SnapShot: Skeletal muscle atrophy.

Skeletal muscle size is highly plastic and sensitive to a variety of stimuli. Muscle atrophy occurs as the result of changes in multiple signaling pathways that regulate both protein synthesis and degradation. The signaling pathways that are activated or inhibited depend on the specific stimuli that are altered. To view this SnapShot, open of download the PDF.

Factors influencing risk-based care of the childhood cancer survivor in the 21st century.

The population of adult survivors of childhood cancer continues to grow as survival rates improve. Although it is well established that these survivors experience various complications and comorbidities related to their malignancy and treatment, this risk is modified by many factors that are not directly linked to their cancer history. Research evaluating the influence of patient-specific demographic and genetic factors, premorbid and comorbid conditions, health behaviors, and aging has identified additional risk factors that influence cancer treatment-related toxicity and possible targets for intervention in this population. Furthermore, although current long-term follow-up guidelines comprehensively address specific therapy-related risks and provide screening recommendations, the risk profile of the population continues to evolve with ongoing modification of treatment strategies and the emergence of novel therapeutics. To address the multifactorial modifiers of cancer treatment-related health risk and evolving treatment approaches, a patient-centered and risk-adapted approach to care that often requires a multidisciplinary team approach, including medical and behavioral providers, is necessary for this population. CA Cancer J Clin 2018;68:133-152. © 2018 American Cancer Society.

Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: NHLBI Workshop Report.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.

ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM).

The critical nature of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician and the microbiologists who provide enormous value to the health care team. This document, developed by experts in both adult and pediatric laboratory and clinical medicine, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. Sections are divided into anatomic systems, including Bloodstream Infections and Infections of the Cardiovascular System, Central Nervous System Infections, Ocular Infections, Soft Tissue Infections of the Head and Neck, Upper Respiratory Infections, Lower Respiratory Tract infections, Infections of the Gastrointestinal Tract, Intraabdominal Infections, Bone and Joint Infections, Urinary Tract Infections, Genital Infections, and Skin and Soft Tissue Infections; or into etiologic agent groups, including arboviral Infections, Viral Syndromes, and Blood and Tissue Parasite Infections. Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. In addition, the pediatric needs of specimen management are also addressed. There is redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a reference to guide physicians in choosing tests that will aid them to diagnose infectious diseases in their patients.

Quantitative computed tomography analysis of body composition changes in paediatric patients with acute lymphoblastic leukaemia.

Children with acute lymphoblastic leukaemia (ALL) are at risk for obesity and cardiometabolic diseases. To gain insight into body composition changes among children with ALL, we assessed quantitative computed tomography (QCT) data for specific body compartments (subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT], total adipose tissue [TAT], lean tissue [LT], LT/TAT and VAT/SAT at lumbar vertebrae L1 and L2) at diagnosis and at off-therapy for 189 children with ALL and evaluated associations between body mass index (BMI) Z-score and clinical characteristics. BMI Z-score correlated positively with SAT, VAT and TAT and negatively with LT/TAT and VAT/SAT. At off-therapy, BMI Z-score, SAT, VAT and TAT values were higher than at diagnosis, but LT, LT/TAT and VAT/SAT were lower. Patients aged ≥10 years at diagnosis had higher SAT, VAT and TAT and lower LT and LT/TAT than patients aged 2.0-9.9 years. Female patients had lower LT and LT/TAT than male patients. Black patients had less VAT than White patients. QCT analysis showed increases in adipose tissue and decreases in LT during ALL therapy when BMI Z-scores increased. Early dietary and physical therapy interventions should be considered, particularly for patients at risk for obesity.

Evaluation of oncology infusion pharmacy practices: A nationwide survey.

PURPOSE: Oncology care continues to evolve at a rapid pace including provision of infusion-based care. There is currently a lack of robust metrics around oncology infusion centers and pharmacy practice. The workgroup completed a nationwide survey to learn about oncology-based infusion pharmacy services offered. The objective was to highlight consistent, measureable oncology-based infusion pharmacy metrics that will provide a foundation to describe overall productivity including emphasis on high patient-safety standards. METHODS: A nationwide survey was developed via a workgroup within the Vizient Pharmacy Cancer Care Group beginning in April 2019 and conducted electronically via the Vizient Pharmacy Network from September to November 2020. The survey was designed to capture a number of key metrics related to oncology-based infusion pharmacy services. RESULTS: Forty-one sites responded to the survey. Responses highlighted hours of operation (median = 11.5), number of infusion chairs (median = 45). Staffing metrics included 7.1 pharmacist full-time equivalent (FTE) and 7.6 technician FTE per week. 80.5% of sites had cleanrooms and 95.1% reported both hazardous and nonhazardous compounding hoods. 68.3% of sites reported using intravenous (IV) technology, 50.0% measured turnaround time, and 31.4% prepared treatment medications in advance. CONCLUSION: There was variability among oncology infusion pharmacy practices in regard to survey responses among sites. The survey results highlight the need for standardization of established productivity metrics across oncology infusion pharmacies in order to improve efficiency and contain costs in the changing oncology landscape. The survey provides insight into oncology infusion pharmacy practices nationwide and provides information for pharmacy leaders to help guide their practices.

