Abstract
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.
Highlights
Both type 1 and type 2 diabetes are associated with decreased muscle strength and quality, which can compromise overall fitness and leads to increased mortality (Park et al, 2006; Barzilay et al, 2009; Orlando et al, 2017)
We find that the expression of most of the genes altered in MIGIRKO muscle are restored to normal when Forkhead box O proteins (FoxO) transcription factors are deleted in muscle quintuple knockout (M-QKO) mice
When comparing transcriptional changes induced by insulin receptors (IR)/IGF-1 receptors (IGF1R) deletion, we find that FoxO-dependent genes comprise > 97% of all changes and include genes related to oxidative phosphorylation, inflammatory signaling, and Tricarboxylic acid (TCA) cycle
Summary
Both type 1 and type 2 diabetes are associated with decreased muscle strength and quality, which can compromise overall fitness and leads to increased mortality (Park et al, 2006; Barzilay et al, 2009; Orlando et al, 2017). Various mechanisms contribute to muscle weakness in diabetes including impaired protein turnover (James et al, 2017), decreased mitochondrial function (Kelley et al, 2002; Mogensen et al, 2007; Ruegsegger et al, 2018; Bhardwaj et al, 2021), and increased oxidative stress (Henriksen et al, 2011), many of which are regulated by transcriptional mechanisms. Previous studies in mice and humans show that insulin treatment, under euglycemic clamp conditions, modulates up to 1000 transcripts in muscle, including genes related to mitochondrial function, autophagy, glucose and lipid utilization, cytoskeletal organization, protein turnover, chromatin remodeling, and mRNA splicing (Rome et al, 2003; Batista et al, 2019), but the transcription factors that mediate these effects are not well defined. Muscle-specific transgenic overexpression of FoxO1 has been shown to decrease cytoskeletal genes and induce genes related to ubiquitin-proteasome and lysosomal degradation, but effects on other pathways is not well studied (Kamei et al, 2004; Stitt et al, 2004). FoxOs respond to various stress conditions, and in this context have been shown to regulate genes of autophagy, oxidative stress, cell cycle, and mitochondrial metabolism (Eijkelenboom and Burgering, 2013)
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