1. The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.
- Author
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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, and Sylow L
- Subjects
- Animals, Humans, Male, Female, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Mitochondrial Proteins metabolism, Mitochondrial Proteins genetics, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Mice, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, RNA Stability, RNA, Mitochondrial metabolism, RNA, Mitochondrial genetics, Exercise physiology, Drosophila metabolism, Neoplasm Proteins, Muscle, Skeletal metabolism, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, RNA, Messenger metabolism, RNA, Messenger genetics, Mitochondria, Muscle metabolism, Physical Conditioning, Animal
- 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., Competing Interests: Competing interests Since the study concluded, Solvejg Hansen, Jens Frey Halling and Anders Krogh Lemminger have become employees and shareholders of Novo Nordisk A/S, Denmark. The remaining authors declare no competing interests., (© 2024. The Author(s).)
- Published
- 2024
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