Rescuing the Last-Line Polymyxins: Achievements and Challenges.

Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and the availability of "safer" antibiotics approved at that time. Therefore, knowledge on polymyxins had been scarce until recently, when enormous efforts have been made by several research teams around the world to elucidate the chemical, microbiological, pharmacokinetic/pharmacodynamic, and toxicological properties of polymyxins. One of the major achievements is the development of the first scientifically based dosage regimens for colistin that are crucial to ensure its safe and effective use in patients. Although the guideline has not been developed for polymyxin B, a large clinical trial is currently being conducted to optimize its clinical use. Importantly, several novel, safer polymyxin-like lipopeptides are developed to overcome the nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin. This review discusses the latest achievements on polymyxins and highlights the major challenges ahead in optimizing their clinical use and discovering new-generation polymyxins. To save lives from the deadly infections caused by Gram negative "superbugs," every effort must be made to improve the clinical utility of the last-line polymyxins. SIGNIFICANCE STATEMENT: Antimicrobial resistance poses a significant threat to global health. The increasing prevalence of multidrug-resistant (MDR) bacterial infections has been highlighted by leading global health organizations and authorities. Polymyxins are a last-line defense against difficult-to-treat MDR Gram negative pathogens. Unfortunately, the pharmacological information on polymyxins was very limited until recently. This review provides a comprehensive overview on the major achievements and challenges in polymyxin pharmacology and clinical use and how the recent findings have been employed to improve clinical practice worldwide.

A critical discussion on the relationship between E3 ubiquitin ligases, protein degradation, and skeletal muscle wasting: it's not that simple.

Ubiquitination is an important post-translational modification (PTM) for protein substrates, whereby ubiquitin is added to proteins through the coordinated activity of activating (E1), ubiquitin-conjugating (E2), and ubiquitin ligase (E3) enzymes. The E3s provide key functions in the recognition of specific protein substrates to be ubiquitinated and aid in determining their proteolytic or nonproteolytic fates, which has led to their study as indicators of altered cellular processes. MuRF1 and MAFbx/Atrogin-1 were two of the first E3 ubiquitin ligases identified as being upregulated in a range of different skeletal muscle atrophy models. Since their discovery, the expression of these E3 ubiquitin ligases has often been studied as a surrogate measure of changes to bulk protein degradation rates. However, emerging evidence has highlighted the dynamic and complex regulation of the ubiquitin proteasome system (UPS) in skeletal muscle and demonstrated that protein ubiquitination is not necessarily equivalent to protein degradation. These observations highlight the potential challenges of quantifying E3 ubiquitin ligases as markers of protein degradation rates or ubiquitin proteasome system (UPS) activation. This perspective examines the usefulness of monitoring E3 ubiquitin ligases for determining specific or bulk protein degradation rates in the settings of skeletal muscle atrophy. Specific questions that remain unanswered within the skeletal muscle atrophy field are also identified, to encourage the pursuit of new research that will be critical in moving forward our understanding of the molecular mechanisms that govern protein function and degradation in muscle.

Therapeutic Potential of Intravenous Phage as Standalone Therapy for Recurrent Drug-Resistant Urinary Tract Infections.

Recurrent urinary tract infections (rUTI) are common in kidney transplant recipients (KTR) and are associated with multidrug resistance and increased morbidity/mortality. Novel antibiotic alternatives to reduce UTI recurrence are critically needed. We describe a case of rUTI due to extended spectrum beta lactamase (ESBL) Klebsiella pneumoniae in a KTR that was treated successfully with 4 weeks of adjunctive intravenous bacteriophage therapy alone, without concomitant antibiotics, and with no recurrence in a year of follow-up.

Physical therapy and nutrition therapy: synergistic, antagonistic, or independent interventions?

