Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice.

Human hallmarks of sarcopenia include muscle weakness and a blunted response to exercise. Nicotinamide N-methyltransferase inhibitors (NNMTis) increase strength and promote the regenerative capacity of aged muscle, thus offering a promising treatment for sarcopenia. Since human hallmarks of sarcopenia are recapitulated in aged (24-month-old) mice, we treated mice from 22 to 24 months of age with NNMTi, intensive exercise, or a combination of both, and compared skeletal muscle adaptations, including grip strength, longitudinal running capacity, plantarflexor peak torque, fatigue, and muscle mass, fiber type, cross-sectional area, and intramyocellular lipid (IMCL) content. Exhaustive proteome and metabolome analyses were completed to identify the molecular mechanisms underlying the measured changes in skeletal muscle pathophysiology. Remarkably, NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. Importantly, the grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber CSA. Detailed skeletal muscle proteome and metabolome analyses revealed unique molecular mechanisms associated with NNMTi treatment and distinct molecular mechanisms and cellular processes arising from a combination of NNMTi and exercise relative to those given a single intervention. These studies suggest that NNMTi-based drugs, either alone or combined with exercise, will be beneficial in treating sarcopenia and a wide range of age-related myopathies.

The 24-Hour Time Course of Integrated Molecular Responses to Resistance Exercise in Human Skeletal Muscle Implicates MYC as a Hypertrophic Regulator That is Sufficient for Growth.

Molecular control of recovery after exercise in muscle is temporally dynamic. A time course of biopsies around resistance exercise (RE) combined with -omics is necessary to better comprehend the molecular contributions of skeletal muscle adaptation in humans. Vastus lateralis biopsies before and 30 minutes, 3-, 8-, and 24-hours after acute RE were collected. A time-point matched biopsy-only group was also included. RNA-sequencing defined the transcriptome while DNA methylomics and computational approaches complemented these data. The post-RE time course revealed: 1) DNA methylome responses at 30 minutes corresponded to upregulated genes at 3 hours, 2) a burst of translation- and transcription-initiation factor-coding transcripts occurred between 3 and 8 hours, 3) global gene expression peaked at 8 hours, 4) ribosome-related genes dominated the mRNA landscape between 8 and 24 hours, 5) methylation-regulated MYC was a highly influential transcription factor throughout the 24-hour recovery and played a primary role in ribosome-related mRNA levels between 8 and 24 hours. The influence of MYC in human muscle adaptation was strengthened by transcriptome information from acute MYC overexpression in mouse muscle. To test whether MYC was sufficient for hypertrophy, we generated a muscle fiber-specific doxycycline inducible model of pulsatile MYC induction. Periodic 48-hour pulses of MYC over 4 weeks resulted in higher muscle mass and fiber size in the soleus of adult female mice. Collectively, we present a temporally resolved resource for understanding molecular adaptations to RE in muscle and reveal MYC as a regulator of RE-induced mRNA levels and hypertrophy.

Impact of healthcare-associated infections within 7-days of acute stroke on health outcomes and risk of care-dependency: a multi-centre registry-based cohort study.

Healthcare-associated infections (HCAIs) in patients admitted with acute conditions remain a major challenge to healthcare services. Here, we assessed the impact of HCAIs acquired within 7-days of acute stroke on indicators of care-quality outcomes and dependency. Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme for 3309 patients (mean age = 76.2 yr, SD = 13.5) admitted to four UK hyperacute stroke units (HASU). Associations between variables were assessed by multivariable logistic regression (odds ratios, 95% confidence intervals), adjusted for age, sex, co-morbidities, pre-stroke disability, swallow screening, stroke type and severity. Within 7-days of admission, urinary tract infection (UTI) and pneumonia occurred in 7.6% and 11.3% of patients. Female (UTI only), older age, underlying hypertension, atrial fibrillation, previous stroke, pre-stroke disability, intracranial haemorrhage, severe stroke, and delay in swallow screening (pneumonia only) were independent risk factors of UTI and pneumonia. Compared to patients without UTI or pneumonia, those with either or both of these HCAIs were more likely to have prolonged stay (> 14-days) on HASU: 5.1 (3.8-6.8); high risk of malnutrition: 3.6 (2.9-4.5); palliative care: 4.5 (3.4-6.1); in-hospital mortality: 4.8 (3.8-6.2); disability at discharge: 7.5 (5.9-9.7); activity of daily living support: 1.6 (1.2-2.2); and discharge to care-home: 2.3 (1.6-3.3). In conclusion, HCAIs acquired within 7-days of an acute stroke led to prolonged hospitalisation, adverse health consequences and risk of care-dependency. These findings provide valuable information for timely intervention to reduce HCAIs, and minimising subsequent adverse outcomes.

