Date of Defense

4-16-2025

Date of Graduation

4-2025

Department

Biological Sciences

First Advisor

John Spitsbergen

Second Advisor

Todd Barkman

Abstract

Aging is associated with diminished autonomic regulation of the heart, potentially driven by declines in neurotrophic support from target tissues. Glial cell line–derived neurotrophic factor (GDNF) and nerve growth factor (NGF) are critical for the maintenance and regeneration of autonomic and sensory neurons. While previous research has explored neurotrophic regulation in skeletal muscle and the central nervous system, less is known about how these factors are modulated in cardiac tissue across the lifespan, especially in the context of sex differences and exercise interventions. This study investigates how age, sex, and voluntary exercise affect cardiac GDNF and NGF content in male and female Sprague-Dawley rats.

Rats were categorized by age (8, 12, 52, or 78 weeks), sex, and activity level (sedentary or exercised), and cardiac neurotrophic factor levels were quantified via ELISA. Results showed a general age-related decline in GDNF and NGF content across groups, with the lowest levels observed in 78-week sedentary females. Exercise had a modest or negligible effect on neurotrophic factor levels in young animals, but substantially increased both GDNF and NGF levels in aged females, restoring them to values comparable to or exceeding those seen in younger groups. Notably, GDNF levels in 52-week sedentary females (8.47 ± 1.45 pg/ml) closely matched those reported in 52-week sedentary males in a prior study (Alves Dissertation), supporting a consistent age-related decline across sexes.

Sex differences were most pronounced at 12 weeks. Male rats expressed significantly higher levels of NGF than females (145.08 ± 17.40 pg/ml vs. 81.94 ± 11.45 pg/ml; p = 0.039), while GDNF showed a similar but nonsignificant trend. These patterns suggest differential regulation of sympathetic and parasympathetic neurotrophic support by sex, potentially mediated by hormonal influences. Unexpectedly, exercise decreased GDNF levels in 12-week-old males, contrasting with literature that typically reports GDNF upregulation with physical activity. This inconsistency may reflect transient downregulation, methodological variation, or unique responses in cardiac tissue compared to skeletal muscle.

These findings underscore the complex, context-dependent nature of neurotrophic regulation in the heart. They demonstrate that age and sex significantly influence baseline neurotrophic factor levels, and that exercise offers its greatest neuroprotective benefit in aged animals, particularly females. The distinct responses between GDNF and NGF further highlight the need to consider neurotrophins individually when designing interventions to preserve or restore autonomic function.

Future studies should investigate the anatomical correlates of these biochemical changes using immunohistochemical mapping of cardiac innervation, as well as explore the influence of sex steroids through gonadectomy or hormonal manipulation. Longitudinal time-course studies may clarify whether early exercise produces delayed neurotrophic benefits not captured by endpoint analysis. Understanding the interplay between sex, aging, and physical activity on cardiac neurotrophic signaling may offer new strategies for reducing arrhythmic risk and improving autonomic balance in aging populations.

Access Setting

Honors Thesis-Restricted

Restricted to Campus until

6-3-2026

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