Voluntary exercise delays progressive deterioration of markers of metabolism and behavior in a mouse model of Parkinson's disease

Abstract

Although a good deal is known about the genetics and pathophysiology of Parkinson's disease (PD), and information is emerging about its cause, there are no pharmacological treatments shown to have a significant, sustained capacity to prevent or attenuate the ongoing neurodegenerative processes. However, there is accumulating clinical results to suggest that physical exercise is such a treatment, and studies of animal models of the dopamine (DA) deficiency associated with the motor symptoms of PD further support this hypothesis. Exercise is a non-pharmacological, economically practical, and sustainable intervention with little or no risk and with significant additional health benefits. In this study, we investigated the long-term effects of voluntary exercise on motor behavior and brain biochemistry in the transgenic MitoPark mouse PD model with progressive degeneration of the DA systems caused by DAT-driven deletion of the mitochondrial transcription factor TFAM in DA neurons. We found that voluntary exercise markedly improved behavioral function, including overall motor activity, narrow beam walking, and rotarod performance. There was also improvement of biochemical markers of nigrostriatal DA input. This was manifested by increased levels of DA measured by HPLC, and of the DA membrane transporter measured by PET. Moreover, exercise increased oxygen consumption and, by inference, ATP production via oxidative phosphorylation. Thus, exercise augmented aerobic mitochondrial oxidative metabolism vs glycolysis in the nigrostriatal system. We conclude that there are clear-cut physiological mechanisms for beneficial effects of exercise in PD.

Keywords: Dopamine; Exercise; Mitochondria; PET; Parkinson’s disease.

Fig. 1.

Wheel running in MitoPark mice and wild type littermates. After 12 weeks, and at later stages, MitoPark mice run progressively less than WT animals (see also Ekstrand et al 2007) p<0.05 weeks 6–9.

Fig. 2.

A. Exercising MitoPark mice were fed in the home cage which also contained the running wheel. B. Running wheel rotations per day of MitoPark mice (N = 7). C. A schematic graph of behavioral tests for MitoPark mice with and without access to running wheel exercise. We investigated DA neuron activity by PET scanning and behavior at the indicated times (7 MitoPark mice in each group)

Fig 3.

Effect of exercise on time to cross a beam. Stars indicate significances between exercised and non-exercised MitoPark mice. *** P < 0.001, ** P < 0.01, * P < 0.05.

Fig. 4.

Effects of exercise on motor coordination of MitoPark mice determined using the rotarod test. The latency (A), the rotational velocity (B) and the distance (C) of MitoPark mice compared with MitoPark-Exercise mice. *** P < 0.001, ** P < 0.01, * P < 0.05. (D) Rotarod data from MitoPark mice with and without exercise normalized to wild type animals *p<0.05 (7 MitoPark mice in each group).

Fig. 5.

Dopamine neuron activity determined by PET using a DAT ligand. A. Examples of the distribution of [18F]-FE-PE2 in MitoPark mice without and with exercise 6, 10, and 20 weeks after intravenous administration. B. Ligand binding in striatum in MitoPark mice with exercise compared with MitoPark mice without exercise. ** P < 0.01(5 MitoPark mice in each group)

Fig. 6.

Bioenergetics, DA and DA metabolites in striatum from sedentary and exercised MitoPark mice. Top: Seahorse assays (7 MitoPark mice in each group) of mitochondrial respiration rate (oxygen consumption rate, OCR) (left) and glycolytic rate (extracellular acidification rate, ECAR) (right). Bottom: Levels of Dopamine, Dopac and HVA from 5 MitoPark mice in each group. ** P < 0.01, * P < 0.05.