Olanzapine induces Mdivi-1-resistant disruption of insulin signaling in skeletal muscle cells

Introduction Second‐generation antipsychotics such as olanzapine (OLZ) are widely prescribed because they produce fewer extrapyramidal adverse effects than first‐generation agents. However, OLZ is strongly associated with metabolic dysfunction, and alterations in mitochondrial dynamics have been proposed to contribute to these effects. We investigated whether OLZ‐induced mitochondrial dysfunction is linked to impaired insulin signaling in skeletal muscle cells and explored a potential interaction with the mitochondrial fission regulator dynamin‐related protein 1 (DRP1). Methods L6 skeletal myoblasts were treated with OLZ, alone or in combination with the mitochondrial fission inhibitor Mdivi‐1. Insulin signaling, glucose uptake, mitochondrial morphology, and insulin‐stimulated mitochondrial bioenergetics were evaluated. In parallel, molecular dynamics simulations and MM/PBSA calculations were performed using a common DRP1/Mg 2 + receptor model to compare the interactions of protonated OLZ and Mdivi‐1 within the DRP1 GTPase domain. Results OLZ reduced insulin‐mediated signaling and glucose uptake, promoted mitochondrial fragmentation, and impaired the insulin‐induced increase in mitochondrial bioenergetic activity. Co-treatment with Mdivi‐1 partially rescued OLZ‐induced mitochondrial fragmentation but did not restore insulin responsiveness. Molecular simulations showed that protonated OLZ and Mdivi‐1 remained within the same hydrophobic region of the DRP1 GTPase domain and shared an anchoring interaction involving Ile252. Their calculated MM/PBSA interaction free energies were similar (–22.26 ± 1.7 and –24.50 ± 0.5 kcal mol − 1 , respectively), supporting compatible occupancy of a shared binding region but not demonstrating high‐affinity or GTP‐competitive binding. Discussion These findings indicate that OLZ disrupts mitochondrial dynamics and bioenergetics while decreasing insulin sensitivity in skeletal muscle cells. However, the dissociation between recovery of mitochondrial morphology and persistence of insulin resistance suggests that excessive mitochondrial fission alone does not account for OLZ‐induced metabolic dysfunction. The computational results are compatible with an interaction of OLZ with the DRP1 GTPase domain but do not establish DRP1 as its primary pharmacological target. OLZ‐associated insulin resistance therefore likely involves additional, potentially extramitochondrial mechanisms.