GENOTYPE AND SEX-BASED DIFFERENCE IN CIRCADIAN, METABOLIC, COGNITIVE, AND NEUROMUSCULAR PERFORMANCE IN AGED GROWTH HORMONE RECEPTOR KNOCKOUT MICE

Author

Sean Michael Hicks, Southern Illinois University CarbondaleFollow

Date of Award

12-1-2025

Degree Name

Master of Science

Department

Biological Sciences

First Advisor

Tischkau, Shelley

Abstract

Growth Hormone Deficiency (GHD) and Growth Hormone Insensitivity (GHI) are endocrine disorders characterized by either insufficient growth hormone (GH) production or an impaired ability of GH to bind and stimulate the growth hormone receptor (GHR). These endocrinopathies can occur if the anterior pituitary is unable to synthesize adequate quantities of GH, or if genetic aberrations result in structural distortions of the GHR that disrupt ligand-receptor binding and consequently impair the downstream post-receptor intracellular signaling cascade. The growth hormone receptor knockout (GHR-KO) mouse, utilized in this study and sometimes referred to as the Laron Mouse, was derived from crossing 129Ola/BALB/c GHR +/- mice with C57BL/6J and C3H/J strains (GHR-/-), and most closely resembles human Laron syndrome (LS). In GHR-KO mice, the GHR is absent due to targeted gene knockout, resulting in chronically elevated GH and diminished IGF-1 levels within the body, thereby mimicking the endocrine and metabolic features of GHI. Approximately 350 individuals worldwide have been diagnosed with this condition, with the largest concentration of affected people (around 100) in southern Ecuador and the other population residing in Israel. Studies in Ecuador have elucidated that LS is rarely associated with cancer or diabetes. Research has shown that LS may offer protective effects against genetic damage when exposed to oxidative stressors. Despite the beneficial insights provided by the GHR-KO model, its impact on the later stages of life remains poorly understood. This project investigated sex- and genotype-specific differences in circadian activity, metabolic efficiency, and neuromuscular and neurocognitive performance in aged GHR-KO mice, under varying light–dark (LD) and constant dark (DD) conditions. Female growth hormone receptor wildtype (fGHR-WT) mice exhibited significantly elevated total activity, enhanced amplitude, and diminished fragmented rhythms compared to female growth hormone receptor knockout (fGHR-KO) mice; however, required more days to re-entrain following a phase shift. Male and female GHR-KO mice exhibited enhanced neuromuscular function, balance, and locomotor capacity, with fGHR-KO mice displaying higher average speeds relative to WT mice. Respiratory quotient (RQ) data revealed significant sex- and genotype-based differences, with observed differences in metabolic substrate preference. Elevated immobility was observed in male growth hormone receptor knockout (mGHR-KO) mice, whereas fGHR-WT and fGHR-KO mice exhibited superior cognition. Circadian disruption (CD) revealed vulnerabilities in fGHR-WT and fGHR-KO mice, characterized by declines in neuromuscular performance, locomotion, cognition, and increased Intradaily Variability (IV). Post-CD showed a decrease in energy expenditure (EE) across most groups. Together, these results demonstrate that aged fGHR-KO mice, despite exhibiting enhanced neuromuscular performance and resistance to specific aging attributes, display sex-specific vulnerabilities in circadian regulation, cognition, and metabolic adaptation following CD, similar to those observed in fGHR-WT mice.