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.
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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

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Figure 7

Deletion of IR/IGF1R in muscle decreases complex I core subunits in a FoxO-dependent manner and disrupts complex I–dependent supercomplex assembly and activity.

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Deletion of IR/IGF1R in muscle decreases complex I core subunits in a Fo...
(A and B) Heatmaps displaying RNA-Seq transcript levels of OXPHOS subunits in mixture of quad and gast from MIGIRKO and M-QKO compared with floxed controls. Heatmap of complex I, including core complex subunits (A). Heatmap of complexes II–V (B) (n = 4–6). Floxed controls are combined M-IR/IGF1Rfl/fl and M-Qfl/fl controls. §§FDR < 0.01, §§§FDR< 0.001 MIGIRKO vs. floxed; #P < 0.05 M-QKO vs. floxed. (C–E) BN-PAGE (C) with densitometry of individual complexes I–V (D) and supercomplexes (E) in quad from IND-IGIRKO and IR/IGF1Rfl/fl (n = 5–6). C, complex. (F and G) Clear native gel showing complex I in-gel activity (F) and densitometry (G) in quad from IND-IGIRKO and IR/IGF1Rfl/fl (n = 4). Results are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 vs. littermate control, t test for 2 groups.