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Long-term head-down bed rest (HDBR) results in musculoskeletal losses similar to those observed during long-term space flight. Agents such as testosterone, in addition to regular exercise, are effective countermeasures for reducing loss of skeletal muscle mass and function. We investigated the skeletal muscle proteome of healthy men in response to long term HDBR alone (CON) and to HDBR with exercise (PEX) or exercise plus testosterone (TEX) countermeasures. Biopsies were performed on the vastus lateralis before (pre) HDBR and on HDBR days 32 (mid) and 64 (post). Extracted proteins from these skeletal muscle biopsies were subjected to 2-dimensional gel electrophoresis (2DE), stained for phosphoproteins (Pro-Q Diamond dye) and total proteins (Sypro Ruby dye). Proteins showing significant fold differences (t-test p ≤ 0.05) in abundance or phosphorylation state at mid or post were identified by mass spectroscopy (MS). From a total of 932 protein spots, 130 spots were identified as potentially altered in terms of total protein or phosphoprotein levels due to HDBR and/or countermeasures, and 59 unique molecules emerged from MS analysis. Top canonical pathways identified through IPA included calcium signaling, actin cytoskeleton signaling, integrin linked kinase (ILK) signaling, and epithelial adherens junction signaling. Data from the pre-HDBR proteome supported the potential for predicting physiological post-HDBR responses such as the individual's potential for loss vs. maintenance of muscle mass and strength. HDBR resulted in alterations to skeletal muscle abundances and phosphorylation of several structural and metabolic proteins. Inclusion of exercise alone or in combination with testosterone treatment modulated the proteomic responses towards cellular reorganization and hypertrophy, respectively. Finally, the baseline proteome may aid in the development of personalized countermeasures to mitigate health risks in astronauts as related to loss of muscle mass and function.

Patients who suffer a traumatic brain injury (TBI) often experience chronic and sometimes debilitating sequelae. Recent reports have illustrated both acute and long-term dysbiosis of the gastrointestinal microbiome with significant alterations in composition and predicted functional consequences. Working with participants from past research, metagenomic stability of the TBI- associated fecal microbiome (FMB) was evaluated by custom qPCR array comparing a fecal sample from 2015 to one collected in 2020. Metatranscriptomics identified differently expressed bacterial genes and biochemical pathways in the TBI FMB. Microbiota that contributed the largest RNA amounts identified a set of core bacteria most responsible for functional consequences of the TBI FMB. A remarkably stable FMB metagenome with significant similarity (two-tail Spearman nonparametric correlation < 0.001) was observed between 2015 and 2020 fecal samples from subjects with TBI. Comparing the 2020 TBI FMB metagenome to FMBs from healthy controls confirmed and extended the dysbiotic genera and species. Abundance differences between average TBI and healthy FMBs revealed . spp., spp., spp., and Ordoribacter spp. were significantly different. Functionally, the genus contributed the highest percentage of RNA sequences in control FMBs followed by the genus as the second highest contributor. In the TBI FMB, the genus contributed the most RNA followed by the genus. and were distinct in the top 10 contributing genera in the TBI FMB while and were unique to the top 10 in controls. Comparing RNA profiles, TBI samples had ∼1.5 fold more expressed genes with almost 700 differently expressed genes (DEGs) mapped to over 100 bacterial species. Bioinformatic analysis associated DEGs with pathways led identifying 311 functions in the average TBI FMB profile and 264 in the controls. By average profile comparison, 30 pathways had significantly different abundance ( < 0.05, -test) or were detected in >80% of the samples in only one of the cohorts (binary distinction). Functional differences between TBI and healthy control FMBs included amino acid metabolism, energy and carbon source usage, fatty acid metabolism, bacterial cell wall component production and nucleic acid synthesis and processing pathways. Together these data shed light on the functional consequences of the dysbiotic TBI FMB decades after injury.

