Abstract
αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR) including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI) in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin) abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.
Highlights
Ischemic heart disease is a major determinant of human mortality and morbidity worldwide, accounting for approximately 90% of deaths in aged Western populations [1]
These mice show high levels of transcripts encoding an anorexigenic neuropeptide in the brain along with low levels of transcripts for several orexigenic neuropeptides [8], all known to be subjected to leptin regulation and involved in leptin-mediated satiety [13]. αMUPA mice have low levels of the hunger-inducing hormone ghrelin, but interstingly, no change in adiponectin [8], a multifunctional adipokine inversely associated with adiposity [14,15], that increases under caloric restriction (CR) [16,17] and protects against cardiac dysfunction following myocardial infarction (MI) [18]. αMUPA mice exhibit a unique metabolic phenotype of low calorie intake and reduced adipose tissue yet high leptin levels but no change in adiponectin
The results show that serum levels of adiponectin were significantly increased after CR compared with ALfed mice (Fig 5A), but were similar in wild type (WT) or αMUPA mice at the two ages tested (Fig 5B)
Summary
Ischemic heart disease is a major determinant of human mortality and morbidity worldwide, accounting for approximately 90% of deaths in aged Western populations [1]. ΑMUPA mice exhibit a satiated and obesity-resistant phenotype primarily due to high serum levels of leptin [8,9], an adipocyte-derived hormone that regulates food intake and energy expenditure [10,11] and declines under CR [12]. These mice show high levels of transcripts encoding an anorexigenic neuropeptide in the brain along with low levels of transcripts for several orexigenic neuropeptides [8], all known to be subjected to leptin regulation and involved in leptin-mediated satiety [13]. Despite the aforementioned metabolic differences, αMUPA and CR mice share many benefits including increased life span, reduced body weight and fat mass, reduced body temperature, increased insulin sensitivity, reduced serum levels of insulin-like growth factor-1 (IGF-1) and reduced incidence of spontaneous cancers and induced tumorigenic lesions [7,8,19,20]
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