Tribbles 3 Deletion Improves Glucose Tolerance but Does Not Augment Exercise-Induced Mitochondrial Biogenesis

Tribbles 3 (TRB3) is a pseudokinase that influences metabolic and differentiation pathways through its inhibition of Akt phosphorylation. Although the protein has been studied in metabolic dysregulation, the extent to which its absence influences the adaptive responses to endurance exercise remains unclear. To determine whether loss of TRB3 enhances exercise-induced metabolic remodeling, we examined TRB3 knockout (KO) and wide-type (WT) mice following six weeks of either voluntary wheel running or involuntary treadmill exercise. Across both exercise modalities, KO mice consistently demonstrated improved whole-body glucose tolerance compared to WT controls. Despite this favorable effect on systemic glucose handling, KO did not potentiate exercise-induced skeletal muscle adaptations, evidenced by no changes in GLUT4 and hexokinase II (HXKII) proteins compared to WT mice. Molecular markers for mitochondrial biogenesis (PGC1α, COX4, Cyt c) were not different at either the protein or mRNA level in KO mice compared to WT controls. Citrate synthesis increases with training, however, there was no significance observed in the knockout group. Taken together, these findings indicate that whole TRB3 deletion enhances glucose tolerance independently of exercise, it does not further augment the molecular or mitochondrial adaptations of skeletal muscle to endurance training, suggesting that TRB3 primarily influences systemic glucose regulation rather than acting as a central modulator of exercise-induced remodeling in skeletal muscle. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.