Abstract
Objective: In this study we use the CAG140 HD mouse model, chosen for its slow progression with motor symptoms emerging at 12 months of age and provide evidence of the benefits of long-term treadmill running.
Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive decline in cognitive and motor functions with neuropsychiatric disturbances. Defects in the respiratory chain in HD have been observed in early biochemical studies. Severe reduction in the activity of complex II/III and milder reduction of complex IV were found in post mortem samples of the caudate/putamen in HD patients. The cerebral cortex showed minor changes in respiratory chain enzymes. Massive loss of aconitase activity has been found in the caudate (~90%), and putamen (~70%). Nitric oxide is a hydrophobic gas which can cross all biological membranes without mediation of channels or receptors. Nitric oxide is biosynthesized endogenously from L-arginine, nitric oxide synthase (NOS), oxide, and nicotinamide adenine dinucleotide phosphate (NADPH) enzymes. Nitric oxide is membrane permeable and has the ability to diffuse into dopaminergic neurons, thereby allowing NO receptors to be utilized for signaling transduction for intracellular communication.
Design/Methods: HD and WT mice of two separate ages (9 and 15 months) ran for 3 months 60 mins per day 5 days a week. Studies include mitochondrial complex activity with isolated brain mitochondria, behavior and motor function tests, and measurements of substrate related to the nitric oxide pathway in brain homogenate.
Results: Chronic cardiovascular exercise improved mitochondrial complex activities, motor function, cognition, and elevated nitrite/nitrate and aconitase levels in the brain.
Conclusions: We explore a novel hypothesis that elevated nitric oxide stored as nitrosothiols from chronic exercise links mitochondrial brain metabolism and cerebral vasculature through the proposed mechanism of decreasing transglutaminase activity.
Disclosure: Dr. Caldwell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BluePath Solutions. Dr. Cadenas has nothing to disclose.
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