Sex Differences in Quadriceps Atrophy After Anterior Cruciate Ligament Tear.

BACKGROUND: Female athletes lag behind their male counterparts in recovery from anterior cruciate ligament (ACL) injury. Quadriceps muscle size and strength are crucial factors for regaining function after ACL injury, but little is known about how these metrics vary due to biological sex. HYPOTHESIS: Female patients have reduced vastus lateralis fiber cross-sectional area (CSA) and lower quadriceps strength after ACL injury than male patients. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 60 participants with recent ACL tear were evaluated for vastus lateralis muscle fiber CSA, isometric quadriceps peak torque, and quadriceps rate of torque development. Linear mixed models were fit to determine differences across sex and limb for each variable of interest. RESULTS: The female group averaged almost 20% atrophy between limbs (P < 0.01), while the male group averaged just under 4% (P = 0.05). Strength deficits between limbs were comparable between female and male groups. CONCLUSION: Immediately after ACL injury, female patients have greater between-limb differences in muscle fiber CSA but between-limb strength deficits comparable with those of male patients. CLINICAL RELEVANCE: These results indicate that the underpinnings of strength loss differ based on biological sex, and thus individual patients could benefit from a sex-specific treatment approach to ACL injury.

Adreno-Muscarinic Synergy of Contractile Responses From Human Hyperplastic Prostate.

PURPOSE: Adreno-muscarinic synergy, a supra-additional contractile response to simultaneous application of α-adrenoreceptor and muscarinic receptor agonists, is a feature of several lower urinary tract regions that have dual sympathetic and parasympathetic innervation. We tested the hypothesis that synergy is also a feature of prostate tissue obtained from men with benign prostatic enlargement. METHODS: Isolated tissue strips were dissected from prostate 'chips', collected after transurethral prostate resection procedures for in vitro experiments, to measure isometric tension at 36°C. RESULTS: Added separately to the superfusate, phenylephrine and carbachol generated contractions with mean pEC50 (-log10EC50) values of 5.36 and 5.58, respectively, although phenylephrine maximal responses were about six-fold greater. In the presence of carbachol, the mean phenylephrine pEC50 was significantly increased to 5.84 and maximal response increased by 28%; overall, a significant synergistic response was demonstrated. The synergistic response was reduced by muscarinic receptor antagonists, most potently by the M3-selective agent 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide), and less so by M2 and M1-selective inhibitors gallamine and pirenzepine, but with an overall profile indicating M3/M2 mediation of the synergistic response. The magnitude of the synergistic response was variable between prostate chips that provided isolated preparations suggesting regional heterogenicity, although their zonal origin could not be determined. CONCLUSION: These experiments show that adreno-muscarinic contractile synergy is a feature of human hyperplastic prostate tissue. This has implications for the use of a combination therapy of α-blockers and anti-muscarinic agent to relieve secondary symptoms associated with benign prostatic hyperplasia, at least in men who can tolerate antimuscarinics without a risk of retention.

Sex-specific independent risk factors of urinary incontinence in acute stroke patients: A multicentre registry-based cohort study.