PURPOSE OF REVIEW: Physical therapy and nutrition therapy have predominantly been studied separately in the critically ill, however in clinical practice are often delivered in combination. It is important to understand how these interventions interact. This review will summarize the current science - where they are potentially synergistic, antagonistic, or independent interventions. RECENT FINDINGS: Only six studies were identified within the ICU setting that combined physical therapy and nutrition therapy. The majority of these were randomized controlled trials with modest sample sizes. There was an indication of benefit in the preservation of femoral muscle mass and short-term physical quality of life - particularly with high-protein delivery and resistance exercise, in patients who were predominantly mechanically ventilated patients, with an ICU length of stay of approximately 4-7 days (varied across studies). Although these benefits did not extend to other outcomes such as reduced length of ventilation, ICU or hospital admission. No recent trials were identified that combined physical therapy and nutrition therapy in post-ICU settings and is an area that warrants investigation. SUMMARY: The combination of physical therapy and nutrition therapy might be synergistic when evaluated within the ICU setting. However, more careful work is required to understand the physiological challenges in the delivery of these interventions. Combining these interventions in post-ICU settings is currently under-investigated, but may be important to understand any potential benefits to patient longitudinal recovery.

Imaging of pediatric hematopoietic stem cell transplant recipients: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Imaging in hematopoietic stem cell transplantation patients is not targeted at evaluating the transplant per se. Rather, imaging is largely confined to evaluating peri-procedural and post-procedural complications. Alternatively, imaging may be performed to establish a baseline study for comparison should the patient develop certain post-procedural complications. This article looks to describe the various imaging modalities available with recommendations for which imaging study should be performed in specific complications. We also provide select imaging protocols for different indications and modalities for the purpose of establishing a set minimal standard for imaging in these complex patients.

Feasibility of indocyanine green-guided localization of pulmonary nodules in children with solid tumors.

BACKGROUND: Clearing all pulmonary metastases is essential for curing pediatric solid tumors. However, intraoperative localization of such pulmonary nodules can be challenging. Therefore, an intraoperative tool that localizes pulmonary metastases is needed to improve diagnostic and therapeutic resections. Indocyanine green (ICG) real-time fluorescence imaging is used for this purpose in adult solid tumors, but its utility in pediatric solid tumors has not been determined. METHODS: A single-center, open-label, nonrandomized, prospective clinical trial (NCT04084067) was conducted to assess the ability of ICG to localize pulmonary metastases of pediatric solid tumors. Patients with pulmonary lesions who required resection, either for therapeutic or diagnostic intent, were included. Patients received a 15-minute intravenous infusion of ICG (1.5 mg/kg), and pulmonary metastasectomy was performed the following day. A near-infrared spectroscopy iridium system was optimized to detect ICG, and all procedures were photo-documented and recorded. RESULTS: ICG-guided pulmonary metastasectomies were performed in 12 patients (median age: 10.5 years). A total of 79 nodules were visualized, 13 of which were not detected by preoperative imaging. Histologic examination confirmed the following histologies: hepatoblastoma (n = 3), osteosarcoma (n = 2), and one each of rhabdomyosarcoma, Ewing sarcoma, inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, and papillary thyroid carcinoma. ICG guidance failed to localize pulmonary metastases in five (42%) patients who had inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, or papillary thyroid carcinoma. CONCLUSIONS: ICG-guided identification of pulmonary nodules is not feasible for all pediatric solid tumors. However, it may localize most metastatic hepatic tumors and high-grade sarcomas in children.

Longitudinal Comparison of Orbital Volumes from Enucleated Eyes with Hydroxyapatite Orbital Implant in Unilateral Retinoblastoma Patients.

PURPOSE: To compare the orbital volume between enucleated and contralateral, uninvolved orbits over a 5-year period in patients with unilateral retinoblastoma who underwent enucleation with hydroxyapatite (HA) implant placement by a single surgeon. METHODS: A retrospective review was performed on the clinical records and radiographic images of unilateral retinoblastoma patients who underwent enucleation with primary HA implantation from 2003 to 2020 at a single institution. Bilateral orbital volume measurements were taken from the initial postoperative MRI scan and again at 1- and 5-years postenucleation. The main outcome measure was the longitudinal change in volume difference (∆𝑉). The implant size, age at enucleation, and sex were also evaluated. A linear mixed-effect model was used for analysis. RESULTS: A total of 124 patients (73 males) with HA implants following enucleation were included. Overall, the unaffected orbit trended toward having a greater volume compared with the enucleated orbit, but this was not statistically significant (ß = 0.003; p = 0.122). The mean age at enucleation was 2.4 years. The median time between enucleation and the initial, 1-year, and 5-year postoperative MRIs was 6 months, 17 months, and 55 months, respectively. There was no statistical correlation between age at enucleation, gender, implant size, or orbital volume at any time points (p > 0.05). CONCLUSIONS: Patients treated with enucleation and primary HA implant placement for unilateral retinoblastoma did not display significant asymmetry in orbital volume on 5-year postenucleation MRIs, suggesting that HA implants promote orbital growth comparable to a nonenucleated orbit in the pediatric population.

