P520Resting cardiac sympathetic activity is required for the maintenance of cardiomyocyte trophism in the adulthood and is impaired during aging

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Abstract

Purpose

The cardiac sympathetic nervous system (SNS) regulates heart function during stress and enables the physiological postnatal hypertrophy. Whether ‘resting’ SNS activity modulates cardiomyocyte (CM) trophism in the adult is still unknown. Cardiac SNS dysfunction associates with pathophysiological conditions including cardiac hypertrophy and aging. This study aims to: i) investigate the role of resting SNS activity in the regulation of CM size and ii) test if the impairment in Sympathetic Terminal (ST)-target CM interaction contributes to the aging-related sympathetic neurodegeneration.

Methods

We analyzed hearts from i) 3 mo. wt, ii) 24 mo. wt iii) 3 mo. SNS denervated, iv) 3 mo. MuRF1 KO and v) 3 mo. denervated MuRF1 KO mice. Cardiac SNS denervation was obtained by either 6-OH-DOPA or surgical left stellate ganglia ablation. Cardiac function was assessed by echocardiography. Cryosections underwent morphometric and immunofluorescence analyses. WB and quantitative RT-PCR were used to investigate markers of protein degradation and synthesis, as well as adrenergic signaling. In vivo delivery of NPY and noradrenaline (NE) by osmotic minipumps was performed in denervated mice.

Results

In adult mice cardiac STs interact directly with CM membrane. The ST-CM distance increases in aged hearts, which showed a 60% decrease in sympathetic innervation, consistent with an aging-related SNS dysfunction. In aged as well as denervated hearts, characterized by partial and total denervation, respectively, we observed cardiac atrophy (8% and 14% decrease in HW/BW) and similarly reduced CM size. Denervated mice showed no alterations in ejection fraction. No signs of fibrosis or fetal gene reactivation were detected in denervated hearts. MuRF1 expression was increased 5-fold in denervated hearts compared to controls, without alterations in the autophagy markers (LC3, p62, beclin). WB analyses demonstrated decreased levels of Akt, S6 and ERK in denervated hearts, suggesting a decreased protein synthesis. Consistent with the role of the UPS system in determining denervation atrophy, MuRF-1 KO mice did not develop cardiac atrophy nor reduction in protein synthesis markers upon sympathectomy. NPY delivery, but not NE, rescued heart atrophy in denervated mice.

Conclusions

The SNS is a previously unrecognized regulator of CM trophism, by a constitutive repression of the ubiquitin/proteasome protein degradation machinery, presumably through NPY. A SNS dysfunction occurs spontaneously during aging and affects regulation of CM size.

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