Cognitive decline with age and other clinical conditions are linked with reduced hypothalamic-pituitary-adrenal (HPA) axis function. Stimulating the HPA axis with supplemental growth hormone (GH) treatment can improve cognition, however, potential direct effects of stimulation with growth hormone releasing hormone (GHRH) are not established. In a double-blind, placebo-controlled pilot trial, we assessed 22 subjects with baseline cognition ranging from normal cognition to mild cognitive impairment before and after 10 weeks of treatment with low-dose tesamorelin (1 mg; GHRH analog) or placebo. We compared groupwise changes in body composition, fatigue, sleep, physical performance, glucose tolerance, cognitive function, and brain morphometry and functional connectivity. Low-dose GHRH treatment was not directly linked with significant changes in study measures. Using advanced machine learning (ML) models to further examine the data we identified potential treatment-related differences in areas of the brain related to cognitive function including the right anterior cingulate and left superior frontal occipital fasciculus. This pilot study highlights the potential benefits of pairing cognitive tests and neuroimaging with ML tools to achieve greater sensitivity for treatment-related effects. The clinical trial registration number is: NCT02553603.

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

The hyperactivation of mTOR is a significant contributor to the development and progression of a number of human diseases, including a majority of human cancers. Although there have been many scientific and clinical efforts to reduce the impact of mTOR hyperactivation on downstream cellular metabolism, we aimed to mitigate this hyperactivation through a novel targeted gene edit of the intrinsic mTOR inhibitor, DEP domain containing MTOR interacting protein (DEPTOR), in MCF7 human breast cancer cells. Using publicly available bioinformatics tools, we demonstrate that DEPTOR gene expression is low in breast cancers compared with healthy tissues and that DEPTOR expression predicts overall survival, recurrence-free survival, and distant metastasis-free survival in breast cancer patients. We show that a directed overexpression of DEPTOR protein leads to significant alteration of downstream mTORC1 targets and subsequently reduces overall rates of protein synthesis. In addition, treatment of DEPTOR overexpressing cells with small-molecule DEPTOR inhibitor NSC126405 leads to a reversal of this effect, indicating a direct causal mechanism between DEPTOR protein levels and mTORC1 activation.NEW & NOTEWORTHY We identify DEPTOR as a predictor of mortality in breast cancer and show that precision gene editing to restore DEPTOR expression in breast cancer slows cell growth by inhibiting mTOR activity.

IntroductionPatients 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.MethodsWorking 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.ResultsA remarkably stable FMB metagenome with significant similarity (two-tail Spearman nonparametric correlation p < 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 Bacteroides caccae, B. uniformis, Blautia spp., Collinsella spp., Dialister spp., and Ordoribacter spp. were significantly different. Functionally, the Parabacteroides genus contributed the highest percentage of RNA sequences in control FMBs followed by the Bacteroides genus as the second highest contributor. In the TBI FMB, the Corynebacterium genus contributed the most RNA followed by the Alistipes genus. Corynebacterium and Pseudomonas were distinct in the top 10 contributing genera in the TBI FMB while Parabacteroides and Ruminococcus 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 (p < 0.05, t-test) or were detected in >80% of the samples in only one of the cohorts (binary distinction).DiscussionFunctional 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.

AbstractFollowing 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.

INTRODUCTION:Cognitive impairment is reported in a variety of clinical conditions including Alzheimer's disease, Parkinson's and 'long-COVID'. Interestingly, many of these clinical conditions are also associated with microbial dysbiosis. This comanifestation of cognitive and microbiome findings in seemingly unrelated maladies suggests that they could share a common mechanism and potentially presents a treatment target. Although a rapidly growing body of literature has documented this comorbid presentation within specific conditions, an overview highlighting potential parallels across healthy and clinical populations is lacking. The objective of this umbrella review, therefore, is to summarise and synthesise the findings of these systematic reviews. METHODS AND ANALYSIS:On 2 April 2023, we searched MEDLINE (Pubmed), Embase (Ovid), the Web of Science (Core Collection), the Cochrane Library of Systematic Reviews and Epistemonikos as well as grey literature sources, for systematic reviews on clinical conditions and interventions where cognitive and microbiome outcomes were coreported. An updated search will be conducted before completion of the project if the search-to-publication date is >1 year old. Screening, data abstraction and quality assessment (AMSTAR 2, A MeaSurement Tool to Assess systematic Reviews) will be conducted independently and in duplicate, with disagreements resolved by consensus. Evidence certainty statements for each review's conclusions (eg, Grading of Recommendations Assessment, Development and Evaluation (GRADE)) will be extracted or constructed de novo. A narrative synthesis will be conducted and delineated by the review question. Primary study overlap will be visualised using a citation matrix as well as calculated using the corrected covered area method. ETHICS AND DISSEMINATION:No participant-identifying information will be used in this review. No ethics approval was required due to our study methodology. Our findings will be presented at national and international conferences and disseminated via social media and press releases. We will recruit at least one person living with cognitive impairment to collaborate on writing the plain language summary for the review. PROSPERO REGISTRATION NUMBER:CRD42023412903.