Following SARS‐CoV‐2 infection, some patients develop lingering neurologic symptoms of post‐acute sequelae of COVID‐19 (PASC) that commonly include fatigue and “brain fog.” PASC symptoms are also linked with reduced growth hormone (GH) secretion, but GH treatment has not been tested to relieve symptoms. We enrolled 13 adults with neurologic PASC symptoms and peak stimulated GH secretion less than 10 ng/mL (glucagon stimulation) in a pilot study to receive 9 months of daily GH injections and an additional 3 months of off‐treatment assessment. We compared peak stimulated GH secretion at baseline and 12 months and assessed measures of cognition, metabolism, body composition, and physical performance over the first 6 months of treatment. Patient‐reported outcomes of fatigue, quality of life, sleep, and mood were recorded at baseline and compared with timepoints at 6, 9, and 12 months. GH treatment was associated with significantly improved scores for Brief Fatigue Inventory, Multidimensional Fatigue Symptom Inventory, Quality of Life Assessment of Growth Hormone Deficiency in Adults, Profile of Mood States, and Beck Depression Inventory‐II, with no significant change in Pittsburgh Sleep Quality Index. Six months of adjunct GH treatment was not associated with significant changes in cognition, body composition, resting energy expenditure, or physical performance. Peak stimulated GH secretion was not altered at 12 months following 9 months of GH treatment. GH treatment significantly improved neurologic symptoms in PASC patients but cognition, sleep, and physical performance were not significantly altered. Following the initial infection, some patients develop lingering post acute sequelae of SARS‐CoV‐2 that may include neurologic symptoms of fatigue and brain fog along with reduced growth hormone secretion. In a study of 13 individuals, 9 months of growth hormone treatment improved patients reported quality of life, depression, fatigue, and mood but did not significantly alter physical performance, sleep, body composition, or performance on neurocognitive testing.

Patients with chronic traumatic brain injury (TBI) requiring long-term, permanent care suffer a myriad of clinical symptoms (i.e., impaired cognition, fatigue, and other conditions) that persist for years beyond the acute brain injury. In addition to these comorbid clinical symptoms, chronic TBI patients exhibit altered amino acid and hormonal profiles with distinct cytokine patterns suggesting chronic inflammation. This metabolic link suggests a role of the gut-brain axis in chronic TBI. Thus, we utilized a two-site trial to investigate the role of the gut-brain axis in comorbidities of chronic TBI. The fecal microbiome profile of 22 moderate/severe TBI patients residing in permanent care facilities in Texas and California was compared to 18 healthy age-matched control subjects working within the participating facilities. Each fecal microbiome was characterized by 16S(V4) ribosomal RNA (rRNA) gene sequencing and metagenomic genome sequencing approaches followed by confirmatory full 16S rRNA gene sequencing or focused tuf gene speciation and specific quantitative polymerase chain reaction evaluation of selected genera or species. The average chronic TBI patient fecal microbiome structure was significantly different compared to the control cohort, and these differences persisted after group stratification analysis to identify any unexpected confounders. Notably, the fecal microbiome of the chronic TBI cohort had absent or reduced Prevotella spp. and Bacteroidies spp. Conversely, bacteria in the Ruminococcaceae family were higher in abundance in TBI compared to control profiles. Previously reported hypoaminoacidemia, including significantly reduced levels of l-tryptophan, l-sarcosine, ß-alanine, and alanine, positively correlated with the reduced levels of Prevotella spp. in the TBI cohort samples compared to controls. Although the sequelae of gut-brain axis disruption after TBI is not fully understood, characterizing TBI-related alterations in the fecal microbiome may provide biomarkers and therapeutic targets to address patient morbidity.

We explored the effects of recombinant human growth hormone (rhGH) replacement on physical and cognitive functioning in subjects with a moderate-to-severe traumatic brain injury (TBI) with abnormal growth hormone (GH) secretion. Fifteen individuals who sustained a TBI at least 12 months prior to study enrollment were identified as having abnormal GH secretion by glucagon stimulation testing (maximum GH response less than 8 ng/mL). Peak cardiorespiratory capacity, body composition, and muscle force testing were assessed at baseline and one year after rhGH replacement. Additionally, standardized neuropsychological tests that assess memory, processing speed, and cognitive flexibility, as well as self-report inventories related to depression and fatigue, were administered at baseline and 1 year after rhGH replacement. Comparison tests were performed with proper post hoc analyses. All analyses were carried out at α < 0.05. Peak O2 consumption, peak oxygen pulse (estimate of cardiac stroke volume), and peak ventilation all significantly increased (p < 0.05). Maximal isometric and isokinetic force production were not altered. Skeletal muscle fatigue did not change but the perceptual rating of fatigue was reduced by ∼25% (p = 0.06). Cognitive performance did not change significantly over time, whereas self-reported symptoms related to depression and fatigue significantly improved. The observed changes suggest that rhGH replacement has a positive impact on cardiorespiratory fitness and a positive impact on perceptual fatigue in survivors of TBI with altered GH secretion.