BACKGROUND: The presence of urinary incontinence (UI) in acute stroke patients indicates poor outcomes in men and women. However, there is a paucity and inconsistency of data on UI risk factors in this group and hence we conducted a sex-specific analysis to identify risk factors. METHODS: Data were collected prospectively (2014-2016) from the Sentinel Stroke National Audit Program for patients admitted to four UK hyperacute stroke units. Relevant risk factors for UI were determined by stepwise multivariable logistic regression, presented as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The mean (±SD) age of UI onset in men (73.9 year ± 13.1; n = 1593) was significantly earlier than for women (79.8 year ± 12.9; n = 1591: p < 0.001). Older age between 70 and 79 year in men (OR = 1.61: CI = 1.24-2.10) and women (OR = 1.55: CI = 1.12-2.15), or ≥80 year in men (OR = 2.19: CI = 1.71-2.81), and women (OR = 2.07: CI = 1.57-2.74)-reference: <70 year-both predicted UI. In addition, intracranial hemorrhage (reference: acute ischemic stroke) in men (OR = 1.64: CI = 1.22-2.20) and women (OR = 1.75: CI = 1.30-2.34); and prestroke disability (mRS scores ≥ 4) in men (OR = 1.90: CI = 1.02-3.5) and women (OR = 1.62: CI = 1.05-2.49) (reference: mRS scores < 4); and stroke severity at admission: NIHSS scores = 5-15 in men (OR = 1.50: CI = 1.20-1.88) and women (OR = 1.72: CI = 1.37-2.16), and NIHSS scores = 16-42 in men (OR = 4.68: CI = 3.20-6.85) and women (OR = 3.89: CI = 2.82-5.37) (reference: NIHSS scores = 0-4) were also significant. Factors not selected were: a history of congestive heart failure, hypertension, atrial fibrillation, diabetes and previous stroke. CONCLUSIONS: We have identified similar risk factors for UI after stroke in men and women including age >70 year, intracranial hemorrhage, prestroke disability and stroke severity.

Urinary incontinence indicates mortality, disability, and infections in hospitalised stroke patients.

OBJECTIVES: To assess the impact of urinary incontinence (UI) on health outcomes over the entire spectrum of acute stroke severity (National Institutes of Health Stroke Scale [NIHSS] scores: 0-42), due to a paucity of data on patients with milder strokes. PATIENTS AND METHODS: Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme (1593 men, 1591 women; mean [SD] age 76.8 [13.3] years) admitted to four UK hyperacute stroke units (HASUs). Relationships between variables were assessed by multivariable logistic regression. Data were adjusted for age, sex, comorbidities, pre-stroke disability and intra-cranial haemorrhage, and presented as odds ratios with 95% confidence intervals. RESULTS: Amongst patients with no symptoms or a minor stroke (NIHSS scores of 0-4), compared to patients without UI, patients with UI had significantly greater risks of poor outcomes including: in-hospital mortality; disability at discharge; in-hospital pneumonia; urinary tract infection within 7 days of admission; prolonged length of stay on the HASU; palliative care by discharge; activity of daily living (ADL) support, and new discharge to care home. In patients with more moderate stroke (NIHSS score of 5-15) the same outcomes were identified; being at greater risk for patients with UI, except for palliative care by discharge and ADL support. With the highest stroke severity group (NIHSS score of 16-48) all outcomes were identified except in-patient mortality, pneumonia, and ADL support. However, odds ratios diminished as NIHSS scores increased. CONCLUSIONS: Urinary incontinence is a useful indicator of poor short-term outcomes in older patients with an acute stroke, but irrespective of stroke severity. This provides valuable information to healthcare professionals to identify at-risk individuals.

Muscle Fiber Cross-Sectional Area Is Associated With Quadriceps Strength and Rate of Torque Development After ACL Injury.

ABSTRACT: Graham, MC, Thompson, KL, Hawk, GS, Fry, CS, and Noehren, B. Muscle fiber cross-sectional area is associated with quadriceps strength and rate of torque development after ACL injury. J Strength Cond Res 38(6): e273-e279, 2024-The purpose of this study was to investigate the relationship between muscle fiber type-specific properties of the vastus lateralis and quadriceps muscle performance in individuals after an anterior cruciate ligament (ACL) tear. 26 subjects (22.0 ± 5.4 years) were included in this cross-sectional study, and all data were collected before ACL reconstruction. Quadriceps peak torque (QPT) and early (0-100 ms) and late (100-200 ms) rate of torque development (RTD) were obtained from maximal voluntary isometric quadriceps strength testing. Muscle fiber cross-sectional area (fCSA) and percent fiber type distribution (FT%) were evaluated through immunohistochemical analysis of a muscle biopsy. Between-limb differences in fiber characteristics were assessed using paired t-tests (with α-level 0.05). Relationships between fiber-specific properties and quadriceps muscle performance were determined using separate multiple linear regression analyses for ACL-injured and noninjured limbs. There were significant differences in fCSA between ACL-injured and noninjured limbs across all fiber types, but no differences in FT%. Type 1 fCSA, type 2a fCSA, and their interaction effect were the explanatory variables with the strongest relationship to all performance outcomes for the ACL-injured limb. The explanatory variables in the ACL-injured limb had a significant relationship to QPT and late RTD, but not early RTD. These findings suggest that QPT and late RTD are more heavily influenced by fCSA than FT% in ACL-injured limbs. This work serves as a foundation for the development of more specific rehabilitation strategies aimed at improving quadriceps muscle function before ACL reconstruction or for individuals electing nonsurgical management.