BACKGROUND:Following traumatic brain injury (TBI) some patients develop lingering comorbid symptoms of fatigue and cognitive impairment. The mild cognitive impairment self-reported by patients is often not detected with neurocognitive tests making it difficult to determine how common and severe these symptoms are in individuals with a history of TBI. This study was conducted to determine the relative prevalence of fatigue and cognitive impairment in individuals with a history of TBI.METHODS:The Fatigue and Altered Cognition Scale (FACs) digital questionnaire was used to assess self-reported fatigue and cognitive impairment. Adults aged 18-70 were digitally recruited for the online anonymous study. Eligible participants provided online consent, demographic data, information about lifetime TBI history, and completed the 20 item FACs questionnaire.RESULTS:A total of 519 qualifying participants completed the online digital study which included 204 participants with a history of TBI of varied cause and severity and 315 with no history of TBI. FACs Total Score was significantly higher in the TBI group (57.7 ± 22.2) compared to non-TBI (39.5 ± 23.9; p<0.0001) indicating more fatigue and cognitive impairment. When stratified by TBI severity, FACs score was significantly higher for all severity including mild (53.9 ± 21.9, p<0.0001), moderate (54.8 ± 24.4, p<0.0001), and severe (59.7 ± 20.9, p<0.0001) TBI. Correlation analysis indicated that more severe TBI was associated with greater symptom severity (p<0.0001, r = 0.3165). Ancillary analysis also suggested that FACs scores may be elevated in participants with prior COVID-19 infection but no history of TBI.CONCLUSIONS:Adults with a history of even mild TBI report significantly greater fatigue and cognitive impairment than those with no history of TBI, and symptoms are more profound with greater TBI severity.

The gut microbiome has been implicated in a variety of neuropathologies with recent data suggesting direct effects of the microbiome on host metabolism, hormonal regulation, and pathophysiology. Studies have shown that gut bacteria impact host growth, partially mediated through the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. However, no study to date has examined the specific role of GH on the fecal microbiome (FMB) or the changes in this relationship following a traumatic brain injury (TBI). Current literature has demonstrated that TBI can lead to either temporary or sustained abnormal GH secretion (aGHS). More recent literature has suggested that gut dysbiosis may contribute to aGHS leading to long-term sequelae now known as brain injury associated fatigue and cognition (BIAFAC). The aGHS observed in some TBI patients presents with a symptom complex including profound fatigue and cognitive dysfunction that improves significantly with exogenous recombinant human GH treatment. Notably, GH treatment is not curative as fatigue and cognitive decline typically recur upon treatment cessation, indicating the need for additional studies to address the underlying mechanistic cause.

OBJECTIVE:To determine if patients that develop lingering neurologic symptoms of fatigue and "brain fog" after initial recovery from coronavirus disease 2019 (COVID-19) have persistent low growth hormone (GH) secretion as seen in other conditions with similar symptom etiology. DESIGN:In this case-control observational pilot study, patients reporting lingering neurologic post-acute sequelae of SARS-CoV-2 (PASC, n = 10) symptoms at least 6 months after initial infection were compared to patients that recovered from COVID-19 without lingering symptoms (non-PASC, n = 13). We compared basic blood chemistry and select metabolites, lipids, hormones, inflammatory markers, and vitamins between groups. PASC and non-PASC subjects were tested for neurocognition and GH secretion, and given questionnaires to assess symptom severity. PASC subjects were also tested for glucose tolerance and adrenal function. RESULTS:PASC subjects reported significantly worse fatigue, sleep quality, depression, quality of life, and gastrointestinal discomfort compared to non-PASC. Although PASC subjects self-reported poor mental resilience, cognitive testing did not reveal significant differences between groups. Neurologic PASC symptoms were not linked to inflammatory markers or adrenal insufficiency, but were associated with reduced growth hormone secretion. CONCLUSIONS:Neurologic PASC symptoms are associated with gastrointestinal discomfort and persistent disruption of GH secretion following recovery from acute COVID-19. (www. CLINICALTRIALS:gov; NCT04860869).

