Castration results in a substantial proinflammatory-associated myopathy in the 3xTg-AD mouse model of Alzheimer’s disease

In addition to cognitive deficits, patients with Alzheimer’s disease (AD) are plagued by a debilitating myopathy characterized by loss of muscle mass and contractile weakness. While the development of AD neural pathology is primarily thought to initiate the myopathy, preclinical models of AD challenge this dogma as they suggest that neural pathology alone may not be sufficient to induce severe myopathy. Indeed, aged male and female 3xTg-AD mice develop AD neural pathology and cognitive deficits, but aged males do not develop any measurable myopathy. In male 3xTg-AD mice, the protection against myopathy development may be due at least in part to the lack of comorbidities that typically afflict men with AD. Specifically, men with AD typically present with low testosterone (hypogonadism), while male 3xTg-AD mice do not. As hypogonadism is known to induce certain myopathic features on its own, it is possible the presence of hypogonadism in humans may lead to the development of severe myopathy. Thus, the purpose of this study was to determine whether low testosterone leads to myopathic features in the 3xTg male mouse, thus recapitulating the human condition. At 12 months of age, male wild type (WT) and male 3xTg-AD mice were randomized to undergo sham or castration surgery. At 6-month post-surgery (18 months of age), forelimb grip strength was tested, and muscle tissues were harvested. At 6 months post-surgery, absolute grip strength and grip strength normalized to body mass was lower in all castrated groups, but both absolute and normalized grip strengths were ~50% lower in 3xTg-AD castrated mice compared to non-castrated WT, non-castrated 3xTg-AD, and castrated WT groups. Similarly, masses of the tibialis anterior (TA) and the gastrocnemius were also lower in castrated groups, but masses of those muscles were ~40% lower in castrated 3xTg-AD mice compared to all other groups. RNA sequencing analysis showed expressed genes within the TA of castrated 3xTg-AD mice were significantly enriched into inflammatory-associated pathways relative to castrated WT values. Specifically, genes encoding chemokines and cytokine/chemokine receptors were significantly higher in the TA of castrated 3xTg-AD mice compared to the castrated WT levels, suggesting the severe myopathy that develops is due in part to an extensive proinflammatory phenotype. Overall, these data suggest hypogonadism is a critical comorbidity during AD that renders muscle susceptible to severe myopathy development. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.