

keywords = "Animals, Humans, Muscle, Skeletal/metabolism, RNA-Binding Proteins/metabolism, Male, RNA, Messenger/metabolism, Female, Mitochondria, Muscle/metabolism, Physical Conditioning, Animal, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism, Mitochondrial Proteins/metabolism, DNA, Mitochondrial/genetics, Mice, Drosophila melanogaster/genetics, RNA Stability, RNA, Mitochondrial/metabolism, Exercise/physiology, Drosophila/metabolism, Neoplasm Proteins",

author = "Pham, {Tang Cam Phung} and Raun, {Steffen Henning} and Essi Havula and Carlos Henriquez-Olgu{\'i}n and Diana Rubalcava-Gracia and Emma Frank and Fritzen, {Andreas M{\ae}chel} and Jannig, {Paulo R} and Andersen, {Nicoline Resen} and Rikke Kruse and Ali, {Mona Sadek} and Andrea Irazoki and Halling, {Jens Frey} and Stine Ringholm and Needham, {Elise J} and Solvejg Hansen and Lemminger, {Anders Krogh} and Peter Schjerling and Petersen, {Maria Houborg} and {de Almeida}, {Martin Eisemann} and Jensen, {Thomas Elbenhardt} and Bente Kiens and Morten Hostrup and Steen Larsen and Niels {\O}rtenblad and Kurt H{\o}jlund and Michael Kj{\ae}r and Ruas, {Jorge L} and Aleksandra Trifunovic and Wojtaszewski, {J{\o}rgen Frank Pind} and Joachim Nielsen and Klaus Qvortrup and Henriette Pilegaard and Richter, {Erik Arne} and Lykke Sylow",

year = "2024",

month = nov,

day = "13",

doi = "10.1038/s41467-024-54183-4",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Pham, TCP, Raun, SH, Havula, E, Henriquez-Olguín, C, Rubalcava-Gracia, D, Frank, E, Fritzen, AM, Jannig, PR, Andersen, NR, Kruse, R, Ali, MS, Irazoki, A, Halling, JF, Ringholm, S, Needham, EJ, Hansen, S, Lemminger, AK, Schjerling, P, Petersen, MH, de Almeida, ME, Jensen, TE, Kiens, B, Hostrup, M, Larsen, S, Ørtenblad, N , Højlund, K, Kjær, M, Ruas, JL, Trifunovic, A, Wojtaszewski, JFP, Nielsen, J, Qvortrup, K, Pilegaard, H, Richter, EA & Sylow, L 2024, 'The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms', Nature Communications, vol. 15, 9826. https://doi.org/10.1038/s41467-024-54183-4

TY - JOUR

T1 - The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms

AU - Pham, Tang Cam Phung

AU - Raun, Steffen Henning

AU - Havula, Essi

AU - Henriquez-Olguín, Carlos

AU - Rubalcava-Gracia, Diana

AU - Frank, Emma

AU - Fritzen, Andreas Mæchel

AU - Jannig, Paulo R

AU - Andersen, Nicoline Resen

AU - Kruse, Rikke

AU - Ali, Mona Sadek

AU - Irazoki, Andrea

AU - Halling, Jens Frey

AU - Ringholm, Stine

AU - Needham, Elise J

AU - Hansen, Solvejg

AU - Lemminger, Anders Krogh

AU - Schjerling, Peter

AU - Petersen, Maria Houborg

AU - de Almeida, Martin Eisemann

AU - Jensen, Thomas Elbenhardt

AU - Kiens, Bente

AU - Hostrup, Morten

AU - Larsen, Steen

AU - Ørtenblad, Niels

AU - Højlund, Kurt

AU - Kjær, Michael

AU - Ruas, Jorge L

AU - Trifunovic, Aleksandra

AU - Wojtaszewski, Jørgen Frank Pind

AU - Nielsen, Joachim

AU - Qvortrup, Klaus

AU - Pilegaard, Henriette

AU - Richter, Erik Arne

AU - Sylow, Lykke

PY - 2024/11/13

Y1 - 2024/11/13

N2 - Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

AB - Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

KW - Animals

KW - Humans

KW - Muscle, Skeletal/metabolism

KW - RNA-Binding Proteins/metabolism

KW - Male

KW - RNA, Messenger/metabolism

KW - Female

KW - Mitochondria, Muscle/metabolism

KW - Physical Conditioning, Animal

KW - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism

KW - Mitochondrial Proteins/metabolism

KW - DNA, Mitochondrial/genetics

KW - Mice

KW - Drosophila melanogaster/genetics

KW - RNA Stability

KW - RNA, Mitochondrial/metabolism

KW - Exercise/physiology

KW - Drosophila/metabolism

KW - Neoplasm Proteins

U2 - 10.1038/s41467-024-54183-4

DO - 10.1038/s41467-024-54183-4

M3 - Journal article

C2 - 39537626

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 9826

ER -

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

Abstract

Keywords

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