Treadmill exercise attenuates aging-related bradykinesia: potential involvement of increased nigral GFR-ɑ1 expression and dopamine tissue content

Given the burgeoning increase in our elderly population, lifestyle strategies that mitigate aging-related impairments are essential. Bradykinesia, a cardinal symptom of Parkinson’s disease (PD), also affects up to 30% of the elderly population. Exercise can ameliorate locomotor impairment in PD models and patients, but the neuroanatomical and molecular basis for these effects have not been delineated. Striatal dopamine loss exceeds 80% at onset of bradykinesia in PD, but the greatest loss ever reported in aging humans or animal models is ~50%. Furthermore, exercise-related improvements in locomotor function can occur without significant effects on striatal dopamine in PD models. Here, we hypothesize that an established treadmill exercise regimen could attenuate aging-related bradykinesia (ARB) in conjunction with increased dopamine and the glial cell line-derived neurotrophic factor (GDNF) receptor, GDNF family receptor-alpha 1 (GFR-α1) in the substantia nigra (SN). The rationale for this hypothesis is based on observations that striatal infusion of GDNF in aging models increases locomotor activity and dopamine in the SN, but not striatum. Second, GFR-α1 decreases only in the SN in aging. Third, replenishing the quantity of GFR-α1 lost due to aging increases locomotor activity in combination with increased dopamine and tyrosine hydroxylase (TH) expression in SN, but not striatum, in aged rats. A critical component of this hypothesis is that GDNF, which has been shown to increase following exercise, may also increase GFR-α1 expression. Using our treadmill exercise regimen, we assessed the impact of short- and long-term exercise on ARB and GDNF signaling in aged rats. Our results demonstrate that two rounds of our exercise regimen increased GFR-α1 expression and dopamine in SN of aged rats: a result that reflects the previously reported effect of exogenous GDNF. Notably, a repeated regimen of long-term exercise followed by an equal amount of rest eventually attenuated ARB when compared to non-exercise rats. These studies may be applicable in PD models, in that augmentation of dopamine biosynthesis in SN, instead of striatum, may be an important mechanism of improving locomotor impairment. Finally, our work may delineate molecular targets to enable development of therapeutic strategies that target bradykinesia, particularly in those who may be physically unable or unwilling to exercise.