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.

The ATP-sensitive potassium (K ATP ) channel-encoded dSUR gene is required for Drosophila heart function and is regulated by tinman

“…in heart failure rate is due to a reduction in K ATP channel activity, either directly in the heart or by an indirect mechanism (25,36). Cardiac-specific knock-down of dSUR has the same effect as short treatment with tolbutamide, suggesting that the sulfonylurea druginduced increase in heart failure is likely due to a direct effect on the heart (Fig.…”

“…A progressive elevation of pacing-induced heart failure rate is also observed during the natural age-related decline in fly cardiac function (36). We compared the level of dSUR expression in the heart of young (1-week-old) and aged (5-week-old) flies by using real-time RT-PCR with RNA from isolated hearts (Fig.…”

Downstream of Homeotic Genes: In the Heart of Hox function

“…55 Finally, the genetic programs preceding to Drosophila cardiogenesis have been extensively characterized, 63,64 as well as the consequences of their inactivation upon cell fate and differentiation and, more recently, on organ physiology. 55,[65][66][67] These studies have provided multiple useful criteria to appreciate the consequences of gene inactivation or misexpression. This extensive read out, combined with the strength of the genetic tools available, constitutes a real power in the analysis of what Hox genes are precisely doing and when their functions are required.…”

Pathologies et vieillissement cardiaque

“…Une étude pionnière [36] a mis en évidence, que chez la mouche, le vieillissement s'accompagne d'une diminution de la réserve cardiaque 4 et d'une augmentation des arythmies, deux caractéristiques centrales du vieillissement qui sont partagées avec les mammifères. D'autres études [37][38][39] ont depuis largement confirmé ces observations. Elles ont montré que le vieillissement s'accompagne également d'une diminution du débit cardiaque [39,40] et de défauts structuraux au niveau des cardiomyocytes, qui sont liés à une désorga-nisation progressive du réseau de myofibrilles [20].…”

“…Elles ont montré que le vieillissement s'accompagne également d'une diminution du débit cardiaque [39,40] et de défauts structuraux au niveau des cardiomyocytes, qui sont liés à une désorga-nisation progressive du réseau de myofibrilles [20]. Au niveau génétique et moléculaire, les études réalisées par Wessels et ses collaborateurs [37] ont établi que l'inhibition de la voie de l'insuline au niveau du coeur est suffisante pour ralentir les effets du vieillissement sur la performance cardiaque. Cet effet, localisé au niveau du muscle cardiaque, n'a cependant pas de conséquence sur la longévité, sans doute en raison de la détérioration liée à l'âge d'autres organes essentiels.…”