Disparities in smoking prevalence and associations with mental health and substance use disorders in underserved communities across the United States.

BACKGROUND: Smoking contributes to the top 3 deadliest cancers, cancers of the lung, colon, and pancreas, which account for nearly 40% of all cancer-related deaths in the United States. Despite historicly low smoking rates, substantial disparities remain among people with mental health conditions and substance use disorders (SUDs). METHODS: The study examined the prevalence of smoking among adults from underserved communities who are served at federally qualified health centers through an analysis of the 2014 Health Center Patient Survey. Furthermore, the study assessed associations of smoking with co-occurring mental health conditions and SUDs among adult smokers (n = 1735). RESULTS: The prevalence of smoking among health center patients was 28.1%. Among current smokers, 59.1% had depression and 45.4% had generalized anxiety. Non-Hispanic Black smokers had more than 2 times the odds of reporting SUDs (adjusted odds ratio [aOR], 2.13; 95% confidence interval [CI], 1.06-4.30). Individuals at or below 100% of the federal poverty level had more than 2 times the odds of having mental health conditions (aOR, 2.55; 95% CI, 1.58-4.11), and those who were unemployed had more than 3 times the odds for SUDs (aOR, 3.21; 95% CI, 1.27-8.10). CONCLUSIONS: The prevalence of smoking in underserved communities is nearly double the national prevalence. In addition, the study underscores important socioeconomic determinants of health in smoking cessation behavior and the marked disparities among individuals with mental health conditions and SUDs. Finally, the findings illuminate the unique need for tailored treatments supporting cancer prevention care to address challenges confronted by vulnerable populations.

Activation of Crtc2/Creb1 in skeletal muscle enhances weight loss during intermittent fasting.

The Creb-Regulated Transcriptional Coactivator (Crtc) family of transcriptional coregulators drive Creb1-mediated transcription effects on metabolism in many tissues, but the in vivo effects of Crtc2/Creb1 transcription on skeletal muscle metabolism are not known. Skeletal muscle-specific overexpression of Crtc2 (Crtc2 mice) induced greater mitochondrial activity, metabolic flux capacity for both carbohydrates and fats, improved glucose tolerance and insulin sensitivity, and increased oxidative capacity, supported by upregulation of key metabolic genes. Crtc2 overexpression led to greater weight loss during alternate day fasting (ADF), selective loss of fat rather than lean mass, maintenance of higher energy expenditure during the fast and reduced binge-eating during the feeding period. ADF downregulated most of the mitochondrial electron transport genes, and other regulators of mitochondrial function, that were substantially reversed by Crtc2-driven transcription. Glucocorticoids acted with AMPK to drive atrophy and mitophagy, which was reversed by Crtc2/Creb1 signaling. Crtc2/Creb1-mediated signaling coordinates metabolic adaptations in skeletal muscle that explain how Crtc2/Creb1 regulates metabolism and weight loss.

Evidence-based surgical guidelines for treating children with Wilms tumor in low-resource settings.

BACKGROUND: Survival of Wilms tumor (WT) is > 90% in high-resource settings but < 30% in low-resource settings. Adapting a standardized surgical approach to WT is challenging in low-resource settings, but a local control strategy is crucial to improving outcomes. OBJECTIVE: Provide resource-sensitive recommendations for the surgical management of WT. METHODS: We performed a systematic review of PubMed and EMBASE through July 7, 2020, and used the GRADE approach to assess evidence and recommendations. RECOMMENDATIONS: Initiation of treatment should be expedited, and surgery should be done in a high-volume setting. Cross-sectional imaging should be done to optimize preoperative planning. For patients with typical clinical features of WT, biopsy should not be done before chemotherapy, and neoadjuvant chemotherapy should precede surgical resection. Also, resection should include a large transperitoneal laparotomy, adequate lymph node sampling, and documentation of staging findings. For WT with tumor thrombus in the inferior vena cava, neoadjuvant chemotherapy should be given before en bloc resection of the tumor and thrombus and evaluation for viable tumor thrombus. For those with bilateral WT, neoadjuvant chemotherapy should be given for 6-12 weeks. Neither routine use of complex hilar control techniques during nephron-sparing surgery nor nephron-sparing resection for unilateral WT with a normal contralateral kidney is recommended. When indicated, postoperative radiotherapy should be administered within 14 days of surgery. Post-chemotherapy pulmonary oligometastasis should be resected when feasible, if local protocols allow omission of whole-lung irradiation in patients with nonanaplastic histology stage IV WT with pulmonary metastasis without evidence of extrapulmonary metastasis. CONCLUSION: We provide evidence-based recommendations for the surgical management of WT, considering the benefits/risks associated with limited-resource settings.

