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...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54183-4 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Tang Cam Phung Pham |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ed2fae7f50be41fcb8c22822e7b50e9c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-ed2fae7f50be41fcb8c22822e7b50e9c2024-11-17T12:35:04ZengNature PortfolioNature Communications2041-17232024-11-0115112110.1038/s41467-024-54183-4The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanismsTang Cam Phung Pham0Steffen Henning Raun1Essi Havula2Carlos Henriquez-Olguín3Diana Rubalcava-Gracia4Emma Frank5Andreas Mæchel Fritzen6Paulo R. Jannig7Nicoline Resen Andersen8Rikke Kruse9Mona Sadek Ali10Andrea Irazoki11Jens Frey Halling12Stine Ringholm13Elise J. Needham14Solvejg Hansen15Anders Krogh Lemminger16Peter Schjerling17Maria Houborg Petersen18Martin Eisemann de Almeida19Thomas Elbenhardt Jensen20Bente Kiens21Morten Hostrup22Steen Larsen23Niels Ørtenblad24Kurt Højlund25Michael Kjær26Jorge L. Ruas27Aleksandra Trifunovic28Jørgen Frank Pind Wojtaszewski29Joachim Nielsen30Klaus Qvortrup31Henriette Pilegaard32Erik Arne Richter33Lykke Sylow34Department of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of CopenhagenStem Cells and Metabolism Research Program, Faculty of Medicine, University of HelsinkiDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenDivision of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenMolecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska InstitutetDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenSteno Diabetes Center Odense, Odense University HospitalDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Biology, University of CopenhagenDepartment of Biology, University of CopenhagenCharles Perkins Centre, School of Life and Environmental Sciences, University of SydneyDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenInstitute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg HospitalSteno Diabetes Center Odense, Odense University HospitalSteno Diabetes Center Odense, Odense University HospitalDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Sports Science and Clinical Biomechanics, University of Southern DenmarkSteno Diabetes Center Odense, Odense University HospitalInstitute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg HospitalMolecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska InstitutetInstitute for Mitochondrial Diseases and Aging, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), Medical Faculty, University of CologneDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenDepartment of Sports Science and Clinical Biomechanics, University of Southern DenmarkDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Biology, University of CopenhagenDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of CopenhagenAbstract 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.https://doi.org/10.1038/s41467-024-54183-4 |
| spellingShingle | 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 The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms Nature Communications |
| title | The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms |
| title_full | The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms |
| title_fullStr | The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms |
| title_full_unstemmed | The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms |
| title_short | The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms |
| title_sort | mitochondrial mrna stabilizing protein slirp regulates skeletal muscle mitochondrial structure and respiration by exercise recoverable mechanisms |
| url | https://doi.org/10.1038/s41467-024-54183-4 |
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