Abstract IntroductionCritical illness associated with intensive care unit (ICU) admission often results in persistent skeletal muscle wasting and may lead to frailty in older and patients with multi‐morbidity. Early recognition of patients at high‐risk of long‐term complications could provide opportunities to minimize the impact of critical illness and improve health and quality of life. MicroRNAs (miRs) are short, non‐coding RNAs that regulate approximately two‐thirds of the human genome and are involved in most biological processes. Multiple studies have demonstrated their role in muscle development and disease and their potential as biomarkers of muscle wasting.Aim and methodsThis systematic review examined the potential of miRs as biomarkers and therapeutics for muscle wasting during and following critical illness. PubMed and Scopus databases were searched for terms associated with critical illness, ICU, muscle wasting, frailty and microRNAs from inception to June 2022 (PROSPERO number CRD42022339531).ResultsOut of 537 articles, seven studies met the inclusion criteria and examined skeletal muscle and circulating miRs in the context of muscle wasting and/or frailty related to critical illness. Across the seven studies, 27 different miRs were identified that were reported to be dysregulated in the muscle and four in the blood, plasma or serum of critically ill patients. Four miRs were reported to be altered in both muscle and blood during critical illness and their levels moderately correlated with parameters of muscle function. These included canonical muscle‐enriched miRs (myomiRs), such as miR‐133, miR‐1 and miR‐181, which correlated with muscle strength in critically ill patients. However, most of the miRs reported to be dysregulated in the muscle following critical illness were examined in one article only.ConclusionsThis systematic review highlights the potential of miRs as biomarkers of skeletal muscle wasting and ICU‐associated weakness following critical illness, suggesting the need for larger validation studies using unbiased techniques. We have described circulating and muscle microRNAs, which correlated with muscle parameters during critical illness. However, the limited number of studies in this area highlights the requirement for further studies before these could be considered in clinical practice.

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RS reports grants from Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad, during the conduct of the study. SvH has been a paid consultant for and/or received honoraria payments from AstraZeneca, Bayer, Boehringer Ingelheim, BRAHMS, Chugai, Grünenthal, Helsinn, Hexal, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Respicardia, Roche, Servier, Sorin, and Vifor and reports research support from Amgen, Boehringer Ingelheim, Pharmacosmos, IMI, and the German Centre for Cardiovascular Research (DZHK).

Abstract BackgroundAn increase in waist circumference (WC) is a factor in lifestyle‐related diseases. The rectus abdominis muscle is a skeletal muscle that attaches to the pelvis from the xiphoid process and is thought to be affected by kyphosis deformity and posterior pelvic tilt. The purpose of this study is to examine differences between sacral‐abdominal wall distance (SAD) and WC and to determine whether they are associated with fall risk, frailty, markers of sarcopenia (grip strength and lean body mass), and spinal alignment. A secondary objective is to examine these differences by stratification by grip strength.MethodsThis retrospective study included 239 women aged 65 years or older (mean age 76.5 ± 6.7 years) attending an outpatient osteoporosis clinic. Bone mineral density and skeletal body composition (muscle mass index and trunk lean mass) were measured using dual‐energy X‐ray absorptiometry. SAD, pelvic tilt, and sagittal longitudinal axis were measured from simple X‐ray images of the spine sides. WC, grip strength, frailty, and fall risk score were investigated. Statistics were performed using Stat Flex, with two‐sided P < 0.05 being significantly different.ResultsWC was correlated with SAD (R = 0.68, P < 0.001). The SAD cut‐off value for a WC of 90 cm was 167 mm. The relationship between grip strength, SAD, and WC, weaker grip strength was associated with greater SAD; however, no significant difference was noted in WC. WC was not correlated with pelvic alignment but was correlated with body mass index (P < 0.01). Meanwhile, SAD was correlated with body mass index, pelvic tilt, sagittal longitudinal axis (P < 0.01), spinal alignment, and WC. Logistic regression analysis was performed with a grip strength of less than 18 kg as the objective variable. We found that the conditions for a grip strength of less than 18 kg were older age (P < 0.001), increased SAD (P = 0.02), and decreased trunk lean body mass. There was a decrease in grip strength (P < 0.05) and an increase in frailty (P < 0.05) and falls (P < 0.01) score in patients with SAD of 167 mm or greater.ConclusionsSAD and WC were found to be correlated; SAD was associated with body weight, posterior pelvic tilt, and anterior spinal tilt deformity, while WC was related to body weight. Increased SAD was found to be linked with decreased grip strength and increased risk of falls. This study was the first to examine a new measurement, SAD, for its utility in assessing grip strength, spinal alignment, frailty, and fall risk.