Individuals with a history of traumatic brain injury (TBI) are at increased risk for a number of disorders, including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. However, mediators of the long-term morbidity are uncertain. We conducted a multi-site, prospective trial in chronic TBI patients (∼18 years post-TBI) living in long-term 24-h care environments and local controls without a history of head injury. Inability to give informed consent was exclusionary for participation. A total of 41 individuals (17 moderate-severe TBI, 24 controls) were studied before and after consumption of a standardized breakfast to determine if concentrations of amino acids, cytokines, C-reactive protein, and insulin are potential mediators of long-term TBI morbidity. Analyte concentrations were measured in serum drawn before (fasting) and 1 h after meal consumption. Mean ages were 44 ± 15 and 49 ± 11 years for controls and chronic TBI patients, respectively. Chronic TBI patients had significantly lower circulating concentrations of numerous individual amino acids, as well as essential amino acids (p = 0.03) and large neutral amino acids (p = 0.003) considered as groups, and displayed fundamentally altered cytokine-amino acid relationships. Many years after injury, TBI patients exhibit abnormal metabolic responses and altered relationships between circulating amino acids, cytokines, and hormones. This pattern is consistent with TBI, inducing a chronic disease state in patients. Understanding the mechanisms causing the chronic disease state could lead to new treatments for its prevention.

Abstract Disclosure: M. Pan: None. R.J. Urban: None. T.J. Wright: None. R.B. Pyles: None. M. Sheffield-Moore: None. K. Randolph: None. K.A. McGovern: None. C.P. Danesi: None. T. Wexler: None. B. Masel: None. A.L. Miller: None. C. Maxwell: None. K.C. Yuen: None. R.D. Batson: None. Introduction Ulcerative colitis is a lifelong condition marked by continuous colonic lesions and inflammation in the mucosal and submucosal layers of the colon and rectum. Patients with this type of inflammatory bowel disease experience symptoms such as bloody diarrhea, rectal urgency, fecal incontinence, and abdominal pain. Common treatments include sulfasalazine and 5-aminosalicylates, with proctocolectomy considered in cases where medical management fails. This report aims to describe symptom improvement in an ulcerative colitis patient receiving growth hormone replacement therapy (GHRT) for 6 months. Clinical Case (Diagnostic evaluation, treatment, follow-up) A 45-year-old female with severe ulcerative colitis (total colectomy at age 16) and a remote history of mild traumatic brain injury (mTBI) presented with symptoms of chronic, debilitating fatigue and brain fog. Based on her history of mTBI, she was tested for growth hormone deficiency (GHD). Adult-onset growth hormone deficiency (AGHD) was confirmed via the glucagon stimulation test (GST) with a peak GH level of 2.7 ng/mL (BMI 24.5 kg/m2). She underwent GHRT with daily injections of 0.6 mg recombinant human growth hormone for 6 months. Following the initial treatment period, she elected to continue GHRT based on notable improvements in fatigue, mood, gastrointestinal symptoms, and IGF-1 levels (pretreatment 52 ng/mL, posttreatment 182 ng/mL, range 118-298, mean 205). Prior to and following treatment, the patient underwent a modified 6-minute walk test and completed self-report measures including the Brief Fatigue Inventory (BFI), Multidimensional Fatigue Symptom Inventory (MFSI), Profile of Mood States (POMS), Beck Depression Inventory (BDI), Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA), Pittsburgh Sleep Quality Index (PSQI), and the Gastrointestinal Symptom Rating Scale (GSRS). Substantial improvements (percent change) were seen in the modified 6-minute walk test, BFI Global Fatigue (12%), MFSI General Fatigue (41.67%), POMS Depression (53%), BDI-II/Depression (91%), POMS Tension-Anxiety (73%), POMS Vigor (160%), POMS Confusion (37.5%), POMS Total Mood Disturbance (72%), QoL-AGHDA (59%), and GSRS (50%). Most notably, she experienced marked decreases in abdominal pain (57%) and diarrhea (78%) scores on the GSRS. Clinical Lessons/Conclusions We present a case of a patient with ulcerative colitis who underwent GHRT for 6 months. The documented improvements in this patient’s symptoms, including abdominal pain and diarrhea as well as physical performance measures, highlight the potential benefits of GHRT for patients with confirmed AGHD who suffer from the long-term symptom burden of ulcerative colitis. Keywords: Ulcerative colitis, growth hormone, brain fog Presentation: Monday, July 14, 2025

