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. 2016 Jul 25:6:30290.
doi: 10.1038/srep30290.

Reduced insulin/insulin-like growth factor signaling decreases translation in Drosophila and mice

Paul Essers  1 , Luke S Tain  1 , Tobias Nespital  1 , Joana Goncalves  1 , Jenny Froehlich  1 , Linda Partridge  1   2
Affiliations

Reduced insulin/insulin-like growth factor signaling decreases translation in Drosophila and mice

Paul Essers et al. Sci Rep. .

Abstract

Down-regulation of insulin/insulin-like growth factor signaling (IIS) can increase lifespan in C. elegans, Drosophila and mice. In C. elegans, reduced IIS results in down-regulation of translation, which itself can extend lifespan. However, the effect of reduced IIS on translation has yet to be determined in other multicellular organisms. Using two long-lived IIS models, namely Drosophila lacking three insulin-like peptides (dilp2-3,5(-/-)) and mice lacking insulin receptor substrate 1 (Irs1(-/-)), and two independent translation assays, polysome profiling and radiolabeled amino acid incorporation, we show that reduced IIS lowers translation in these organisms. In Drosophila, reduced IIS decreased polysome levels in fat body and gut, but reduced the rate of protein synthesis only in the fat body. Reduced IIS in mice decreased protein synthesis rate only in skeletal muscle, without reducing polysomes in any tissue. This lowered translation in muscle was independent of Irs1 loss in the muscle itself, but a secondary effect of Irs1 loss in the liver. In conclusion, down-regulation of translation is an evolutionarily conserved response to reduced IIS, but the tissues in which it occurs can vary between organisms. Furthermore, the mechanisms underlying lowered translation may differ in mice, possibly associated with the complexity of the regulatory processes.

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Figures

Figure 1
Figure 1. Polysome formation is decreased in the fat body and gut of dilp2-3,5 mutants.
(a) Representative polysome profiles of isolated 10 day old Drosophila tissues. Insets show the area under the curve measurements for monosomes and combined polysomes. Unpaired student t-test was used to establish significance. *p < 0.05 (n = 4). (b) Relative 35S counts in dilp2-3,5 mutants for thoraces (n = 17), fat bodies (n = 37), and guts (n = 37). Values were first normalized by protein content, then to batch average. Outliers were removed based on the Grubbs test, unpaired student t-test was used to establish significance. *p < 0.05.
Figure 2
Figure 2. Protein synthesis is reduced in the muscles of Irs1 mutants, without decreased polysome formation.
(a) Representative polysome profiles of dissected mouse tissues (74 week old). Insets show area under the curve measurements for monosomes and combined polysomes, wt (n = 4), Irs1−/− (n = 3). Note that the amount of material loaded varied per tissue, so profiles should not be directly compared between tissues. Unpaired student t-test was used to establish significance. (b) Relative 35S counts in Irs1−/− mouse tissues, wt (n = 4), Irs1−/− (n = 3). For all conditions n = 4 unless stated otherwise. Unpaired student t-test was used to establish significance. *p < 0.05.
Figure 3
Figure 3. Translation is non-tissue autonomously reduced upon loss of Irs1.
(a) Representative polysome profiles of dissected mouse tissues from muscle specific (Ckmm-Cre::Irs1fl/fl) and liver specific (Alfp-Cre::Irs1fl/fl) Irs1 knockouts compared to controls (Irs1fl/fl) (n ≥ 3). Insets show area under the curve measurements for monosomes and combined polysomes. Unpaired student t-test was used to establish significance. (b) 35S counts for muscle specific (Ckmm-Cre::Irs1fl/fl) Irs1 knockouts and controls (Irs1fl/fl). (c) 35S counts for liver specific (Alfp-Cre::Irs1fl/fl) Irs1 knockouts and controls (Irs1fl/fl). Values were first normalized to protein content, then to batch average. (d) 35S counts in an independent set of Alfp-Cre::Irs1fl/fl mice to verify the findings of Fig. 3C. For all conditions n = 4 unless stated otherwise. Unpaired student t-test was used to establish significance. *p < 0.05, **p < 0.01, ***p < 0.001.
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