Insulin and IGF-1 receptors regulate complex I–dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle
Gourav Bhardwaj, … , E. Dale Abel, Brian T. O’Neill
Gourav Bhardwaj, … , E. Dale Abel, Brian T. O’Neill
Published August 3, 2021
Citation Information: J Clin Invest. 2021;131(18):e146415. https://doi.org/10.1172/JCI146415.
View: Text | PDF
Research Article Endocrinology

Insulin and IGF-1 receptors regulate complex I–dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle

Abstract

Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. The actions of insulin and IGF-1 through the insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of forkhead box O (FoxO) transcription factors, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. We show that mitochondrial respiration and complex I activity were decreased in streptozotocin (STZ) diabetic muscle, but these defects were reversed in muscle-specific FoxO1, -3, and -4 triple-KO (M-FoxO TKO) mice rendered diabetic with STZ. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR KO (M-IR–/–) or combined IR/IGF1R KO (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR, IGF1R, and FoxO1, -3, and -4 quintuple-KO mice (M-QKO). Acute tamoxifen-inducible deletion of IR and IGF1R also decreased muscle pyruvate respiration, complex I activity, and supercomplex assembly. Although autophagy was increased when IR and IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-Seq revealed that complex I core subunits were decreased in STZ-diabetic and MIGIRKO muscle, and these changes were not present with FoxO KO in STZ-FoxO TKO and M-QKO mice. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex I–driven mitochondrial respiration and supercomplex assembly in part by FoxO-mediated repression of complex I subunit expression.

Authors

Gourav Bhardwaj, Christie M. Penniman, Jayashree Jena, Pablo A. Suarez Beltran, Collin Foster, Kennedy Poro, Taylor L. Junck, Antentor O. Hinton Jr., Rhonda Souvenir, Jordan D. Fuqua, Pablo E. Morales, Roberto Bravo-Sagua, William I. Sivitz, Vitor A. Lira, E. Dale Abel, Brian T. O’Neill

×

Figure 1

Deletion of FoxOs in muscle prevents complex I–mediated mitochondrial defects in response to insulin-deficient diabetes.

Options: View larger image (or click on image) Download as PowerPoint
Deletion of FoxOs in muscle prevents complex I–mediated mitochondrial de...
(A and B) Maximal mitochondrial respiration (A) and ATP synthesis (B) using glutamate/malate/succinate substrates in mitochondrial-enriched fractions from quad/gast muscle from Tfl/fl controls, STZ diabetic Tfl/fl, M-FoxO TKO, and STZ FoxO-TKO mice (n = 4–12). (C) H2O2 production using glutamate/malate/succinate in isolated mitochondria from quad/gast muscle STZ-treated control and M-FoxO TKO mice at various concentrations of ADP (n = 8–10). (D) Heatmap of RNA-Seq fold changes of complex I core subunit transcripts in quad from STZ diabetic Tfl/fl, M-FoxO TKO, and STZ-FoxO TKO compared with Tfl/fl controls (n = 4–6). &FDR < 0.05, &&FDR < 0.01 STZ diabetic Tfl/fl vs. control; †P < 0.05, ††P < 0.01, ratio of STZ-FoxO TKO/M-FoxO TKO to STZ diabetic Tfl/fl/citrate-treated Tfl/fl. (E and F) Western blot (E) and densitometry (F) of Ndufs1 (complex I protein) in STZ diabetic Tfl/fl and STZ-FoxO TKO quad with respective controls (n = 6). (G–I) OXPHOS complex I (G), complex II (H), and complex III (I) activity in gast from STZ diabetic Tfl/fl and STZ-FoxO TKO with respective controls. Results are represented as mean ± SEM. #P < 0.05, ##P < 0.01, 2-way ANOVA.