Meta-analysis and construction of simple-to-use nomograms for approximating testosterone levels gained from weight loss in obese men.

BACKGROUND: Obesity-induced hypogonadism, which manifests as erectile dysfunction and a lack of libido, is a less visible and under-recognized obesity-related disorder in men. OBJECTIVE: We examined the impact of weight loss on total (TT) and free testosterone (FT) levels, and constructed nomograms to provide an easy-to-use visual aid for clinicians. MATERIALS AND METHODS: Meta-analysis was conducted using RevMan (v5.3) and expressed in standardized mean differences (SMD) for testosterone. Parallel-scale nomograms were constructed from baseline and target body mass index values to estimate the gain in testosterone. RESULTS: In total, 44 studies were included, comprising 1,774 participants and 2,159 datasets, as some studies included several datasets at different time points. Weight loss was controlled by low calorie diet (LCD) in 19 studies (735 participants, 988 datasets), by bariatric surgery (BS) in 26 studies (1,039 participants, 1,171 datasets), and by both in one study. The median follow-up was 26 weeks (interquartile range = 12-52). The range of baseline mean age was 21-68 yr, BMI: 26.2-71.2 kg/m2 , TT: 7-20.2 nmol/L and FT: 140-583 pmol/L. TT levels increased after weight loss by LCD: SMD (95%CI) = 2.5 nmol/L (1.9-3.1) and by BS: SMD = 7.2 nmol/L (6.0-8.4); the combined TT gain was 4.8 nmol/L (3.9-5.6). FT levels increased after weight reduction by LCD: SMD = 19.9 pmol/L (7.3-32.5) and by BS: SMD = 58.0 pmol/L (44.3-71.7); the combined gain was 42.2 pmol/L (31.4-52.9). Greater amounts of total and free testosterone could be gained by weight loss in men with higher baseline BMI, or lower levels of SHBG, TT and FT, while gain in TT was relatively greater in older and FT in younger age. Age-stratified nomograms revealed that compared to older men (> 40 yr), younger men (≤ 40 yr) gained less TT but more FT for a given weight loss. DISCUSSION AND CONCLUSION: Both TT and FT levels increased after weight loss, relatively greater with higher baseline BMI, or lower levels of SHBG, TT and FT. Nomograms constructed from a large number of participants with a wide range of BMI and testosterone values provide an evidence-based and simple-to-use tool in clinical practice.

Isoflurane and Pentobarbital Anesthesia for Pulmonary Studies Requiring Prolonged Mechanical Ventilation in Mice.

Mechanical ventilation can be used in mice to support high-risk anesthesia or to create clinically relevant, intensive care models. However, the choice of anesthetic and inspired oxygen concentration for prolonged procedures may affect basic physiology and lung inflammation. To characterize the effects of anesthetics and oxygen concentration in mice experiencing mechanical ventilation, mice were anesthetized with either isoflurane or pentobarbital for tracheostomy followed by mechanical ventilation with either 100% or 21% oxygen. Body temperature, oxygen saturation, and pulse rate were monitored continuously. After 6 h, mice were euthanized for collection of blood and bronchoalveolar lavage fluid for evaluation of biomarkers of inflammation and lung injury, including cell counts and cytokine levels. Overall, both isoflurane and pentobarbital provided suitable anesthesia for 6 h of mechanical ventilation with either 21% or 100% oxygen. We found no differences in lung inflammation biomarkers attributable to either oxygen concentration or the anesthetic. However, the combination of pentobarbital and 100% oxygen resulted in a significantly higher concentration of a biomarker for lung epithelial cell injury. This study demonstrates that the combination of anesthetic agent, mechanical ventilation, and inspired oxygen concentrations can alter vital signs and lung injury biomarkers during prolonged procedures. Their combined impact may influence model development and the interpretation of research results, warranting the need for preliminary evaluation to establish the baseline effects.

