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

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

doi:10.1172/JCI86522

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

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

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, …

The Journal of clinical investigation, Vol.126(9), pp.3433-3446

09/01/2016

DOI: 10.1172/JCI86522

PMCID: PMC5004956

PMID: 27525440

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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.

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Title: Subtitle: Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis
Creators: Brian T O’Neill - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Kevin Y Lee - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Katherine Klaus - Division of Endocrinology and Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
Samir Softic - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Megan T Krumpoch - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Joachim Fentz - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Kristin I Stanford - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Matthew M Robinson - Division of Endocrinology and Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
Weikang Cai - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Andre Kleinridders - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Renata O Pereira - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Michael F Hirshman - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
E. Dale Abel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Domenico Accili - Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, New York, USA
Laurie J Goodyear - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
K. Sreekumaran Nair - Division of Endocrinology and Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
C. Ronald Kahn - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.126(9), pp.3433-3446
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI86522
PMID: 27525440
PMCID: PMC5004956
ISSN: 0021-9738
eISSN: 1558-8238
Language: English
Date published: 09/01/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024518002771

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