The SARS-CoV-2 pandemic created a multitude of medical crossroads requiring real time adaptations of best practice covering preventative and interventional aspects of care. Among the many discoveries borne from efforts to address the myriad clinical presentations across multiple organ systems was a common impact on tissues with cells that express the ACE-2 receptor. The vast majority of acute infections began and often ended in the respiratory tract, but more recent evaluations have confirmed significant extrapulmonary manifestations including symptom clusters that extend beyond the acute phase of infection collectively referred to as "post-acute sequelae SARS-CoV-2 infection" (PASC) or more commonly as "long (-haul) COVID". Both acute SARS-CoV-2 infection and PASC are associated with gut microbiome dysbiosis and alterations in the gut-brain and HPA-axis in a subset of the infected. Mounting evidence suggests these extrapulmonary manifestations may ultimately lead to reduced growth hormone (GH) secretion as demonstrated following stimulation tests. Disrupted GH secretion could cause or exacerbate long lasting neuropsychological symptoms as seen in other similar manifesting conditions. Ongoing clinical research has shown promising improvement in PASC patients with fatigue and cognition complaints can be achieved via GH replacement therapy. GH stimulation testing should be considered in PASC workups and future research should delve deeper into the mechanistic effects of GH on acute COVID and PASC.

Debilitating symptoms of fatigue and accompanying "brain fog" are observed among patients with various chronic health conditions. Unfortunately, an efficient and psychometrically sound instrument to assess these co-occurring symptoms is unavailable. Here, we report the development and initial psychometric properties of the Fatigue and Altered Cognition Scale (the FACs), a measure of self-reported central fatigue and brain fog. Traumatic brain injury (TBI) was chosen to model and develop the FACs due to research team expertise and established links between TBI and the symptom complex. Potential items were generated by researchers and clinicians with experience treating these symptoms, drawing from relevant literature and review of patient responses to measures from past and current TBI studies. The 20 candidate items for the FACs-ten each to assess altered cognition (i.e., brain fog) and central fatigue-were formatted on an electronic visual analogue response scale (eVAS) via an online survey. Demographic information and history of TBI were obtained. A total of 519 participants consented and provided usable data (average age = 40.23 years; 73% female), 204 of whom self-reported a history of TBI (75% reported mild TBI). Internal consistency and reliability values were calculated. Confirmatory factor analysis (CFA) examined the presumed two-factor structure of the FACs and a one-factor solution for comparison. A measurement invariance test of the two latent constructs (altered cognition, fatigue) among participants with and without TBI was conducted. All items demonstrated normal distribution. Cronbach's alpha coefficients indicated good internal consistency for both factors (α's = .95). Omega reliability values were favorable (α's = .95). CFA supported the presumed two-factor model and item loadings which outperformed the one-factor model. Measurement invariance found the two-factor structure was consistent between the two groups. Implications of these findings, study limitations, and potential use of the FACs in clinical research and practice are discussed.

Many cancer patients undergoing treatment experience cancer-related fatigue (CRF). Inflammatory markers are correlated with CRF but are not routinely targeted for treatment. We previously demonstrated in an NIH-funded placebo-controlled, double-blind, randomized clinical trial (NCT00878995, closed to follow-up) that seven weekly injections of 100 mg adjunct testosterone preserved lean body mass in cancer patients undergoing standard-of-care treatment in a hospital setting. Because testosterone therapy can reduce circulating proinflammatory cytokines, we conducted an ancillary analysis to determine if this testosterone treatment reduced inflammatory burden and improved CRF symptoms and health-related quality of life. Randomization was computer-generated and managed by the pharmacy, which dispensed testosterone and placebo in opaque syringes to the administering study personnel. A total of 24 patients were randomized (14 placebo, 10 testosterone), and 21 were included in the primary analysis (11 placebo, 10 testosterone). Testosterone therapy did not ameliorate CRF symptoms (placebo to testosterone difference in predicted mean multidimensional fatigue symptom inventory scores: −5.6, 95% CI: −24.6 to 13.3), improve inflammatory markers, or preserve health-related quality of life and functional measures of performance in late-stage cancer patients.

