| First Author | Levy E | Year | 2015 |
| Journal | PLoS One | Volume | 10 |
| Issue | 12 | Pages | e0144593 |
| PubMed ID | 26673217 | Mgi Jnum | J:269029 |
| Mgi Id | MGI:6251904 | Doi | 10.1371/journal.pone.0144593 |
| Citation | Levy E, et al. (2015) Long-Lived alphaMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection. PLoS One 10(12):e0144593 |
| abstractText | alphaMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestors due to endogenously increased levels of the satiety hormone leptin. alphaMUPA 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 alphaMUPA 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, alphaMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while alphaMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in alphaMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in alphaMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin) abrogated the alphaMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the alphaMUPA myocardium. alphaMUPA 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 alphaMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in alphaMUPA mice, indicating the attenuation of cardiac aging. alphaMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR. |
