Key points are not available for this paper at this time.
Introduction: Skeletal muscle mitochondrial content declines in patients with type 2 diabetes (T2D), which is driven by prolonged hyperactivation of DRP1-mediated organelle fission. However, the mechanism underlying activation of fission and its relation to the regulation of glucose uptake in T2D remains largely unknown. The purpose of this study was to examine the influence of ubiquitin function on mitochondrial quality control and DRP1 hyperactivation in patients with T2D. Methods: 58 sedentary adults (37±12 years) were enrolled into one of three groups based upon the following criteria: (1) healthy weight without T2D (HW); (2) obesity without T2D (Ob); or (3) obesity with T2D (T2D). Participants underwent a 3-day inpatient stay for measurements of body composition (DXA), aerobic capacity (VO2MAX), and insulin sensitivity (hyperinsulinemic euglycemic clamp). A skeletal muscle biopsy was obtained for determination of mitochondrial dynamics (Western blot) and isolation of primary human skeletal muscle (pHSkM) cells. pHSkM cells were transfected with FLAG-USP15/USP30 to induce overexpression. Glucose uptake was measured by incorporation of 3H-2-deoxy-d-glucose. Comparisons were made by one-way ANOVA with contrasts. Results: USP13, USP15, and USP30 expression were increased in T2D relative to Ov/Ob and HW (all P0.05). USP15 and USP30 interaction with Parkin decreased in T2D relative to Ov/Ob and HW (all P0.05). USP15 (R2=0.55, P0.0001) and USP30 (R2=0.40, P0.0001) expression negatively correlated with peripheral insulin sensitivity. USP15 and USP30 overexpression activated DRP1 while blocking ubiquitin-mediated Parkin activation. Conclusions: Ubiquitin protease function is heightened in patients with T2D which impairs mitochondrial quality control, promotes excessive mitochondrial fission, depletes mitochondrial volume, and restricts glucose uptake. Disclosure C.L. Axelrod: None. W.S. Dantas: None. E.C. Heintz: None. E.R.M. Zunica: None. G. Davuluri: None. J.P. Kirwan: None. Funding National Institutes of Health (DK108089 and GM104940)
Axelrod et al. (Fri,) studied this question.