Date of Award

4-2024

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

John M. Spitsbergen, Ph.D.

Second Advisor

Pamela Hoppe, Ph.D.

Third Advisor

Monica McCullough, Ph.D.

Fourth Advisor

Christopher Pearl, Ph.D.

Keywords

Endplate, glial cell line-derived neurotrophic factor, neuromuscular junction, voluntary exercise

Abstract

Premenopausal women display lower incidence and severity of neurological disease compared to men of the same age, yet these populations are often treated similarly. A decline in neuromuscular function is associated with aging, which may be partially explained by a decline in neurotrophic factor expression with age. A possible way to maintain neuroprotection would be to regulate the production and release of a target-derived neurotrophic factor, such as glial cell line-derived neurotrophic factor (GDNF). GDNF has been shown to be the most potent survival factor for motor neurons and GDNF content of skeletal muscle has been shown to increase with exercise.

This study examined GDNF levels and endplate morphology in skeletal muscle of males and females at different ages and with exercise. We hypothesize that the neuromuscular junction (NMJ) area and endplate dispersion will increase with sedentary aging in both sexes. We also hypothesize that prior to reproductive senescence, GDNF content will be higher in female rats than age-matched males. Furthermore, we hypothesize that exercise will increase estrogen levels and GDNF expression in skeletal muscle.

Hindlimb muscles soleus (SOL) and plantaris (PLA), and serum estrogen were taken from sedentary and exercised male and female Sprague-Dawley rats from 4 to 78 weeks of age. Sedentary groups consisted of 4, 6, 8, 12, 52, and 78-week-old females, and 4, 6, 8, and 12-week-old males. Exercise groups consisted of male and female 4-week-old animals that voluntarily exercised in a running wheel for 2 weeks, 8-week-old animals exercised for 4 weeks, and for females a 52-week-old group exercised for 26 weeks. Right SOL and PLA were used for immunohistochemical analysis. Acetylcholine receptors at the NMJ were stained with α-bungarotoxin. Left SOL and PLA were used for analysis of GDNF protein content by using enzyme-linked immunosorbent assay (ELISA). Trunk blood was taken, and the serum was used for quantification of estrogen levels using ELISA.

Our findings indicate that as individuals age, there is a noticeable change in the area and dispersion of endplates. Through exercise, we saw endplate area increase, coupled with a reduction in dispersion. However, in male rats, exercise did not significantly change endplate dispersion. Our study stands to be a pioneering investigation into the connection between endplate structure, aging, and exercise in female rats. Our results additionally reveal that levels of GDNF protein were higher in younger females compared to age-matched males. Physical activity increased GDNF levels in both sexes, consistently maintaining higher levels in females up until 12 weeks of age, when exercised males displayed the highest GDNF content overall. Furthermore, exercise induced an increase in estradiol levels. These collective findings contribute to the expanding narrative highlighting the positive effects of exercise across the lifespan, benefiting the individual both neurologically and physically.

Access Setting

Dissertation-Open Access

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