Inhibition of p53-MDM2 binding reduces senescent cell abundance and improves the adaptive responses of skeletal muscle from aged mice.

Skeletal muscle adaptation to external stimuli, such as regeneration following injury and hypertrophy in response to resistance exercise, are blunted with advanced age. The accumulation of senescent cells, along with defects in myogenic progenitor cell (MPC) proliferation, have been strongly linked as contributing factors to age-associated impairment in muscle adaptation. p53 plays an integral role in all these processes, as upregulation of p53 causes apoptosis in senescent cells and prevents mitotic catastrophe in MPCs from old mice. The goal of this study was to determine if a novel pharmaceutical agent (BI01), which functions by upregulating p53 through inhibition of binding to MDM2, the primary p53 regulatory protein, improves muscle regeneration and hypertrophy in old mice. BI01 effectively reduced the number of senescent cells in vitro but had no effect on MPC survival or proliferation at a comparable dose. Following repeated oral gavage with 2 mg/kg of BI01 (OS) or vehicle (OV), old mice (24 months) underwent unilateral BaCl2 injury in the tibialis anterior (TA) muscle, with PBS injections serving as controls. After 7 days, satellite cell number was higher in the TA of OS compared to OV mice, as was the expression of genes involved in ATP production. By 35 days, old mice treated with BI01 displayed reduced senescent cell burden, enhanced regeneration (higher muscle mass and fiber cross-sectional area) and restoration of muscle function relative to OV mice. To examine the impact of 2 mg/kg BI01 on muscle hypertrophy, the plantaris muscle was subjected to 28 days of mechanical overload (MOV) in OS and OV mice. In response to MOV, OS mice had larger plantaris muscles and muscle fibers than OV mice, particularly type 2b + x fibers, associated with reduced senescent cells. Together our data show that BI01 is an effective senolytic agent that may also augment muscle metabolism to enhance muscle regeneration and hypertrophy in old mice.

Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage.

Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following knee injury (anterior cruciate ligament tear). Following injury, transcriptomic analysis revealed downregulation of mitochondrial metabolism-related gene networks, which were supported by reduced mitochondrial respiratory flux rates. Additionally, enrichment of reactive oxygen species (ROS)-related pathways were upregulated in muscle following knee injury, and further investigation unveiled marked oxidative damage in a progressive manner following injury and surgical reconstruction. We then investigated whether antioxidant protection is effective in preventing muscle atrophy and weakness after knee injury in mice that overexpress Mn-superoxide dismutase (MnSOD+/-). MnSOD+/- mice showed attenuated oxidative damage, atrophy, and muscle weakness compared to wild type littermate controls following ACL transection surgery. Taken together, our results indicate that ROS-related damage is a causative mechanism of muscle dysfunction after knee injury, and that mitochondrial antioxidant protection may hold promise as a therapeutic target to prevent weakness and development of disability.

An orthogeriatric service can reduce prolonged hospital length of stay in hospital for older adults admitted with hip fractures: a monocentric study.

BACKGROUND: The Blue Book (2005), recommended guidelines for patients care with fragility fractures. Together with introduction of a National Hip Fracture Database Audit and Best Practice Tariff model to financially incentivise hospitals by payment of a supplement for patients whose care satisfied six clinical standards), have improved hip fracture after-care. However, there is a lack of data-driven evidence to support its effectiveness. We aimed to verify the impact of an orthogeriatric service on hospital length of stay (LOS)-duration from admission to discharge. METHODS: We conducted a repeated cross-sectional study over a 10 year period of older individuals aged ≥ 60 years admitted with hip fractures to a hospital. RESULTS: Altogether 2798 patients, 741 men and 2057 women (respective mean ages; 80.5 ± 10.6 and 83.2 ± 8.9 years) were admitted from their own homes with a hip fracture and survived to discharge. Compared to 2009-2014, LOS during 2015-2019, when the orthogeriatric service was fully implemented, was shorter for all discharge destinations: 10.4 vs 17.5 days (P < 0.001). Each discharge destination showed reductions: back to own homes, 9.7 vs 17.7 days (P < 0.001); to rehabilitation units: 10.8 vs 13.1 days (P < 0.001); to residential care: 15.4 vs 26.2 days (P = 0.001); or nursing care, 24.4 vs 53.1 days (P < 0.001). During 2009-2014, the risk of staying > 3 weeks in hospital was greater by six-fold and pressure ulcers by three-fold. The number of bed days for every thousand patients per year was also shortened during 2015-2019 by: 1665 days for discharge back to own homes; 469 days with transfer to rehabilitation units; 1258 days for discharge to residential care, and 5465 days to nursing care. Estimated annual savings (2017 costs) per thousand patients after complete establishment of the service was about £2.7 m. CONCLUSIONS: Implementation of an orthogeriatric service generated significant reductions in hospital LOS for all patients, with associated cost-savings, especially for those discharged to nursing care.

GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury.

Musculoskeletal disorders contribute substantially to worldwide disability. Anterior cruciate ligament (ACL) tears result in unresolved muscle weakness and posttraumatic osteoarthritis (PTOA). Growth differentiation factor 8 (GDF8) has been implicated in the pathogenesis of musculoskeletal degeneration following ACL injury. We investigated GDF8 levels in ACL-injured human skeletal muscle and serum and tested a humanized monoclonal GDF8 antibody against a placebo in a mouse model of PTOA (surgically induced ACL tear). In patients, muscle GDF8 was predictive of atrophy, weakness, and periarticular bone loss 6 months following surgical ACL reconstruction. In mice, GDF8 antibody administration substantially mitigated muscle atrophy, weakness, and fibrosis. GDF8 antibody treatment rescued the skeletal muscle and articular cartilage transcriptomic response to ACL injury and attenuated PTOA severity and deficits in periarticular bone microarchitecture. Furthermore, GDF8 genetic deletion neutralized musculoskeletal deficits in response to ACL injury. Our findings support an opportunity for rapid targeting of GDF8 to enhance functional musculoskeletal recovery and mitigate the severity of PTOA after injury.

New therapeutic targets to prevent benign prostatic enlargement and symptomatic progression to benign prostatic obstruction-ICI-RS 2023.

AIMS: Benign prostatic enlargement (BPE) can impact lower urinary tract function due to its potential progression to benign prostatic obstruction (BPO). Treatment options include removal of the obstruction by surgery or through use of therapeutics designed to slow growth or reduce tissue stress imposed by muscular stromal components. Inflammation and development of fibrosis can also raise intrinsic tissue stress within the gland, further impacting obstruction. Outflow tract obstruction can also impact emission and ejaculation if the obstruction persists. METHODS: This review summarizes an ICI-RS think tank considering novel drug treatments that might address BPO caused by progressive development of BPE, as well as manage decompensation changes to bladder function. RESULTS: Topics included recent advances in our understanding of pathological changes occurring to the prostate and other lower urinary tract tissues during progressive development of BPE, and how prevention or reversal might benefit from the identification of novel drug targets. These included contractile properties of prostatic tissues, the impact of BPE and its effects on bladder function, the deposition of intramural fibrotic tissue with protracted BPO, the role of inflammation in the development of BPE and its progression to BPO. In particular, we discussed current therapeutic options for treating BPE/BPO, and new therapeutic targets, what they treat and their advantage over current medications. CONCLUSION: Several new drug targets were identified, including soluble guanylate cyclase (sGC), the receptor for nitric oxide (NO•), and sGC activators that promotes sGC-mediated cGMP production when sGC is inactivated and unresponsive to NO•.

Pharmacologic Inhibition of Myostatin With a Myostatin Antibody Improves the Skeletal Muscle and Bone Phenotype of Male Insulin-Deficient Diabetic Mice.

