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Lei Xu, Lena T Phu, Abraham M Bell, John D Ash; Genetic loss of the metabolic sensor AMPK results in an accelerated aging of the retina. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3017.
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© ARVO (1962-2015); The Authors (2016-present)
5' adenosine monophosphate-activated protein kinase (AMPK) is an enzyme that plays a central role in regulation of energy and metabolism homeostasis. It is a heterotrimeric complex protein that contains a, b and g three subunits. We have shown previously AMPK catalytic subunit α1 and α2 has non redundant roles in cone photoreceptor function. The goal of this study is to further elucidate the role of AMPK signaling, particularly in aging.
Neural retina knockout of AMPK α subunit mice (Chx10-Cre; AMPKα1f/f AMPKα2 f/f) were examined at various ages. Scotopic and photonic electroretinography (ERG) were used to measure photoreceptor and retinal pigmented epithelium (RPE) function. Retinal structure and morphology was observed by Spectral Domain Optical Coherence Tomography (SD-OCT) and histology. Quantitate qPCR were used to measure the relative ratio of mitochondria DNA (mtDNA) and nuclear DNA copy number. The mRNA expression of genes were measured by qPCR. All procedures with animals were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Neural retina-specific AMPKa knockout mice had normal retinal structure, outer nuclear layer (ONL) thickness. Scotopic, and photopic ERGs were normal at very early age. However, over time cone function was reduced followed by reduced rod function. By 9 months of age, knockout mice had thinner ONLs compared to controls. At 12 months of age, there was extensive changes in retinal morphology, including significant reduction in ONL, inner nuclear layer (INL), as well as inner segment (IS) thicknesses. The RPE was also highly vacuolated. Expression of genes involved in mitochondrial biogenesis and fatty acid metabolism were deceased at 6 months, but there was no change in anti-oxidant defense genes. Relative mitochondrial DNA copy number was reduced in the knockout mice.
In this study, we found retina specific deletion of AMPKa causes extensive changes in the retinal structure with age. This suggests AMPK plays an important role in maintaining retinal function and survival in normal aging. We hypothesize that mitochondria are dysregulated in AMPKa knockout mice, since we found evidence of IS shortening and a reduction in relative mitochondrial DNA copy number.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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