Chrysostomou Vicki, Galic Sandra, van Wijngaarden Peter, Trounce Ian A, Steinberg Gregory R, Crowston Jonathan G
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, 32 Gisborne Street, East Melbourne, Vic., 3002, Australia.
St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic., 3065, Australia.
Aging Cell. 2016 Dec;15(6):1082-1091. doi: 10.1111/acel.12512. Epub 2016 Sep 9.
Retinal ganglion cells (RGCs) become increasingly vulnerable to injury with advancing age. We recently showed that this vulnerability can be strongly modified in mice by exercise. However, the characteristics and underlying mechanisms of retinal protection with exercise remain unknown. Hence, the aim of this study was to investigate cellular changes associated with exercise-induced protection of aging retinal cells and the role of local and peripheral trophic signalling in mediating these effects. We focussed on two molecules that are thought to play key roles in mediating beneficial effects of exercise: brain-derived neurotrophic factor (BDNF) and AMP-activated protein kinase (AMPK). In middle-aged (12 months old) C57BL/6J mice, we found that exercise protected RGCs against dysfunction and cell loss after an acute injury induced by elevation of intra-ocular pressure. This was associated with preservation of inner retinal synapses and reduced synaptic complement deposition. Retinal expression of BDNF was not upregulated in response to exercise alone. Rather, exercise maintained BDNF levels in the retina, which were decreased postinjury in nonexercised animals. Confirming a critical role for BDNF, we found that blocking BDNF signalling during exercise by pharmacological means or genetic knock-down suppressed the functional protection of RGCs afforded by exercise. Protection of RGCs with exercise was independent of activation of AMPK in either retina or skeletal muscle. Our data support a previously unidentified mechanism in which exercise prevents loss of BDNF in the retina after injury and preserves neuronal function and survival by preventing complement-mediated elimination of synapses.
随着年龄的增长，视网膜神经节细胞（RGCs）越来越容易受到损伤。我们最近发现，运动可以显著改变小鼠的这种易损性。然而，运动对视网膜保护的特征和潜在机制仍不清楚。因此，本研究的目的是探讨与运动诱导的衰老视网膜细胞保护相关的细胞变化，以及局部和外周营养信号在介导这些效应中的作用。我们聚焦于两种被认为在介导运动有益作用中起关键作用的分子：脑源性神经营养因子（BDNF）和AMP激活的蛋白激酶（AMPK）。在中年（12个月大）C57BL/6J小鼠中，我们发现运动可保护RGCs免受眼内压升高诱导的急性损伤后的功能障碍和细胞丢失。这与视网膜内层突触的保留和突触补体沉积减少有关。BDNF的视网膜表达不会因单独运动而上调。相反，运动维持了视网膜中的BDNF水平，而在未运动的动物中，损伤后BDNF水平会降低。通过药理学方法或基因敲除在运动期间阻断BDNF信号，证实了BDNF的关键作用，这抑制了运动对RGCs的功能保护。运动对RGCs的保护与视网膜或骨骼肌中AMPK的激活无关。我们的数据支持一种先前未被识别的机制，即运动可防止损伤后视网膜中BDNF的丢失，并通过防止补体介导的突触消除来维持神经元功能和存活。
