SMYD2 is a non-canonical regulator of skeletal muscle glucose availability

Rapid changes in systemic glucose control following a reduction in physical activity are linked to physiological adaptations occurring in skeletal muscle; however, the molecular mechanisms responsible for inducing these effects are not well understood. Using a transcriptomic approach, we previously identified SET [Su(Var)3-9, Enhancer-of-zeste and Trithorax] and MYND [Myeloid, Nervy, and DEAF-1]-domain containing 2 (SMYD2) as a putative mediator of early inactivity-driven metabolic adaptations. The aim of this project was to determine the effects of small molecule SMYD2 inhibition on muscle glucose availability and systemic glucose regulation in vivo. We hypothesized that SMYD2 inhibition would modulate blood glucose concentrations indirectly, via mechanisms controlling muscle glucose availability. Chow-fed female (n=10 per group) and male (n=9 per group) 14-week-old C57BL/6NJ mice received once daily intraperitoneal injections of either vehicle (v/v, 45% 0.9% w/v saline, 40% PEG300, 5% Tween 80, and 10% DMSO) or the small molecule SMYD2 inhibitor BAY-598 (50 mg/kg prepared in vehicle) over a two-week period. Compared to vehicle treatment, SMYD2 inhibition had no effect on blood glucose concentrations after 24 h but by the fourth day, glucose concentrations were decreased in both male (-7.7%, p=0.029) and female mice (-11.4%, p=0.060). After 14 days of SMYD2 inhibition, glucose concentrations during an intraperitoneal glucose tolerance test tended to be increased (AUC females: +6.3%, p=0.070; males +8.0%, p=0.246), an effect primarily driven by a greater magnitude glucose peak at 15 min post-glucose injection (females: +19.3%, p=0.0825; males: +9.7%, p=0.289). SMYD2 inhibition increased the amount of glycogen stored in the plantaris muscle in male mice (+20.1%, p< 0.001) despite liver glycogen stores remaining similar between groups. Increased muscle glycogen was associated with altered expression of key proteins involved in glycogenolysis, including an increase in the abundance of total and phosphorylated forms of the muscle isoform of glycogen phosphorylase (PYGM: +15.5%, p=0.021; phospho-PYGMS430: +56.1%, p=0.027), whereas the abundance of the alpha and gamma subunits of phosphorylase kinase (which activates PYGM) were either decreased (PHKA1: -17.4%, p=0.04) or unchanged (PHKG1). Notably, two weeks of SMYD2 inhibition had little effect on grip strength or maximal running capacity during a graded treadmill test; however, glucose concentrations at the end of the maximal running test were reduced in response to SMYD2 inhibition (females: -9.1%, p=0.005; males: -5.1%, p=0.203) despite post-exercise blood lactate concentrations remaining similar between groups. Together, these findings suggest that SMYD2 plays a previously undefined role in regulating glucose homeostasis, likely via mechanisms that control skeletal muscle glucose availability via glycogen breakdown. Future studies will delineate the specific interaction partners through which SMYD2 mediates these effects and define whether elevations in SMYD2 in the early stages of physical inactivity contribute to the rapid manifestation of muscle insulin resistance and impaired glucose control. 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.