Journal article
Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart
Molecular and cellular biology, Vol.42(10), pp.1-17
09/20/2022
DOI: 10.1128/mcb.00163-22
PMCID: PMC9583714
PMID: 36125265
Abstract
Insulin and insulin-like growth factor 1 (IGF1) signaling is transduced by insulin receptor substrate 1 (IRS1) and IRS2. To elucidate physiological and redundant roles of insulin and IGF1 signaling in adult hearts, we generated mice with inducible cardiomyocyte-specific deletion of insulin and IGF1 receptors or IRS1 and IRS2. Both models developed dilated cardiomyopathy, and most mice died by 8 weeks post-gene deletion. Heart failure was characterized by cardiomyocyte loss and disarray, increased proapoptotic signaling, and increased autophagy. Suppression of autophagy by activating mTOR signaling did not prevent heart failure. Transcriptional profiling revealed reduced serum response factor (SRF) transcriptional activity and decreased mRNA levels of genes encoding sarcomere and gap junction proteins as early as 3 days post-gene deletion, in concert with ultrastructural evidence of sarcomere disruption and intercalated discs within 1 week after gene deletion. These data confirm conserved roles for constitutive insulin and IGF1 signaling in suppressing autophagic and apoptotic signaling in the adult heart. The present study also identifies an unexpected role for insulin and IGF1 signaling in regulating an SRF-mediated transcriptional program, which maintains expression of genes encoding proteins that support sarcomere integrity in the adult heart, reduction of which results in rapid development of heart failure.
Details
- Title: Subtitle
- Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart
- Creators
- Christian Riehle - University of IowaEric T. Weatherford - University of IowaNicholas S. McCarty - University of IowaAlec Seei - University of IowaBharat P. Jaishy - University of IowaRajkumar Manivel - University of IowaPaolo Galuppo - Medizinische Hochschule HannoverChantal Allamargot - University of IowaTariq Hameed - University of IowaRyan L. Boudreau - University of IowaJohann Bauersachs - Medizinische Hochschule HannoverRobert M. Weiss - University of IowaE. Dale Abel - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.42(10), pp.1-17
- DOI
- 10.1128/mcb.00163-22
- PMID
- 36125265
- PMCID
- PMC9583714
- NLM abbreviation
- Mol Cell Biol
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Publisher
- American Society for Microbiology
- Number of pages
- 17
- Grant note
- R01HL112413 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) OD019941 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) R01HL127764 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) R01-HL148796 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) R01HL108379 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) R01DK092065 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) Deutsche Forschungsgemeinschaft (DFG) (https://doi.org/10.13039/501100001659) R01-HL150557 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) R01-HL144717 / HHS | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002)
- Language
- English
- Date published
- 09/20/2022
- Academic Unit
- Core Research Facilities; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984296207402771
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