Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes

Authors

• Wagner S. Dantas, Pennington Biomedical Research Center, Baton Rouge, LA
• Elizabeth C. Heintz, Pennington Biomedical Research Center, Baton Rouge, LA
• Elizabeth R M Zunica, Pennington Biomedical Research Center, Baton Rouge, LA
• Jacob T. Mey, Pennington Biomedical Research Center, Baton Rouge, LA
• Melissa L. Erickson, Pennington Biomedical Research Center, Baton Rouge, LA
• Kathryn P. Belmont, Pennington Biomedical Research Center, Baton Rouge, LA
• Analisa L. Taylor, Pennington Biomedical Research Center, Baton Rouge, LA
• Gangarao Davuluri, Pennington Biomedical Research Center, Baton Rouge, LA
• Hisashi Fujioka, Case Western Reserve University, Cleveland, OH
• Ciarán E. Fealy, Cleveland Clinic Foundation, Cleveland, OH
• Charles L. Hoppel, Pennington Biomedical Research Center, Baton Rouge, LA
• Christopher L. Axelrod, Pennington Biomedical Research Center, Baton Rouge, LA
• John P. Kirwan, Pennington Biomedical Research Center, Baton Rouge, LA

Document Type

Article

Publication Date

3-4-2025

Publication Title

Journal of Cachexia, Sarcopenia and Muscle

Abstract

Background Activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. We hypothesized that differences in mitochondrial dynamics, structure and bioenergetics in humans would explain the onset and progression of type 2 diabetes (T2D). Methods Fifty-eight sedentary adults (37 ± 12 years) were enrolled into one of three groups: (1) healthy weight (HW), (2) overweight and obesity (Ow/Ob), or (3) T2D. Body composition, aerobic capacity, and insulin sensitivity were assessed during a 3-day inpatient stay. A fasted skeletal muscle biopsy was obtained to assess mitochondrial functions. C2C12 myoblasts were transfected with FLAG-HA-USP15 and FLAG-HA-USP30 and harvested to assess mitochondrial dynamics and cellular insulin action. Results Insulin sensitivity and aerobic capacity were lower in Ow/Ob (132% and 28%, respectively) and T2D (1024% and 83%, respectively) relative to HW. Patients with T2D presented with elevated skeletal muscle mitochondrial fission (3.2 fold relative to HW and Ow/Ob), decreased fusion, and impairments in quality control. Mitochondrial content was lower in Ow/Ob (26%) and T2D (56%). USP13 (84%), USP15 (96%) and USP30 (53%) expression were increased with decreased Parkin and Ub activation in T2D alone. USP15 (R2 = 0.55, p <  0.0001) and USP30 (R2 = 0.40, p <  0.0001) expression negatively correlated with peripheral insulin sensitivity. USP15 and USP30 overexpression activated DRP1 (3.6 and 3.7 fold, respectively) while inhibiting AKT (96% and 81%, respectively) and AS160 (2.1 and 3.5 fold, respectively) phosphorylation. Conclusion Mitochondrial fragmentation bypasses defects in mitophagy to sustain skeletal muscle quality control in patients with T2D.

First Page

1*

Last Page

18

DOI

10.1002/jcsm.13763

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Dantas, Wagner S.; Heintz, Elizabeth C.; Zunica, Elizabeth R M; Mey, Jacob T.; Erickson, Melissa L.; Belmont, Kathryn P.; Taylor, Analisa L.; Davuluri, Gangarao; Fujioka, Hisashi; Fealy, Ciarán E.; Hoppel, Charles L.; Axelrod, Christopher L.; and Kirwan, John P., "Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes" (2025). LSU-LCMC Cancer Center Faculty Publications. 216.
https://digitalscholar.lsuhsc.edu/llcc_facpubs/216
10.1002/jcsm.13763