Type 1 diabetes (T1D) is associated with low bone and muscle mass, increased fracture risk, and impaired skeletal muscle function. Myostatin, a myokine that is systemically elevated in humans with T1D, negatively regulates muscle mass and bone formation. We investigated whether pharmacologic myostatin inhibition in a mouse model of insulin-deficient, streptozotocin (STZ)-induced diabetes is protective for bone and skeletal muscle. DBA/2J male mice were injected with low-dose STZ (diabetic) or vehicle (non-diabetic). Subsequently, insulin or palmitate Linbits were implanted and myostatin (REGN647-MyoAb) or control (REGN1945-ConAb) antibody was administered for 8 weeks. Body composition and contractile muscle function were assessed in vivo. Systemic myostatin, P1NP, CTX-I, and glycated hemoglobin (HbA1c) were quantified, and gastrocnemii were weighed and analyzed for muscle fiber composition and gene expression of selected genes. Cortical and trabecular parameters were analyzed (micro-computed tomography evaluations of femur) and cortical bone strength was assessed (three-point bending test of femur diaphysis). In diabetic mice, the combination of insulin/MyoAb treatment resulted in significantly higher lean mass and gastrocnemius weight compared with MyoAb or insulin treatment alone. Similarly, higher raw torque was observed in skeletal muscle of insulin/MyoAb-treated diabetic mice compared with MyoAb or insulin treatment. Additionally, muscle fiber cross-sectional area (CSA) was lower with diabetes and the combination treatment with insulin/MyoAb significantly improved CSA in type II fibers. Insulin, MyoAb, or insulin/MyoAb treatment improved several parameters of trabecular architecture (eg, bone volume fraction [BV/TV], trabecular connectivity density [Conn.D]) and cortical structure (eg, cortical bone area [Ct. Ar.], minimum moment of inertia [Imin]) in diabetic mice. Lastly, cortical bone biomechanical properties (stiffness and yield force) were also improved with insulin or MyoAb treatment. In conclusion, pharmacologic myostatin inhibition is beneficial for muscle mass, muscle function, and bone properties in this mouse model of T1D and its effects are both independent and additive to the positive effects of insulin. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

How does the lower urinary tract contribute to bladder sensation? ICI-RS 2023.

AIM: Bladder sensation is critical for coordinating voluntary micturition to maintain healthy bladder function. Sensations are initiated by the activation of sensory afferents that innervate throughout the bladder wall. However, the physiological complexity that underlies the initiation of bladder sensory signaling in health and disease remains poorly understood. This review summarises the latest knowledge of the mechanisms underlying the generation of bladder sensation and identifies key areas for future research. METHODS: Experts in bladder sensory signaling reviewed the literature on how the lower urinary tract contributes to bladder sensation and identified key research areas for discussion at the 10th International Consultation on Incontinence-Research Society. RESULTS: The importance of bladder sensory signals in maintaining healthy bladder function is well established. However, better therapeutic management of bladder disorders with exaggerated bladder sensation, including overactive bladder syndrome (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) is limited by a lack of knowledge in a number of key research areas including; the contribution of different nerves (pudendal, pelvic, hypogastric) to filling sensations in health and disease; the relative contribution of stretch sensitive (muscular) and stretch-insensitive (mucosal) afferents to bladder sensation in health and disease; the direct and indirect contributions of the muscularis mucosae to bladder contraction and sensation; and the impact of manipulating urothelial release factors on bladder sensation. CONCLUSION: Disturbances in bladder sensory signaling can have severe consequences for bladder sensation and function including the development of OAB and IC/BPS. Advancing therapeutic treatments for OAB and IC/BPS requires a deeper understanding of the mechanisms underlying the generation of bladder sensation, and key areas for future research have been identified.

Nitric oxide signaling pathways in the normal and pathological bladder: Do they provide new pharmacological pathways?-ICI-RS 2023.

AIMS: The nitric oxide (NO•)/soluble guanylate cyclase/cyclic-GMP (cGMP) signaling pathway is ubiquitous and regulates several functions in physiological systems as diverse as the vascular, nervous, and renal systems. However, its roles in determining normal and abnormal lower urinary tract functions are unclear. The aim was to identify potential therapeutic targets associated with this pathway to manage lower urinary tract functional disorders. METHODS: This review summarizes a workshop held under the auspices of ICI-RS with a view to address these questions. RESULTS: Four areas were addressed: NO• signaling to regulate neurotransmitter release to detrusor smooth muscle; its potential dual roles in alleviating and exacerbating inflammatory pathways; its ability to act as an antifibrotic mediator; and the control by nitrergic nerves of lower urinary tract vascular dynamics and the contractile performance of muscular regions of the bladder wall. Central to much of the discussion was the role of the NO• receptor, soluble guanylate cyclase (sGC) in regulating the generation of the enzyme product, the second messenger cGMP. The redox state of sGC is crucial in determining its enzymic activity and the role of a class of novel agents, sGC activators, to optimize activity and to potentially alleviate the consequences of lower urinary tract disorders was highlighted. In addition, the consequences of a functional relationship between nitrergic and sympathetic nerves to regulate vascular dynamics was discussed. CONCLUSIONS: Several potential NO•-dependent drug targets in the lower urinary tract were identified that provide the basis for future research and translation to clinical trials.

