Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors

被引:12
作者
Bhardwaj, Gourav [1 ,2 ]
Penniman, Christie M. [1 ,2 ]
Klaus, Katherine [3 ]
Weatherford, Eric T. [1 ,2 ]
Pan, Hui [4 ]
Dreyfuss, Jonathan M. [4 ]
Nair, K. Sreekumaran [3 ]
Kahn, C. Ronald [5 ]
O'Neill, Brian T. [1 ,2 ,6 ]
机构
[1] Univ Iowa, Fraternal Order Eagles Diabet Res Ctr, Iowa City, IA 52242 USA
[2] Univ Iowa, Div Endocrinol & Metab, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA
[3] Mayo Clin, Coll Med & Sci, Div Endocrinol & Metab, Rochester, MN USA
[4] Harvard Med Sch, Joslin Diabet Ctr, Bioinformat & Biostat Core, Boston, MA 02115 USA
[5] Harvard Med Sch, Sect Integrat Physiol & Metab, Joslin Diabet Ctr, Boston, MA 02115 USA
[6] Vet Affairs Hlth Care Syst, Iowa City, IA 52246 USA
基金
美国国家卫生研究院;
关键词
insulin; IGF-1; receptors; FoxO transcription factors; muscle transcription; diabetes; RNA sequencing; mitochondrial dysfunction; calcium signaling; HUMAN SKELETAL-MUSCLE; GENE-EXPRESSION; RESISTANCE; PATHWAYS; STRENGTH; FKHR; PHOSPHORYLATION; GROWTH; ADULTS;
D O I
10.3389/fphys.2021.779121
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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.
引用
收藏
页数:15
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