Txnrd2 loss in skeletal muscle causes muscle atrophy and drives leanness and obesity resistance.

The mitochondrial selenoenzyme thioredoxin reductase 2 (TXNRD2) plays a critical role in redox homeostasis and reactive oxygen species (ROS) scavenging. While heart-specific deletion of Txnrd2 in mice resulted in cardiac dysfunction, TXNRD2 function in skeletal muscle, the major component of lean body mass, remains unclear. In human GWAS the TXNRD2 locus is associated with total lean mass. Here, we show that Txnrd2 muscle-specific knockout (mTKO) induces a lean phenotype characterized by muscle atrophy and diminished adipose tissues. mTKO mice were resistant to weight gain on standard and high-fat diet. Whole body glucose clearance was increased, and ATP levels in muscle were decreased, suggesting impaired mitochondrial energy production. Transcriptomic and metabolomic analyses revealed alterations in one-carbon metabolism and related pathways. Despite elevated glutathione levels, changes in key factors of cellular detoxification were consistent with compromised antioxidant defence system. In sum, we unravel that Txnrd2 deficiency in skeletal muscle rewires whole-body energy metabolism through mitochondrial dysfunction and impaired redox capacity.