Long duration spaceflight missions will require novel exercise systems to protect astronaut crew from the detrimental effects of microgravity exposure. The SPRINT protocol is a novel and promising exercise prescription that combines aerobic and resistive training using a flywheel device, and it was successfully employed in a 70-day bed-rest study as well as onboard the International Space Station. Our team created a VR simulation to further augment the SPRINT protocol when using a flywheel ergometer training device (the Multi-Mode Exercise Device or M-MED). The simulation aspired to maximal realism in a virtual river setting while providing real-time biometric feedback on heart rate performance to subjects. In this pilot study, five healthy, male, physically-active subjects aged 35 ± 9.0 years old underwent 2 weeks of SPRINT protocol, either with or without the VR simulation. After a 1-month washout period, subjects returned for a subsequent 2 weeks in the opposite VR condition. We measured physiological and cognitive variables of stress, performance, and well-being. While physiological effects did not suggest much difference with the VR condition over 2 weeks, metrics of motivation, affect, and mood restoration showed detectable differences, or trended toward more positive outcomes than exercise without VR. These results provide evidence that a well-designed VR “exergaming” simulation with biometric feedback could be a beneficial addition to exercise prescriptions, especially if users are exposed to isolation and confinement.

Background Organ function is known to decline with age. Optimizing cardiac, pulmonary and renal function in older adults has led to significant improvements in perioperative care. However, when substantial blood loss and fluid shifts occur, perioperative outcomes still remains poor, especially in older adults. We suspect that this could be due to age-related changes in endothelial function—an organ controlling the transport of fluid and solutes. The capillary filtration coefficient (CFC) is an important determinant of fluid transport. The CFC can be measured in vivo, which provides a tool to estimate endothelial barrier function. We have previously shown that the CFC increases when giving a fluid bolus resulting in increased vascular and extravascular volume expansion, in young adults. This study aimed to compare the physiologic determinants of fluid distribution in young versus older adults so that clinicians can best optimize perioperative fluid therapy. Methods Ten healthy young volunteers (ages 21–35) and nine healthy older volunteers (ages 60–75) received a 10 mL/kg fluid bolus over the course of twenty minutes. Hemodynamics, systolic and diastolic heart function, fluid volumetrics and microcirculatory determinants were measured before, during, and after the fluid bolus. Results Diastolic function was reduced in older versus younger adults before and after fluid bolus ( P < 0.01). Basal CFC and plasma oncotic pressure were lower in the older versus younger adults. Further, CFC did not increase in older adults following the fluid bolus, whereas it did in younger adults ( p < 0.05). Cumulative urinary output, while lower in older adults, was not significantly different ( p = 0.059). Mean arterial pressure and systemic vascular resistance were elevated in the older versus younger adults ( p < 0.05). Conclusion Older adults show a less reactive CFC to a fluid bolus, which could reduce blood to tissue transport of fluid. Diastolic dysfunction likely contributes to fluid maldistribution in older adults.

Basal metabolic rate generally scales with body mass in mammals, and variation from predicted levels indicates adaptive metabolic remodeling. As a thermogenic adaptation for living in cool water, sea otters have a basal metabolic rate approximately three times that of the predicted rate; however, the tissue-level source of this hypermetabolism is unknown. Because skeletal muscle is a major determinant of whole-body metabolism, we characterized respiratory capacity and thermogenic leak in sea otter muscle. Compared with that of previously sampled mammals, thermogenic muscle leak capacity was elevated and could account for sea otter hypermetabolism. Muscle respiratory capacity was modestly elevated and reached adult levels in neonates. Premature metabolic development and high leak rate indicate that sea otter muscle metabolism is regulated by thermogenic demand and is the source of basal hypermetabolism.

