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

Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark. · pubmed

Paper

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.

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Research summary

The paper investigates the role of the SLIRP protein in regulating mitochondrial function in skeletal muscle, which is directly linked to muscle mass and strength decline associated with aging and conditions like sarcopenia and type 2 diabetes. By exploring mechanisms of mitochondrial plasticity and the effects of exercise on mitochondrial function, the research contributes to understanding potential interventions for age-related decline in muscle health. However, while the findings are solid, they do not present a groundbreaking advance in the field, thus warranting a moderate impact score.

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