MME+ fibro-adipogenic progenitors are the dominant adipogenic population during fatty infiltration in human skeletal muscle.

Fatty infiltration, the ectopic deposition of adipose tissue within skeletal muscle, is mediated via the adipogenic differentiation of fibro-adipogenic progenitors (FAPs). We used single-nuclei and single-cell RNA sequencing to characterize FAP heterogeneity in patients with fatty infiltration. We identified an MME+ FAP subpopulation which, based on ex vivo characterization as well as transplantation experiments, exhibits high adipogenic potential. MME+ FAPs are characterized by low activity of WNT, known to control adipogenic commitment, and are refractory to the inhibitory role of WNT activators. Using preclinical models for muscle damage versus fatty infiltration, we show that many MME+ FAPs undergo apoptosis during muscle regeneration and differentiate into adipocytes under pathological conditions, leading to a reduction in their abundance. Finally, we utilized the varying fat infiltration levels in human hip muscles and found less MME+ FAPs in fatty infiltrated human muscle. Altogether, we have identified the dominant adipogenic FAP subpopulation in skeletal muscle.

Tender to touch-Prevalence and impact of concomitant fibromyalgia and enthesitis in spondyloarthritis: An ancillary analysis of the ASAS PerSpA study.

OBJECTIVES: The primary objective was to evaluate the co-existence of fibromyalgia (FM) & enthesitis in individuals with spondyloarthritis (SpA). Secondary objectives were to identify clinical features associated with the presence of FM in enthesitis and analyse sex-specific differences. METHODS: This was an ancillary analysis of the Assessment of SpondyloArthritis International Society Peripheral Involvement in SpA (PerSpA) study. Enthesitis was defined as the presence of enthesitis ever. Clinical FM was defined as the rheumatologist's confirmation of the presence of FM. A score of≥5/6 on the Fibromyalgia Rapid Screening Test (FiRST) defined a positive screening test for FM. RESULTS: Enthesitis ever and FM (EFM) co-existed in 10.3% (n=425) of the cohort using FiRST criteria and 5.3% using clinical diagnosis of FM. More individuals with FM by clinical diagnosis had imaging-confirmed enthesitis ever than by FiRST criteria. More females had EFM than males, defined clinically (76.9% vs 23.1%) or by FiRST criteria (62.6% vs 37.4%). Individuals with EFM had more severe disease across all measures compared to those with enthesitis only, with no significant difference between sexes. EFM was significantly associated with age, female sex, BMI, BASDAI and region. CONCLUSION: FM is an important comorbidity in the setting of enthesitis in SpA. While EFM is more common in females, it is not a rare condition in males. EFM is associated with worse disease severity measures in SpA in both males and females. Recognition of FM in the setting of enthesitis is essential to prevent overtreatment and optimise patient outcomes.

Advances in treatment of axial spondyloarthritis are associated with improved patient outcomes: data from the Ankylosing Spondylitis Registry of Ireland (ASRI).

The Ankylosing Spondylitis Registry of Ireland (ASRI) captures both radiographic and non-radiographic axial spondyloarthritis (axSpA) in a large, well characterised cohort. This is a valuable resource for studies in therapeutics and burden of disease, following a period of rapid change in the field of axSpA. This study aims to perform a focused analysis on patient outcomes and pattern of medication usage in axSpA. This is a cross-sectional study of registry data on 885 patients with confirmed axSpA as per the ASAS criteria for axSpA, as diagnosed by a Rheumatologist. Analysis was performed using IBM SPSS version 26. Patients were analysed on the basis of treatment categorised as: no medication, NSAIDs, biologics or combination therapy. Statistical significance was indicated by p value of < 0.05. Currently 885 patients are enrolled in the ASRI, made up of 72.5% (642) males and 26.9% (238) females. The majority of the cohort was categorized as radiographic axSpA 78.3% (693), with 21.7% (192) meeting criteria for non-radiographic disease. Overall 40.6% (359) reported at least one comorbidity. Older age was associated with no medications compared to those on biologic therapy (50.3 vs 45, p = 0.01). Lower levels of disease activity and higher quality of life were noted in those on biologics as compared to NSAIDs alone. This analysis provides detailed epidemiological data on axSpA from a large national registry. These results detail significant differences in prescribing patterns and impact on patient outcomes in axSpA. Ongoing development of registries provides a valuable insight into the real-world effects of axSpA.

Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells.

Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cell (mEC) populations that are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4+ mECs are enriched in red oxidative muscle areas while ATF3/4low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4+ mECs are more angiogenic when compared with white ATF3/4low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4+) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.

COVID-19: What Do Rheumatologists Need to Know?

PURPOSE OF REVIEW: Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in December 2019, rapidly reaching global pandemic proportions. Coronavirus disease 2019 (COVID-19) has presented unique challenges to the rheumatology community. It is known that many individuals with rheumatic disease are at increased risk of severe disease from other infections, sparking a similar fear for COVID-19. In addition, medications routinely used in rheumatology practice are being trialled as treatments, with the potential for drug shortages for rheumatology patients. RECENT FINDINGS: Underlying comorbidities and active disease are associated with worse COVID-19 outcomes in patients with rheumatic disease. Tocilizumab and hydroxychloroquine have not proven to be effective treatments in the management of COVID-19. Telehealth has become an essential tool for the rheumatology community to monitor patients during the pandemic. In this article, we summarise the available COVID-19 evidence that is of relevance to the rheumatology community. We discuss the risk of contracting COVID-19 in individuals with rheumatic disease, along with presenting features and clinical outcomes. We provide an overview of the treatments for COVID-19 which have significance for rheumatology. We highlight published recommendations which can guide our management of rheumatic disease populations during this pandemic. Finally, we discuss the challenges in delivering effective care virtually and present methods and tools which could be adapted for use.

Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization.

Endothelial cell (EC)-derived signals contribute to organ regeneration, but angiocrine metabolic communication is not described. We found that EC-specific loss of the glycolytic regulator pfkfb3 reduced ischemic hindlimb revascularization and impaired muscle regeneration. This was caused by the reduced ability of macrophages to adopt a proangiogenic and proregenerative M2-like phenotype. Mechanistically, loss of pfkfb3 reduced lactate secretion by ECs and lowered lactate levels in the ischemic muscle. Addition of lactate to pfkfb3-deficient ECs restored M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Moreover, VEGF production by lactate-polarized macrophages was increased, resulting in a positive feedback loop that further stimulated angiogenesis. Finally, increasing lactate levels during ischemia rescued macrophage polarization and improved muscle reperfusion and regeneration, whereas macrophage-specific mct1 deletion prevented M2-like polarization. In summary, ECs exploit glycolysis for angiocrine lactate shuttling to steer muscle regeneration from ischemia.

Pharmacological treatment for managing bone health in axial spondyloarthropathy: systematic review and meta-analysis.

Axial spondyloarthropathy (axSpA) is associated with an increased prevalence of osteoporosis, but no recommendations exist to guide management. This systematic review and meta-analysis aim to assess the efficacy of pharmacological and non-pharmacological interventions on bone mineral density (BMD) in axSpA. Electronic databases were searched from inception to June 2019 for randomised controlled trials (RCTs) and quasi (q)-RCTs with pharmacological and non-pharmacological interventions. Independent reviewers undertook screening, and risk of bias and quality assessments. Primary outcomes of interest were BMD at spine and hip. Eight studies (two RCTs and six qRCTs) were included (602 participants). Moderate level evidence favoured alendronate over placebo at femoral neck [mean difference (MD) 2.01, 95% CI 0.67 to 3.35], but there was low-level evidence showing no effect at the spine. There was moderate level evidence showing no effect of tumour necrosis factor inhibitors (TNFi) on BMD at total hip (MD - 0.01, 95% CI - 0.06 to 0.04). Very low-level evidence demonstrated no effect of TNFi on spine or femoral neck. Moderate level evidence favoured neridronate over infliximab at the spine (MD 3.26, 95% CI 1.14 to 5.38), but low-level evidence showed no effect at the total hip (MD 2.75, 95% CI - 0.21 to 5.71). There were no eligible studies investigating the efficacy of non-pharmacological interventions. We conditionally recommend alendronate for management of low BMD in axSpA. The balance of evidence does not recommend the use of TNF-inhibitors for treating low BMD. There is a lack of high-quality evidence guiding clinicians treating osteoporosis in axSpA.

