Loss of Cdk5 Function May Mediate Age‐Related Decline in Voluntary Physical Activity

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Increases in age are associated with declining levels of physical activity in multiple species, including humans, which in turn promotes the development of numerous chronic diseases. However, the neuro‐molecular mechanisms that regulate physical activity motivation at various ages are poorly understood. Our lab has previously observed that, in female Wistar rats, lifetime voluntary wheel running behavior is greatest at 8 wks of age.ObjectiveWe aimed to assess differences in the nucleus accumbens (NAc), a specific brain nucleus postulated to influence rewarding behavior, of wheel running and sedentary female Wistar rats at 8 and 14 weeks (wks) of age (n= 5–8).MethodsWheel running rats were introduced to wheels at 5 wks of age. RNA‐seq, qRT‐PCR and Western blotting were used to assess molecular changes between 8‐ and 14‐wk‐old wheel running and sedentary rats.ResultsVoluntary wheel running was greatest at 8 wks (17.7± 1.0 km/d) and had significantly decreased by 14 wks (11.1± 1.2 km/d). From 619 differentially expressed genes, bioinformatics suggested that cAMP‐mediated signaling, DARPP‐32 feedback, PKA signaling, and synaptic plasticity were increased at 8‐ compared to 14‐wk in wheel running rats. While analyzing transcripts specific to these functions, we observed significant (~20–30%; p< 0.05) decreases in Cadm4, Cdk5, and p39 (Cdk5 activator) mRNAs and proteins from 8 to 14 wks of age in voluntary running rats. Further, Cadm4 (r= 0.84), Cdk5 (r= 0.57), and p39 (r= 0.71) mRNAs were significantly correlated with voluntary running distance during the week of sacrifice. Follow‐up analysis of sedentary 8‐ and 14‐wk‐old rats (n= 5–8) by qRT‐PCR found similar decreases in Cadm4 and p39 mRNAs and proteins from 8 to 14 wks of age (p< 0.05), suggesting an age‐dependent reduction in synaptic function and Cdk5 activity may mediate decreases in wheel running. In light of these transcriptomic and protein changes, we assessed wheel‐running distance following NAc injection of the Cdk5 inhibitor roscovitine (ROS) (80 nmol/0.5μg) (n= 7) or vehicle (n= 5). Compared to vehicle, ROS significantly decreased wheel running distance 0–30 and 30–60 min post‐injection (p< 0.001), and 60–90 min post‐injection (p< 0.01). These effects were present after both 1 day and 5 days of daily injections.ConclusionCollectively, these experiments suggest that an age‐dependent loss in synaptic function and Cdk5/p39 activity in the NAc may mediate the age‐related decline in voluntary running behavior.SignificanceGiven the epidemic levels of physical inactivity and its associated consequences, these data may foster the development of therapies targeted to reduce age‐dependent increases sedentary behavior.Support or Funding InformationResearch was supported by an MU Life Sciences pre‐doctoral fellowship (GNR) and MU development funds (FWB).