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Insulin regulation of heart function in aging fruit flies

Abstract

Insulin-IGF receptor (InR) signaling has a conserved role in regulating lifespan, but little is known about the genetic control of declining organ function. Here, we describe progressive changes of heart function in aging fruit flies: from one to seven weeks of a fly's age, the resting heart rate decreases and the rate of stress-induced heart failure increases. These age-related changes are minimized or absent in long-lived flies when systemic levels of insulin-like peptides are reduced and by mutations of the only receptor, InR, or its substrate, chico. Moreover, interfering with InR signaling exclusively in the heart, by overexpressing the phosphatase dPTEN or the forkhead transcription factor dFOXO, prevents the decline in cardiac performance with age. Thus, insulin-IGF signaling influences age-dependent organ physiology and senescence directly and autonomously, in addition to its systemic effect on lifespan. The aging fly heart is a model for studying the genetics of age-sensitive organ-specific pathology.

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Figure 1: D. melanogaster heart rate changes with age.
Figure 2: D. melanogaster heart contractions under normal and stimulated conditions.
Figure 3: Heart failure as a function of age after external electrical pacing from outbred wild-type offspring (WT; yw × Canton S).
Figure 4: Reduction in insulin receptor signaling improves heart performance at advanced ages.
Figure 5: Reduction in insulin-IGF signaling improves heart performance at advanced ages.
Figure 6: Heart-specific manipulation of insulin-receptor signaling affects age-related changes in cardiac physiology.
Figure 7: Heart-specific manipulation of insulin-IGF signaling alters heart performance autonomously with age.
Figure 8: Survival curves of male (M) and female (F) progeny from the cross of the heart-specific driver GMH5-Gal4 with UAS-InR or UAS-dPTEN.

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Acknowledgements

We thank B. Edgar, E. Hafen, E. Rulifson, B. Hassan, H. Bellen and the Bloomington stock center for sending flies and K. Fitzgerald, A. Strobe and M. Montero for technical assistance with part of the heart performance assays. R.J.W. has been supported by a fellowship from the American Heart Association. This work received support from grants from National Institutes of Health (National Institute on Aging) and The Ellison Medical Foundation to M.T. and by National Institutes of Health (National Heart, Lung and Blood Institute and National Institute on Aging) to R.B.

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Correspondence to Rolf Bodmer.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Arrest rates. (PDF 117 kb)

Supplementary Table 1

Summary of failure, arrest and recovery data for selected genotypes. (PDF 8 kb)

Supplementary Table 2

Adult heart rate data from relevant genotypes is displayed. (PDF 6 kb)

Supplementary Table 3

Comparison of male and female failure rate data. (PDF 6 kb)

Supplementary Table 4

Failure rates at 1 week and 5 weeks for outcrossed flies carrying UAS expression constructs. (PDF 6 kb)

Supplementary Table 5

Pupal heart rates from several wild-type genetic backgrounds are compared to heart rates of pupae expressing InR, dPTEN or dFOXO in the heart, as well as flies carrying each construct outcrossed in to wild-type genetic backgrounds. (PDF 6 kb)

Supplementary Video 1

GMH5-driven GFP expression in the adult myocardium of the heart in abdominal segments A2-A4. Spiral myofibril structure in the GFP-labeled contractile myocardial cells is evident34, and thus demonstrating the myocardial specificity of GFP expression by the GMH5 driver. (AVI 28715 kb)

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Wessells, R., Fitzgerald, E., Cypser, J. et al. Insulin regulation of heart function in aging fruit flies. Nat Genet 36, 1275–1281 (2004). https://doi.org/10.1038/ng1476

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