Calcaneal quantitative ultrasound has a role in out ruling low bone mineral density in axial spondyloarthropathy.

OBJECTIVE: The aim of this study was to investigate the role of quantitative ultrasound (QUS) of the calcaneus in screening for osteoporosis in adults with axial spondyloarthropathy (axSpA). METHOD: Postmenopausal women and men over 50 years with axSpA were recruited for this observational cross-sectional study. Dual-energy x-ray absorptiometry (DXA) assessed bone mineral density (BMD) of the spine and hip. QUS of the calcaneus produced broadband ultrasound attenuation (BUA), speed of sound (SOS), stiffness index (SI), and T-scores. Receiver-operating characteristics (ROC) curve analysis determined the ability of QUS to discriminate between low and normal BMD. Thresholds were identified to (1) out rule low BMD, (2) identify osteoporosis, and (3) identify low BMD. The number of DXAs which could be avoided using this approach was calculated. RESULTS: 56 participants were analyzed. BUA, SI, and T-score QUS parameters correlated with BMD by DXA; SOS did not. All QUS parameters had the ability to discriminate between low and normal BMD (area under the curve varied from 0.695 to 0.779). QUS identified individuals without low BMD with 90% confidence, with BUA performing best (sensitivity 93%, negative predictive value 86%). Using QUS as a triage tool, up to 27% of DXA assessments could have been avoided. QUS could not confidently identify individuals with osteoporosis. CONCLUSIONS: QUS of the calcaneus confidently out ruled low BMD in individuals with axSpA, reducing the need for onward DXA referral by up to 27%. QUS is promising as a non-invasive triage tool in the assessment of osteoporosis in adults with axSpA.Key Points• Osteoporosis is common in axial spondyloarthropathy (SpA), but evaluation of bone health is suboptimal in this population.• Quantitative ultrasound (QUS) of the calcaneus can out rule low bone mineral density in individuals with axial SpA, reducing the need for DXA assessment.• QUS is a promising non-invasive triage tool in the assessment of bone health in axial SpA.

Measuring bone density in axial spondyloarthropathy: Time to turn things on their side?

AIM: Osteoporosis in axial spondyloarthropathy (axSpA) is difficult to accurately diagnose due to osteoproliferation of the spine interfering with conventional (anteroposterior, AP) dual-energy X-ray absorptiometry (DXA). This study compares AP and lateral projections of DXA when assessing bone mineral density (BMD) of the spine and investigates the impact of osteoproliferation on AP DXA. METHOD: In this cross-sectional study, structured standardized assessments collected demographic, clinical, laboratory and radiographic data. DXA assessed BMD of the spine using PA and lateral projections. Hip BMD was assessed in the usual manner. World Health Organization (WHO) criteria assessed prevalence of low BMD. Incorporating lateral DXA in the bone health assessment of axSpA was investigated. SPSS was used for statistical analysis. RESULTS: A total of 100 patients had paired AP and lateral DXA studies: 78% were male, mean (SD) age 52 (12) years. BMD of the spine measured by AP projection was significantly higher than BMD measured by lateral projection (mean difference 0.34 g/cm2 , 95% CI 0.30-0.37). More patients had low BMD with lateral compared to AP projection (47% vs 16%, P = .01). At the hip, 34% of patients had low BMD. Disease duration, body mass index and radiographic severity independently predicted a difference between AP and lateral measurements of the spine. CONCLUSION: Lateral DXA of the spine is unaffected by osteoproliferation of the spine in axSpA and detects significantly more cases of low BMD than conventional AP DXA. Lateral DXA should be included in BMD assessment of patients with axSpA.

PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase.

mTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. We show that loss of the prolyl hydroxylase domain isoform 1 oxygen sensor in mice (PHD1KO) reduces muscle mass. PHD1KO muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Mechanistically, PHD1 interacts with and stabilizes LRS. This interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation. Finally, elderly subjects have lower PHD1 levels and LRS activity in muscle from aged versus young human subjects. In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity.