Determination of independent risk factors for early healthcare-associated infections acquired after acute stroke admission: A multi-centre registry-based cohort study.

OBJECTIVE: Healthcare-associated infections (HCAIs) in patients admitted with acute conditions pose a serious risk to patients and a major challenge to healthcare services. However, there is a lack of consistency in reporting aetiological risk factors, particularly in acute stroke patients. Here, we determined independent risk factors of two common HCAIs (urinary tract infection and pneumonia) acquired within 7-days of admission after an acute stroke. METHODS: Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme for 3,309 patients (mean age=76.2yr, SD=13.5) admitted to four UK hyperacute stroke units. Associations between variables were assessed by forward stepwise multivariable logistic regression (odds ratios, 95 % confidence intervals). RESULTS: The rate of urinary tract infection and/or pneumonia occurring within 7-days of admission was 15.0 %. The risk of urinary tract infection and/or pneumonia was increased amongst women: OR = 1.35 (1.08-1.68); patients from ethnic minority backgrounds: OR = 1.77 (1.01-3.10); patients aged 70-79 years: OR = 2.08 (1.42-3.06), and ≥80 years: OR = 3.20 (2.26-4.55); history of hypertension: OR = 1.59 (1.27-1.98); history of atrial fibrillation: OR = 1.67 (1.32-2.12); pre-stroke disability: OR = 2.08 (1.44-3.00); intracranial haemorrhage: OR = 1.41 (1.07-1.86); severe stroke: OR = 3.21 (2.32-4.45); swallow screening within 4-72 h: OR = 1.42 (1.08-1.86); swallow screening beyond 72 h: OR = 1.70 (1.08-2.70). History of congestive heart failure, diabetes and previous stroke did not significantly associate with HCAIs. CONCLUSIONS: A profile of independent risk factors for two common HCAIs in acute stroke was identified. These findings provide valuable information for timely intervention to reduce HCAIs, and the ability to minimise subsequent adverse outcomes.

Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction.

BACKGROUNDAlthough 25-hydroxyvitamin D [25(OH)D] concentrations of 30 ng/mL or higher are known to reduce injury risk and boost strength, the influence on anterior cruciate ligament reconstruction (ACLR) outcomes remains unexamined. This study aimed to define the vitamin D signaling response to ACLR, assess the relationship between vitamin D status and muscle fiber cross-sectional area (CSA) and bone density outcomes, and discover vitamin D receptor (VDR) targets after ACLR.METHODSTwenty-one young, healthy, physically active participants with recent ACL tears were enrolled (17.8 ± 3.2 years, BMI 26.0 ± 3.5 kg/m2). Data were collected through blood samples, vastus lateralis biopsies, dual energy x-ray bone density measurements, and isokinetic dynamometer measures at baseline, 1 week, 4 months, and 6 months after ACLR. The biopsies facilitated CSA, Western blotting, RNA-seq, and VDR ChIP-seq analyses.RESULTSACLR surgery led to decreased circulating bioactive vitamin D and increased VDR and activating enzyme expression in skeletal muscle 1 week after ACLR. Participants with less than 30 ng/mL 25(OH)D levels (n = 13) displayed more significant quadriceps fiber CSA loss 1 week and 4 months after ACLR than those with 30 ng/mL or higher (n = 8; P < 0.01 for post hoc comparisons; P = 0.041 for time × vitamin D status interaction). RNA-seq and ChIP-seq data integration revealed genes associated with energy metabolism and skeletal muscle recovery, potentially mediating the impact of vitamin D status on ACLR recovery. No difference in bone mineral density losses between groups was observed.CONCLUSIONCorrecting vitamin D status prior to ACLR may aid in preserving skeletal muscle during recovery.FUNDINGNIH grants R01AR072061, R01AR071398-04S1, and K99AR081367.