Musculoskeletal Health Theses and Dissertations

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    The Effects of FNDC5/Irisin on Osteocyte Functions
    (2023-07) Shimonty, Anika; Plotkin, Lilian I.; Bonewald, Lynda F.; Brault, Jeff; Robling, Alexander G.; White, Kenneth E.
    Irisin is a myokine generated when Fibronectin type III Domain Containing protein 5 (FNDC5) is proteolytically cleaved during exercise. While irisin has been shown to be beneficial in the functions of the brain, heart, and adipose tissue, its effect on bone cells remains contradictory. Osteocytes are the most abundant and longest-living bone cells, with different transcriptomes based on sex and age. One of the major functions of osteocytes is osteocytic osteolysis, the removal of their perilacunar matrix. A previous study showed that irisin deletion protects bone from ovariectomy-induced loss due to less osteoclastic resorption and less osteocytic osteolysis. Therefore, we hypothesized that FNDC5/irisin modulates the osteocyte function of osteocytic osteolysis in a sex-dependent manner. Under normal conditions, there was no difference in bone parameters between wildtype and FNDC5-null adult female mice starting from 5 to 20 months of age. However, 5-month-old null male mice had higher bone mass, but weaker bone compared to wildtype males, which persisted up to 20 months. Both 5-month-old female and male null mice had significantly lower TRAP-positive osteocytes, suggesting a role of irisin in priming the osteocytes for bone resorption. Osteocytes from female wildtype mice show higher lacunar area and upregulated resorption genes compared to wildtype males. However, null females and null males do not have significant differences in the lacunar area or resorption genes. Under calcium-deficient conditions, both 5 and 18-month-old female null mice lost less bone compared to their wildtype counterparts. In contrast, both 5 and 18-month-old null male mice lost more bone than age-matched wildtype males. Additionally, the percentage of bone loss was greater in the aged null male mice compared to 5-month-old null males. In summary, in female osteocytes, irisin works to release calcium from bone during lactation, ensuring offspring survival; however, with aging and hypocalcemia, irisin exerts a negative effect on bone mass. In contrast, irisin works to maintain bone mass and strength by modulating male osteocyte function. This study is the first to demonstrate a sex and age-specific irisin effect on the osteocyte function of osteocytic osteolysis, which has implications for the development of osteoporosis treatment.
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    Association of Tryptophan and NAD+ Metabolites with Brain and Skeletal Muscle Function in Critical Care Patients and Survivors
    (2024-07) Yates, Brandon Alston; Coggan, Andrew; Khan, Babar; Kroenke, Kurt; Liu, Ziyue; Newman, John
    Background: Patients who survive Intensive Care Unit (ICU) acquired delirium will likely experience new or worsened physical, mental, and/or cognitive impairments (termed Post-Intensive Care Syndrome (PICS)). Although advances in critical care treatments have reduced mortality rates among older adult ICU survivors, roughly 67% suffer PICS. The most vulnerable to long-term physical and cognitive impairments are older adults or those who exhibit accelerated aging because of pre-existing physical frailty or cognitive frailty. Yet, identification of at-risk patients during admittance is likely difficult because of the 1) homogeneity in the clinical presentation of patients with pre-existing age-related physical frailty and critical illness compared to those suffering from only critical illness and 2) many patients arrive severely debilitated making administration of physical function or other volitional assessments difficult. Therefore, it is essential that new biomarkers to guide early diagnosis, prognosis, and disease monitoring are identified. To this point, tryptophan derivatives, particularly kynurenines and nicotinamide family (e.g., NAD+), have been shown to mediate the relationship between chronic inflammation and physical impairment or signal accelerated aging, respectively. However, it remains unknown if similar associations exist in ICU patients and the prognostic utility of elevated neurotoxic tryptophan metabolites relative to neuroprotective tryptophan metabolites to predict adverse health outcomes while in the ICU. Methods: A secondary analysis of pooled data from three randomized control trials was used to investigate the following aims. To address Aims 1 and 2, blood samples from patients with ICU acquired delirium were analyzed for kynurenine and salvage pathway metabolites. To address Aim 3, blood samples from patients who survived an ICU stay, experienced ICU delirium, and completed both objective and subjective physical function assessments within in month of ICU discharge and before the COVID-19 pandemic. Results: Delirium duration was significantly (p< 0.05) associated with elevated circulating kynurenine and lower NAD+. Delirium severity was significantly associated with elevated circulating lower NAD+ but not kynurenine. Post-ICU physical function performance was significantly associated with elevated circulating kynurenine but not NAD+. Conclusion: Elevated concentration of frailty biomarkers are associated with delirium severity and duration in the ICU and post-ICU physical function.