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 4

Loss of IR or both IR/IGF1R in mixed gast/quad muscle induces FoxO-dependent decline in mitochondrial respiratory function while increasing H2O2 production and protein carbonylation.

Options: View larger image (or click on image) Download as PowerPoint
Loss of IR or both IR/IGF1R in mixed gast/quad muscle induces FoxO-depen...
(A–D) Basal and maximal respiration in quad/gast muscle mitochondria with glutamate/malate and then with sequential addition of ADP, succinate, rotenone, and oligomycin from M-IR–/– (A), M-IGF1R–/– (B), MIGIRKO (C), and M-QKO (D) with respective controls. (E–H) ATP synthesis rates in quad/gast muscle mitochondria from M-IR–/– (E), M-IGF1R–/– (F), MIGIRKO (G), and M-QKO (H) with respective controls. (I–L) H2O2 production in mitochondria from M-IR–/– (I), M-IGF1R–/– (J), MIGIRKO (K), and M-QKO (L) with respective controls at various concentrations of ADP or with oligomycin. (M–O) Oxyblot images with quantification of protein carbonylation in mitochondria from M-IR–/– (M), MIGIRKO (N), and M-QKO (O) (n = 5–6) with controls. Mitochondria were isolated from mixed quad/gast muscle for each experiment. For A–L, n = 8–14 for M-IRfl/fl and M-IR–/–, n = 6 for M-IGF1Rfl/fl and M-IGF1R–/–, n = 3–4 for M-IR/IGF1Rfl/fl and MIGIRKO, and n = 4–5 for M-Qfl/fl and M-QKO. *P < 0.05; **P < 0.01; ***P < 0.001 vs. littermate control, t test for 2 groups.