Sex-specific circadian and behavioral phenotypes in aged growth hormone receptor knockout mice

Growth hormone (GH) exerts complex effects on metabolism, cognition, and overall physiological well-being, and its secretion is highly regulated by the circadian clock. The Growth Hormone Receptor Knockout (GHR-KO) mouse, a model of GH insensitivity, characterized by chronically elevated circulating GH, provides a unique opportunity to examine the consequences of disrupted GH signaling during aging. Given the close relationship between circadian rhythmicity and GH secretion, we investigated sex- and genotype-specific differences in circadian activity, neuromuscular, and neurocognitive performance in aged GHR-KO mice under varying light–dark (LD), constant dark (DD) conditions, and subsequently examined the impact of circadian disruption (CD) on these parameters. Female GHR-wildtype (fGHR-WT) mice showed greater overall total activity, enhanced circadian activity amplitude, and less fragmented rhythms compared to female GHR-knockout (fGHR-KO) mice. In contrast, fGHR-KO mice demonstrated more rapid re-entrainment following phase shifts, indicating differences in circadian adaptation. Both fGHR-WT and fGHR-KO mice exhibited superior working memory compared to male littermates, while GHR-KO mice displayed enhanced neuromuscular performance compared with GHR-WT controls. CD reduced rhythm stability and was associated with declines in neuromuscular and cognitive performance, particularly in females, as well as increased open field (OF) immobility in fGHR-KO. Collectively, these findings indicate that aged GHR-WT and GHR-KO mice exhibit distinct circadian and behavioral phenotypes, and that disruption of circadian organization exacerbates cognitive and neuromuscular vulnerability.