Exercise reverses age-related vulnerability of the retina to injury by preventing complement-mediated synapse elimination via a BDNF-dependent pathway.
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.
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, 32 Gisborne Street, East Melbourne, Vic., 3002, Australia.
Vicki
V
Chrysostomou
St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic., 3065, Australia.
Sandra
S
Galic
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, 32 Gisborne Street, East Melbourne, Vic., 3002, Australia.
Peter
P
van Wijngaarden
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, 32 Gisborne Street, East Melbourne, Vic., 3002, Australia.
Ian A
IA
Trounce
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Gregory R
GR
Steinberg
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, 32 Gisborne Street, East Melbourne, Vic., 3002, Australia.
Jonathan G
JG
Crowston
anti-aging; brain-derived neurotrophic factor; exercise; mouse model; neuroprotection; retinal ganglion cell