Various morphological and metabolic adaptations have equipped mammals to survive diverse habitats including extreme differences in temperature. For homeothermic mammals in cold habitats, insulation is critical to minimize heat loss. However, when insulation is not sufficient, metabolism is increased to generate heat through increased activity, shivering, or other regulated increases in metabolic rate. As a result, there are vast adaptive differences in insulation, temperature tolerance, and metabolic thermogenesis among different mammal species (e.g. tropical vs. polar mammals), and among the same species in different geographic regions (e.g. northern vs. southern populations and low-altitude vs. high-altitude populations). Moreover, metabolic acclimatization is also critical within an individual animal during seasonal, diurnal, and habitat shifts. Thus, an animal’s ability to tolerate varied environmental temperatures can be shaped by both shortterm acclimatization and evolutionary adaptation via changes in morphology (e.g. body size and insulation) and metabolism (e.g. upregulated metabolic thermogenesis) [1]. Although morphological differences between species may be relatively obvious and easily quantified, it is more difficult to identify tissue and cellular level adaptations that influence metabolic rate. Aerobic metabolism in mammals is supported by the integration of respiratory and circulatory systems and regulated at the cellular level by numerous interconnected molecular pathways. Given the complexity of integrative metabolism, the expression or function of a single gene is not responsible for setting a predetermined basal metabolic rate in the whole animal or the metabolic capacity in any one tissue [2]. While it may be difficult to identify the primary mechanisms regulating whole-body metabolism in mammals, the Krogh principle teaches us that studying unique animal models can yield novel insights into resolving this physiological “problem.” Studying hypermetabolism in cold-adapted mammals provides a model of adaptive metabolic plasticity to identify tissues with the ability to respond to changing metabolic demand and pinpoint the associated cellular pathways. Mammalian basal metabolic rate (BMR) is a combined aggregate of tissue-level metabolism. Because assorted body tissues differ in mass and metabolic rate, their individual contributions to BMR and thermogenesis are varied [3]. Skeletal muscle makes up the largest single tissue in most mammals, and although the specific metabolic rate of skeletal muscle (metabolic rate per kg of tissue) is low at rest, it has a high maximal respiratory capacity. This means that skeletal muscle has a large metabolic scope that is not utilized at rest, but has tremendous metabolic and thermogenic potential. The large relative mass also means that even small perturbations in muscle metabolic rate have profound effects on whole-body metabolism and thermogenesis [4]. Although the metabolic rate in resting skeletal muscle is low, it can rapidly increase to support metabolic demand. In skeletal muscle, this increased demand often powers muscle contractions for movement during physical activity, but can also increase for thermogenesis. Increased metabolic heat production can result from shivering (thermogenic muscle contractions that do not support functional movement), or nonshivering thermogenesis. Nonshivering thermogenesis has the advantage of not requiring muscle contraction to increase cellular energy expenditure. Instead, the sequestration of ions in membrane-bound intracellular chambers is made less efficient by “leaky” membranes. This leak requires additional energy expenditure to maintain transmembrane concentration gradients, and includes proton leak across the inner mitochondrial membrane (where TEMPERATURE 2022, VOL. 9, NO. 2, 119–121 https://doi.org/10.1080/23328940.2021.2004048

