TY - JOUR
T1 - Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors
AU - Bhardwaj, Gourav
AU - Penniman, Christie M.
AU - Klaus, Katherine
AU - Weatherford, Eric T.
AU - Pan, Hui
AU - Dreyfuss, Jonathan M.
AU - Nair, K. Sreekumaran
AU - Kahn, C. Ronald
AU - O’Neill, Brian T.
N1 - Funding Information:
This work was supported by the VA Merit Review Award Number lO1 BXOO4468 to BTO from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory R&D (BLRD) Service and by startup funds from the Fraternal Order of Eagles Diabetes Research to BTO and also supported by the NIH grant R01 AG62859, awarded to KN. Postdoc salary of GB was supported from the VA grant (lO1 BXOO4468) awarded to BTO.
Publisher Copyright:
Copyright © 2022 Bhardwaj, Penniman, Klaus, Weatherford, Pan, Dreyfuss, Nair, Kahn and O’Neill.
PY - 2022/2/4
Y1 - 2022/2/4
N2 - 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.
AB - 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.
KW - FoxO transcription factors
KW - RNA sequencing
KW - calcium signaling
KW - diabetes
KW - insulin/IGF-1 receptors
KW - mitochondrial dysfunction
KW - muscle transcription
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UR - http://www.scopus.com/inward/citedby.url?scp=85124993817&partnerID=8YFLogxK
U2 - 10.3389/fphys.2021.779121
DO - 10.3389/fphys.2021.779121
M3 - Article
AN - SCOPUS:85124993817
SN - 1664-042X
VL - 12
JO - Frontiers in Physiology
JF - Frontiers in Physiology
M1 - 779121
ER -