Spaces of Segregation and Health: Complex Associations for Black Immigrant and US-Born Mothers in New York City.

Black immigrants are a growing proportion of the Black population in the USA, and despite the fact that they now comprise nearly a quarter of Black urban residents, few studies address the relationships between racial segregation and maternal and birth outcomes among Black immigrants. In this study of birth outcomes among US-born and immigrant Black mothers in New York City between 2010 and 2014, we applied multilevel models, assessing the association between segregation (measured through a novel kernel-based measure of local segregation) and adverse birth outcomes (preterm birth (PTB) and low birth weight (LBW; < 2500 g)) among African-born, Caribbean-born, and US-born Black mothers. We found that African-born and Caribbean/Latin American-born Black mothers had a significantly lower incidence of PTB compared with US-born Black mothers (7.0 and 10.1, respectively, compared with 11.2 for US-born mothers). We also found disparities in the incidence of infant LBW by nativity, with the highest incidence among infants born to US-born mothers (10.9), compared with African-born (6.9) and Caribbean-born mothers (9.0). After adjusting for maternal (maternal age; higher rates of reported drug use and smoking) and contextual characteristics (neighborhood SES; green space access), we found that maternal residence in an area with high Black segregation increases the likelihood of PTB and LBW among US-born and Caribbean-born Black mothers. In contrast, the association between segregation and birth outcomes was insignificant for African-born mothers. Associations between tract-level socioeconomic disadvantage and birth outcomes also varied across groups, with only US-born Black mothers showing the expected positive association with risk of PTB and LBW.

Ubiquitin Ligases in Longevity and Aging Skeletal Muscle.

The development and prevalence of diseases associated with aging presents a global health burden on society. One hallmark of aging is the loss of proteostasis which is caused in part by alterations to the ubiquitin-proteasome system (UPS) and lysosome-autophagy system leading to impaired function and maintenance of mass in tissues such as skeletal muscle. In the instance of skeletal muscle, the impairment of function occurs early in the aging process and is dependent on proteostatic mechanisms. The UPS plays a pivotal role in degradation of misfolded and aggregated proteins. For the purpose of this review, we will discuss the role of the UPS system in the context of age-related loss of muscle mass and function. We highlight the significant role that E3 ubiquitin ligases play in the turnover of key components (e.g., mitochondria and neuromuscular junction) essential to skeletal muscle function and the influence of aging. In addition, we will briefly discuss the contribution of the UPS system to lifespan. By understanding the UPS system as part of the proteostasis network in age-related diseases and disorders such as sarcopenia, new discoveries can be made and new interventions can be developed which will preserve muscle function and maintain quality of life with advancing age.

Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism.

UBR5 is an E3 ubiquitin ligase positively associated with anabolism, hypertrophy, and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5's role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in vivo. To achieve this aim, we electroporated a UBR5-RNAi plasmid into mouse tibialis anterior muscle to investigate the impact of reduced UBR5 on anabolic signaling MEK/ERK/p90RSK and Akt/GSK3ß/p70S6K/4E-BP1/rpS6 pathways. Seven days after UBR5 RNAi electroporation, although reductions in overall muscle mass were not detected, the mean cross-sectional area (CSA) of green fluorescent protein (GFP)-positive fibers were reduced (-9.5%) and the number of large fibers were lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2, Akt, and GSK3ß activity. Although p90RSK phosphorylation significantly increased, total p90RSK protein levels demonstrated a 45% reduction with UBR5-RNAi. Finally, these early events after 7 days of UBR5 knockdown culminated in significant reductions in muscle mass (-4.6%) and larger reductions in fiber CSA (-18.5%) after 30 days. This was associated with increased levels of phosphatase PP2Ac and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, as well as corresponding reductions in eIF4e. This study demonstrates that UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminates in skeletal muscle atrophy.