Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Citations to this article

Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis
Brian T. O’Neill, … , K. Sreekumaran Nair, C. Ronald Kahn
Brian T. O’Neill, … , K. Sreekumaran Nair, C. Ronald Kahn
Published August 15, 2016
Citation Information: J Clin Invest. 2016;126(9):3433-3446. https://doi.org/10.1172/JCI86522.
View: Text | PDF
Research Article Endocrinology Article has an altmetric score of 8

Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis

  • Text
  • PDF
Abstract

Diabetes strongly impacts protein metabolism, particularly in skeletal muscle. Insulin and IGF-1 enhance muscle protein synthesis through their receptors, but the relative roles of each in muscle proteostasis have not been fully elucidated. Using mice with muscle-specific deletion of the insulin receptor (M-IR–/– mice), the IGF-1 receptor (M-IGF1R–/– mice), or both (MIGIRKO mice), we assessed the relative contributions of IR and IGF1R signaling to muscle proteostasis. In differentiated muscle, IR expression predominated over IGF1R expression, and correspondingly, M-IR–/– mice displayed a moderate reduction in muscle mass whereas M-IGF1R–/– mice did not. However, these receptors serve complementary roles, such that double-knockout MIGIRKO mice displayed a marked reduction in muscle mass that was linked to increases in proteasomal and autophagy-lysosomal degradation, accompanied by a high-protein-turnover state. Combined muscle-specific deletion of FoxO1, FoxO3, and FoxO4 in MIGIRKO mice reversed increased autophagy and completely rescued muscle mass without changing proteasomal activity. These data indicate that signaling via IR is more important than IGF1R in controlling proteostasis in differentiated muscle. Nonetheless, the overlap of IR and IGF1R signaling is critical to the regulation of muscle protein turnover, and this regulation depends on suppression of FoxO-regulated, autophagy-mediated protein degradation.

Authors

Brian T. O’Neill, Kevin Y. Lee, Katherine Klaus, Samir Softic, Megan T. Krumpoch, Joachim Fentz, Kristin I. Stanford, Matthew M. Robinson, Weikang Cai, Andre Kleinridders, Renata O. Pereira, Michael F. Hirshman, E. Dale Abel, Domenico Accili, Laurie J. Goodyear, K. Sreekumaran Nair, C. Ronald Kahn

×

Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 Total
Citations: 6 10 13 15 19 8 14 8 8 101
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2022 (15)

Title and authors Publication Year
Transforming Growth Factor-Beta in Skeletal Muscle Wasting
G Klein
International journal of molecular sciences 2022
Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors
G Bhardwaj, C Penniman, K Klaus, E Weatherford, H Pan, J Dreyfuss, K Nair, C Kahn, B ONeill
Frontiers in physiology 2022
The endothelial Dll4–muscular Notch2 axis regulates skeletal muscle mass
S Fujimaki, T Matsumoto, M Muramatsu, H Nagahisa, N Horii, D Seko, S Masuda, X Wang, Y Asakura, Y Takahashi, Y Miyamoto, S Usuki, K Yasunaga, Y Kamei, R Nishinakamura, T Minami, T Fukuda, A Asakura, Y Ono
Nature metabolism 2022
IGF-1 Signaling Regulates Mitochondrial Remodeling during Myogenic Differentiation
X Guan, Q Yan, D Wang, G Du, J Zhou
Nutrients 2022
Genes and elements involved in the regulation of the nervous system and growth affect the development of spinal deformity in Cyprinus carpio
Z Bagi, K Balog, B Tóth, M Fehér, P Bársony, E Baranyai, S Harangi, M Ashrafzadeh, B Hegedűs, L Stündl, S Kusza, N Foulkes
PloS one 2022
Basic mechanisms of peripheral nerve injury and treatment via electrical stimulation
X Chu, , Q Li, Y Li, F He, X Gu, D Ming
NEURAL REGEN RES 2022
FOXO transcription factors differ in their dynamics and intra/intermolecular interactions
E Spreitzer, T Alderson, B Bourgeois, L Eggenreich, H Habacher, G Brahmersdorfer, I Pritišanac, P Sánchez-Murcia, T Madl
2022
Down-Regulation of Insulin Like Growth Factor 1 Involved in Alzheimer’s Disease via MAPK, Ras, and FoxO Signaling Pathways
K Kang, J Bai, S Zhong, R Zhang, X Zhang, Y Xu, M Zhao, C Zhao, Z Zhou, G Sita
Oxidative Medicine & Cellular Longevity 2022
Differential effect of canagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice
Otsuka H, Yokomizo H, Nakamura S, Izumi Y, Takahashi M, Obara S, Nakao M, Ikeda Y, Sato N, Sakamoto R, Miyachi Y, Miyazawa T, Bamba T, Ogawa Y
Biochemical Journal 2022
Prevention of Loss of Muscle Mass and Function in Older Adults during COVID-19 Lockdown: Potential Role of Dietary Essential Amino Acids
Park S, Chang Y, Wolfe RR, Kim IY
International journal of environmental research and public health 2022
Mechanisms of Kaempferol in the treatment of diabetes: A comprehensive and latest review
Yang Y, Chen Z, Zhao X, Xie H, Du L, Gao H, Xie C
Frontiers in Endocrinology 2022
Farnesysltransferase Inhibitor Prevents Burn Injury-Induced Metabolome Changes in Muscle
Nakazawa H, Wong LP, Shelton L, Sadreyev R, Kaneki M
Metabolites 2022
The Effects of Exercise Training on Glucose Homeostasis and Muscle Metabolism in Type 1 Diabetic Female Mice.
O'Neill CC, Locke EJ, Sipf DA, Thompson JH, Drebushenko EK, Berger NS, Segich BS, Kolwicz SC Jr
Metabolites 2022
Protective Effects of the Chalcone-Based Derivative AN07 on Inflammation-Associated Myotube Atrophy Induced by Lipopolysaccharide
Fang WY, Lin CL, Chang WH, Chang CH, Huang YC, Tsai YH, Chang FR, Lo YC
International journal of molecular sciences 2022
Loss of FoxOs in muscle increases strength and mitochondrial function during aging
Penniman CM, Bhardwaj G, Nowers CJ, Brown CU, Junck TL, Boyer CK, Jena J, Fuqua JD, Lira VA, O'Neill BT
Journal of Cachexia, Sarcopenia and Muscle 2022

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 11 X users
On 1 Facebook pages
Referenced in 3 Wikipedia pages
147 readers on Mendeley
See more details