Pham, T. C. P.; Raun, S. H.; Havula, E.; Henriquez-Olguin, C.; Rubalcava-Gracia, D.; Frank, E.; Fritzen, A. M.; Jannig, P. R.; Andersen, N. R.; Kruse, R.; Ali, M.; Halling, J. F.; Ringholm, S.; Hansen, S.; Lemminger, A. K.; Schjerling, P.; Petersen, M. H.; de Almeida, M. E.; Jensen, T. E.; Kiens, B.; Hostrup, M.; Larsen, S.; Ortenblad, N.; Hojlund, K.; Kjaer, M.; Ruas, J. L.; Trifunovic, A.; Wojtaszewski, J. F. P.; Nielsen, J.; Qvortrup, K.; Pilegaard, H.; Richter, E. A.; Sylow, L.

The decline in mitochondrial function is associated with decreased muscle mass and strength in multiple conditions, including sarcopenia, type 2 diabetes, and cancer. Treatment of these diseases could include improving mitochondrial function, however, there are limited and equivocal data regarding the molecular cues that control muscle mitochondrial plasticity. Here we uncover the mitochondrial-mRNA-stabilizing protein SLIRP, in complex with LRPPRC, as a PGC-1 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 a mechanism likely including increased mitoribosome translation capacity. In human skeletal muscle, exercise training robustly increased SLIRP and LRPPRC protein content across exercise modalities and sexes, yet this increase was less prominent in type 2 diabetes. Our work identifies a new mechanism of posttranscriptional mitochondrial regulation in skeletal muscle through mitochondrial mRNA stabilization. Moreover, it emphasizes exercise as an effective approach to alleviate mitochondrial dysfunction.