Abstract Disclosure: R.D. Batson: None. A.M. Bruton: None. E.S. Pistone: None. A.J. Forrester: None. T.J. Wright: None. R.B. Pyles: None. K.M. Randolph: None. K.A. McGovern: None. C.P. Danesi: None. C.R. Gilkison: None. T.L. Wexler: None. B.E. Masel: None. K.C. Yuen: None. R.J. Urban: None. Introduction: Prior studies have reported that body mass index (BMI) negatively correlated with peak growth hormone (GH) response on the glucagon stimulation test (GST). Very little is known regarding the influence specifically of body composition and weight on peak GH response to glucagon stimulation. We sought to clarify the influence of BMI, weight and body composition on peak GH response to GST in a predominantly mild TBI adult population. Methods: A retrospective analysis of fixed-dose glucagon stimulation test (GST) results from 288 subjects at two centers was conducted. Fixed-dose GST protocols utilized 1 mg glucagon for individuals ≤90 kg and 1.5 mg for those >90 kg. Center A and Center B performed 240-minute and 180-minute GSTs, respectively. Multiple linear regression was used to evaluate the association between the dependent variable of peak GH and the following: BMI, weight, lean mass, fat mass, and fat percent in 5 separate models. Age and sex were added to all models and glucagon dose (1/1.5 mg) was assessed for inclusion. BMI was assessed as continuous, categorical, and binary, plus the interaction terms between them. F-tests and the coefficient of determination (adjusted R2) were used for model selection. Results: The best fit to the data was a model with age, sex, and the interaction between continuous and binary BMI (< or ≥30 kg/m2; N=288; adjusted R2=0.14; p<0.001). The range of BMI for non-obese (<30 kg/m2) participants was 15.8-29.9, and for obese (≥30 kg/m2) participants was 30.0-55.6. Every one-unit increase in BMI in the non-obese group was associated with a 0.54 ng/mL decrease in peak GH (95% CI: -0.82, -0.26; p<0.001). The association between BMI and peak GH in the obese group was non-significant. A restricted cubic spline regression model suggested the association between BMI and peak GH was nonlinear, especially for participants with BMIs between 24-30 kg/m2. Logistic regression revealed that overweight and obese individuals had increased odds of failing the GST compared to normal weight individuals. In a model adjusted for age and sex, every one-kilogram increase in weight was associated with 0.09 ng/mL decrease in peak GH (95% CI: -0.13, -0.05; p<0.001) but the weight model (N=288; adjusted R2=0.11; p<0.001) predicted peak GH less accurately than BMI. In participants with lean mass, fat mass, and fat percent data (N=50) none of the three were significantly associated with peak GH. Glucagon dose was not included in any of the models. Conclusions: In subjects with TBI who underwent GSTs, body weight was significantly associated with peak GH, but fat mass, lean mass, and fat percent were not. Additionally, BMI was negatively associated with peak GH, but only in subjects with BMIs <30 kg/m2. These results, although limited to a TBI population, differ from prior studies demonstrating an inverse relationship between BMI and peak GH in those with BMIs ≥ 30 kg/m2. Presentation: Saturday, July 12, 2025