The exploration of space will require ever-increasing exposure to microgravity environments. The human response to this exposure has been categorized and mitigated via countermeasures, principally exercise. However, additional constraints to future mission design minimizes the allotted space and modalities for exercise, creating a risk for psychological fatigue, a reduction in motivation, and a suite of other categorical factors that could, taken together, present a risk for reduced adherence to the countermeasures and/or mission performance. Thus, the current study will examine the effects of a virtual reality (VR) intervention on spaceflight-validated exercise protocols using a prototype rowing ergometer designed to operate within the constraints of future long-duration exploration missions (LDEM). The Integrated Resistance and Aerobic Training (dubbed "SPRINT") protocol will be used in conjunction with a combination flywheel and resistance training device (M-MED) utilized in prior bedrest studies. The SPRINT protocol trades exercise duration for intensity, providing similar benefits to existing countermeasures while reducing time spent on exercise. The M-MED permits resistance training on the muscles most effected by microgravity exposure on the same device used to train cardiovascular function, thus reducing the volume and weight requirements of the exercise countermeasure. It is upon this framework that we will add the VR rowing simulation. VR has shown to be a lightweight, reliable, and enjoyable technology in numerous studies, while exergaming has been shown to improve measures of motivation and adherence. We will create a rowing simulation that can integrate with a rowing ergometer and any exercise protocol, and then implement it on the M-MED with SPRINT. The simulation will feature virtual teammates, virtual competitors, and other gaming mechanisms that encourage a user to maintain a prescribed heart rate intensity in a way that aims to maximize factors associated with enjoyment and adherence. We plan to conduct a within-subjects experiment on an astronaut-like population. Subjects will be randomly assigned to VR or non-VR in their initial experiment, complete the SPRINT protocol on the M-MED, break for a one-month minimum washout period, then return to complete the protocol again in the other group. As a pilot study, dependent variables have been selected broadly. Physical and psychological outcomes are to be measured alongside adherence to and motivation toward this very challenging protocol. Additional measures are to be made of virtual presence, preexisting bias toward or against VR, and personality traits, which may influence a preference for or against VR. Preliminary data on non-VR subjects shows increasing measures of state-trait anxiety, negative feelings toward the exercise, and amotivation from the start to the end of the protocol. It is hypothesized that overall attitudes toward the protocol will improve with the VR intervention as indicated by metrics of adherence, motivation, affect, and mood restoration. The results of this study will inform future designs of exercise combined with VR applications for implementation during LDEM.

Northern elephant seals (NES, Mirounga angustirostris) undergo an annual molt during which they spend ∼40 days fasting on land with reduced activity and lose approximately one-quarter of their body mass. Reduced activity and muscle load in stereotypic terrestrial mammalian models results in decreased muscle mass and capacity for force production and aerobic metabolism. However, the majority of lost mass in fasting female NES is from fat while muscle mass is largely preserved. Although muscle mass is preserved, potential changes to the metabolic and contractile capacity are unknown. To assess potential changes in NES skeletal muscle during molt, we collected muscle biopsies from 6 adult female NES before the molt and after ∼30 days at the end of the molt. Skeletal muscle was assessed for respiratory capacity using high resolution respirometry, and RNA was extracted to assess changes in gene expression. Despite a month of reduced activity, fasting, and weight loss, skeletal muscle respiratory capacity was preserved with no change in OXPHOS respiratory capacity. Molt was associated with 162 upregulated genes including those favoring lipid metabolism. We identified 172 downregulated genes including those coding for ribosomal proteins and genes associated with skeletal muscle force transduction and glucose metabolism. Following ∼30 days of molt, NES skeletal muscle metabolic capacity is preserved although mechanotransduction may be compromised. In the absence of exercise stimulus, fasting-induced shifts in muscle metabolism may stimulate pathways associated with preserving the mass and metabolic capacity of slow oxidative muscle.

High-throughput sequencing technologies could improve diagnosis and classification of TBI subgroups. Because recent studies showed that circulating microRNAs (miRNAs) may serve as noninvasive markers of TBI, we performed miRNA-seq to study TBI-induced changes in rat hippocampal miRNAs up to one year post-injury. We used miRNA PCR arrays to interrogate differences in serum miRNAs using two rat models of TBI (controlled cortical impact [CCI] and fluid percussion injury [FPI]). The translational potential of our results was evaluated by miRNA-seq analysis of human control and TBI (acute and chronic) serum samples. Bioinformatic analyses were performed using Ingenuity Pathway Analysis, miRDB, and Qlucore Omics Explorer. Rat miRNA profiles identified TBI across all acute and chronic intervals. Rat CCI and FPI displayed distinct serum miRNA profiles. Human miRNA profiles identified TBI across all acute and chronic time points and, at 24 hours, discriminated between focal and diffuse injuries. In both species, predicted gene targets of differentially expressed miRNAs are involved in neuroplasticity, immune function and neurorestoration. Chronically dysregulated miRNAs (miR-451a, miR-30d-5p, miR-145-5p, miR-204-5p) are linked to psychiatric and neurodegenerative disorders. These data suggest that circulating miRNAs in biofluids can be used as “molecular fingerprints” to identify acute, chronic, focal or diffuse TBI and potentially, presence of neurodegenerative sequelae.