Fig. 4: Skeletal muscle PanK4 regulates whole-body insulin sensitivity and muscle glucose uptake.

A, B glucose tolerance in male PanK4 WT and PanK4 mKO mice at indicated ages (n = 8 for WT and n = 6 for mKO). C fasting plasma insulin concentrations in male PanK4 WT and PanK4 mKO mice (n = 8 for WT and n = 6 for mKO). D ex vivo basal- or insulin (3.0 nM)-stimulated glucose uptake in skeletal muscle (EDL) from male PanK4 WT and PanK4 mKO mice (n = 8 for WT/basal, n = 8 for WT/insulin, n = 8 for mKO/basal, n = 7 for mKO/insulin). Maximal running speed (E) and maximal distance (F) during treadmill running of male PanK4 WT and PanK4 mKO (n = 9). G glucose uptake into indicated skeletal muscle during 20 min of rest or treadmill running at 75% of maximal running capacity in male PanK4 WT and PanK4 mKO mice (rest: n = 9 for WT/quad, n = 9 for WT/triceps, n = 10 for WT/gastroc, n = 7 for mKO; running: n = 9 for WT, n = 8 for mKO/quad, n = 6 for mKO/triceps, n = 7 for mKO/gastroc). H acetyl-CoA levels determined by targeted analyses in quadriceps muscle from male PanK4 WT and PanK4 mKO mice that had ran on the treadmill (n = 11 for WT and n = 10 for mKO). Male C57BL/6J mice aged 12–16 weeks were treated with recombinant adeno‐associated virus serotype 6 encoding PanK4 (rAAV6:PanK4) injected into  tibialis anterior (TA) muscle, while contralateral TA was injected with rAAV6:MCS as a control: PanK4 protein abundance (I) and glucose uptake (J, n = 13) in TA muscles were determined 14 days later in fed mice. K acetyl-CoA detected by non-targeted metabolomics in fasted or refed male C57BL6/J mice overexpressing PanK4 in one TA and MCS in contralateral TA (n = 4 for MCS/fast, n = 6 for MCS/fed, n = 4 for PanK4/fast, n = 6 for PanK4/fed). A–H, J, K data are presented as mean values +/− SEM. Statistic: A, B repeated measures two-way (time x genotype) ANOVA; C two-tailed student’s t-test; D two-way (genotype x insulin) ANOVA; G two-way ANOVA (genotype x muscle) within rest or run; H two-tailed student’s t-test. J two-tailed student’s t-test; K two-way (genotype x feeding) ANOVA. Statistical analyses were conducted with log2-transformed data. Šidák post hoc testing. Source data are provided as a Source Data file. Schematic in A was created in BioRender. Kleinert, M. (2024) BioRender.com/m45y371; schematic in I was created in BioRender. Kleinert, M. (2024) BioRender.com/l81e607.