Multimorbidity in Axial Spondyloarthropathy and Its Association with Disease Outcomes: Results from the Ankylosing Spondylitis Registry of Ireland Cohort.

OBJECTIVE: Multimorbidity, the coexistence of 2 or more conditions in an individual, is associated with morbidity and mortality in the general population. This study aims to describe the prevalence of multimorbidity in axial spondyloarthropathy (axSpA) and assess its association with disease outcome measures. METHODS: This cross-sectional study was conducted within the Ankylosing Spondylitis Registry of Ireland (ASRI) cohort. Structured standardized assessment was performed. Multimorbidity was considered as the presence of at least 1 physician-diagnosed chronic condition (excluding extraarticular manifestations) in addition to axSpA. Validated outcome measures were collected: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Health Assessment Questionnaire (HAQ), AS Quality of Life (ASQoL), and Bath AS Metrology Index (BASMI). Adjusted multiple regression was performed to investigate the association between multimorbidity and disease outcomes. RESULTS: A total of 734 patients from 12 centers were included: 77% male, mean (SD) age 45 (12) years. Of the cohort, 55% (n = 403) were multimorbid. Multimorbid patients were significantly (p < 0.01) older than axSpA-only patients [50 (12) vs 40 (11) yrs]. Obesity was the most prevalent chronic condition, affecting 27%. Multimorbid patients had more severe disease than patients with axSpA only. After adjusting for confounders, multimorbidity was associated with higher BASDAI (ß 0.7, 95% CI 0.34-1.05), BASMI (ß 0.45, 95% CI 0.09-0.80), BASFI (ß 0.5, 95% CI 0.23-0.78), HAQ (ß 0.07, 95% CI 0.00-0.13), and ASQoL (ß 0.87, 95% CI 0.28-1.46). CONCLUSION: Multimorbidity is prevalent in axSpA and is associated with more severe disease.

The Warburg Effect in Endothelial Cells and its Potential as an Anti-angiogenic Target in Cancer.

Endothelial cells (ECs) make up the lining of our blood vessels and they ensure optimal nutrient and oxygen delivery to the parenchymal tissue. In response to oxygen and/or nutrient deprivation, ECs become activated and sprout into hypo-vascularized tissues forming new vascular networks in a process termed angiogenesis. New sprouts are led by migratory tip cells and extended through the proliferation of trailing stalk cells. Activated ECs rewire their metabolism to cope with the increased energetic and biosynthetic demands associated with migration and proliferation. Moreover, metabolic signaling pathways interact and integrate with angiogenic signaling events. These metabolic adaptations play essential roles in determining EC fate and function, and are perturbed during pathological angiogenesis, as occurs in cancer. The angiogenic switch, or the growth of new blood vessels into an expanding tumor, increases tumor growth and malignancy. Limiting tumor angiogenesis has therefore long been a goal for anticancer therapy but the traditional growth factor targeted anti-angiogenic treatments have met with limited success. In recent years however, it has become increasingly recognized that focusing on altered tumor EC metabolism provides an attractive alternative anti-angiogenic strategy. In this review, we will describe the EC metabolic signature and how changes in EC metabolism affect EC fate during physiological sprouting, as well as in the cancer setting. Then, we will discuss the potential of targeting EC metabolism as a promising approach to develop new anti-cancer therapies.

The Fascinating Paradox of Osteoporosis in Axial Spondyloarthropathy.

Low bone mineral density (BMD) is a recognized feature of axial spondyloarthropathy (axSpA). However, the osteoproliferation inherent in axSpA can make traditional dual-energy x-ray absorptiometry assessment inaccurate, particularly in structurally advanced disease. As a result, much about osteoporosis in axSpA is unknown. There is a wide variation in prevalence figures for low BMD in the literature. There is also no consensus regarding risk factors for developing low BMD in axSpA. It is accepted that there is an excess of vertebral fractures in patients with axSpA, but the role of low BMD in contributing to this risk is virtually unknown. This article provides a comprehensive review of the current knowledge regarding low BMD in axSpA. It highlights our current BMD measurement techniques along with their potential pitfalls, and discusses the significance of BMD in vertebral fractures. It also identifies gaps in our knowledge and makes recommendations for future research.