Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors
Insulin and IGF-1, acting through the insulin receptor (IR) and IGF-1 receptor (IGF1R), maintain muscle mass and mitochondrial function, at least part of which occurs via their action to regulate gene expression. Here, we show that while muscle-specific deletion of IR or IGF1R individually results i...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.779121/full |
| _version_ | 1818509788563111936 |
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| author | Gourav Bhardwaj Christie M. Penniman Katherine Klaus Eric T. Weatherford Hui Pan Jonathan M. Dreyfuss K. Sreekumaran Nair C. Ronald Kahn Brian T. O’Neill Brian T. O’Neill |
| author_facet | Gourav Bhardwaj Christie M. Penniman Katherine Klaus Eric T. Weatherford Hui Pan Jonathan M. Dreyfuss K. Sreekumaran Nair C. Ronald Kahn Brian T. O’Neill Brian T. O’Neill |
| author_sort | Gourav Bhardwaj |
| collection | DOAJ |
| description | Insulin and IGF-1, acting through the insulin receptor (IR) and IGF-1 receptor (IGF1R), maintain muscle mass and mitochondrial function, at least part of which occurs via their action to regulate gene expression. Here, we show that while muscle-specific deletion of IR or IGF1R individually results in only modest changes in the muscle transcriptome, combined deletion of IR/IGF1R (MIGIRKO) altered > 3000 genes, including genes involved in mitochondrial dysfunction, fibrosis, cardiac hypertrophy, and pathways related to estrogen receptor, protein kinase A (PKA), and calcium signaling. Functionally, this was associated with decreased mitochondrial respiration and increased ROS production in MIGIRKO muscle. To determine the role of FoxOs in these changes, we performed RNA-Seq on mice with muscle-specific deletion of FoxO1/3/4 (M-FoxO TKO) or combined deletion of IR, IGF1R, and FoxO1/3/4 in a muscle quintuple knockout (M-QKO). This revealed that among IR/IGF1R regulated genes, >97% were FoxO-dependent, and their expression was normalized in M-FoxO TKO and M-QKO muscle. FoxO-dependent genes were related to oxidative phosphorylation, inflammatory signaling, and TCA cycle. Metabolomic analysis showed accumulation of TCA cycle metabolites in MIGIRKO, which was reversed in M-QKO muscle. Likewise, calcium signaling genes involved in PKA signaling and sarcoplasmic reticulum calcium homeostasis were markedly altered in MIGIRKO muscle but normalized in M-QKO. Thus, combined loss of insulin and IGF-1 action in muscle transcriptionally alters mitochondrial function and multiple regulatory and signaling pathways, and these changes are mediated by FoxO transcription factors. |
| first_indexed | 2024-12-10T22:50:15Z |
| format | Article |
| id | doaj.art-12e0ed4261ec4c6fa29831c2ccb2b2f1 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-10T22:50:15Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-12e0ed4261ec4c6fa29831c2ccb2b2f12022-12-22T01:30:27ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-02-011210.3389/fphys.2021.779121779121Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription FactorsGourav Bhardwaj0Christie M. Penniman1Katherine Klaus2Eric T. Weatherford3Hui Pan4Jonathan M. Dreyfuss5K. Sreekumaran Nair6C. Ronald Kahn7Brian T. O’Neill8Brian T. O’Neill9Fraternal 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, IA, United StatesFraternal 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, IA, United StatesDivision of Endocrinology and Metabolism, Mayo Clinic College of Medicine and Science, Rochester, MN, United StatesFraternal 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, IA, United StatesBioinformatics and Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA, United StatesBioinformatics and Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA, United StatesDivision of Endocrinology and Metabolism, Mayo Clinic College of Medicine and Science, Rochester, MN, United StatesSection on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, United StatesFraternal 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, IA, United StatesVeterans Affairs Health Care System, Iowa City, IA, United StatesInsulin and IGF-1, acting through the insulin receptor (IR) and IGF-1 receptor (IGF1R), maintain muscle mass and mitochondrial function, at least part of which occurs via their action to regulate gene expression. Here, we show that while muscle-specific deletion of IR or IGF1R individually results in only modest changes in the muscle transcriptome, combined deletion of IR/IGF1R (MIGIRKO) altered > 3000 genes, including genes involved in mitochondrial dysfunction, fibrosis, cardiac hypertrophy, and pathways related to estrogen receptor, protein kinase A (PKA), and calcium signaling. Functionally, this was associated with decreased mitochondrial respiration and increased ROS production in MIGIRKO muscle. To determine the role of FoxOs in these changes, we performed RNA-Seq on mice with muscle-specific deletion of FoxO1/3/4 (M-FoxO TKO) or combined deletion of IR, IGF1R, and FoxO1/3/4 in a muscle quintuple knockout (M-QKO). This revealed that among IR/IGF1R regulated genes, >97% were FoxO-dependent, and their expression was normalized in M-FoxO TKO and M-QKO muscle. FoxO-dependent genes were related to oxidative phosphorylation, inflammatory signaling, and TCA cycle. Metabolomic analysis showed accumulation of TCA cycle metabolites in MIGIRKO, which was reversed in M-QKO muscle. Likewise, calcium signaling genes involved in PKA signaling and sarcoplasmic reticulum calcium homeostasis were markedly altered in MIGIRKO muscle but normalized in M-QKO. Thus, combined loss of insulin and IGF-1 action in muscle transcriptionally alters mitochondrial function and multiple regulatory and signaling pathways, and these changes are mediated by FoxO transcription factors.https://www.frontiersin.org/articles/10.3389/fphys.2021.779121/fullinsulin/IGF-1 receptorsFoxO transcription factorsmuscle transcriptiondiabetesRNA sequencingmitochondrial dysfunction |
| spellingShingle | Gourav Bhardwaj Christie M. Penniman Katherine Klaus Eric T. Weatherford Hui Pan Jonathan M. Dreyfuss K. Sreekumaran Nair C. Ronald Kahn Brian T. O’Neill Brian T. O’Neill Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors Frontiers in Physiology insulin/IGF-1 receptors FoxO transcription factors muscle transcription diabetes RNA sequencing mitochondrial dysfunction |
| title | Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors |
| title_full | Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors |
| title_fullStr | Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors |
| title_full_unstemmed | Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors |
| title_short | Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors |
| title_sort | transcriptomic regulation of muscle mitochondria and calcium signaling by insulin igf 1 receptors depends on foxo transcription factors |
| topic | insulin/IGF-1 receptors FoxO transcription factors muscle transcription diabetes RNA sequencing mitochondrial dysfunction |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.779121/full |
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