Abstract BackgroundAcute skeletal muscle wasting during critical illness is common and causes significant morbidity and functional limitation. Myofibre necrosis is a major histological finding but is often considered an unprogrammed by‐product of muscle inflammation. This study sought to evaluate if a form of programmed necrosis, necroptosis, is activated in skeletal muscle during critical illness.MethodsA cohort of 28 patients from the MUSCLE‐UK study (ClinicalTrials.gov: NCT01106300) with serum and skeletal muscle biopsy samples were identified. Samples were available from ICU admission (T1) and between day 7–10 post admission (T2). Skeletal muscle was stratified by a histopathologist in the original study as necrotic (NEC, N = 14) or non‐necrotic (NONEC, N = 14) using haematoxylin and eosin staining. We used phosphorylated mixed‐lineage kinase domain‐like (pMLKL) protein (a key terminal effector protein) and receptor‐interacting protein kinase 3 (RIPK3) as markers of necroptosis activation using Western blotting and immunohistochemistry.ResultsWe show that pMLKL expression is significantly higher in the NEC group [NEC: T2:T1 expression; 9.1 (IQR 3.9–22.3) vs. NONEC: T2:T1 expression; 0.9 (IQR 0.6–1.1), P = 0.003]. We then confirm this upregulation and describe co‐localization with receptor interacting protein kinase 3 (RIPK3) in skeletal muscle using immunohistochemistry. We show that both RIPK3 and pMLKL are present within intact myofibres at the intermediate timepoint day 3 without cellular infiltrate. At T2, pMLKL is also present in the interstitial space where there is infiltrate of CD68 positive immune cells. The observed necroptosis may originate from both internal and infiltrating sources. These findings were absent in samples from patients who did not exhibit histopathological features of necrosis.ConclusionsWe show that necroptosis machinery, RIPK3 and pMLKL, are associated with conventional histopathological features of myonecrosis in a critically ill cohort.

Abstract BackgroundInflammation is a hallmark of cachexia; however, effective anti‐inflammatory treatments have not yet been identified. Interleukin‐1 receptor‐associated kinase 4 (IRAK4) is a key signalling node linking interleukin‐1 receptor (IL‐1R) and toll‐like receptor (TLR) activation to the production of multiple proinflammatory cytokines that are elevated in cancer cachexia. The purpose of this work is to evaluate whether pharmacological inhibition of IRAK4 kinase activity with PF‐06426779 could prevent cachexia using a model of pancreatic cancer. The effect of appetite stimulation via the ghrelin receptor agonist anamorelin was also examined as a benchmark of clinically validated mechanisms.MethodsFemale C57Bl/6J mice were given an intraperitoneal injection of KrasG12D; p53R172H; Pdx1‐Cre (KPC) pancreatic tumour cells. PF‐06426779 or anamorelin treatment was initiated at the onset of anorexia. Body weight and food intake were measured throughout the study. Body composition, muscle function (force), and physical activity (treadmill running endurance) were assessed at the end of the study.ResultsChronic treatment with PF‐06426779, at doses covering in vitro IC50 and IC90 at Cmin, did not increase body weight, food intake, and muscle function in the KPC tumour model. In contrast, anamorelin (vs. vehicle) increased food intake (P < 0.01), hindlimb skeletal muscle mass (P < 0.01), and muscle strength (P < 0.05); however, treadmill running endurance was not increased.ConclusionsThese data suggest that inhibition of IRAK4 kinase activity is not sufficient to treat cachexia, at least in pancreatic cancer, and exploration of alternative anti‐inflammatory strategies that increase appetite is required.

Abstract BackgroundLoss of skeletal muscle mass is prevalent among patients affected by chronic kidney disease (CKD). It is associated with significant morbidity and mortality. The underlying molecular pathogenesis has yet to be fully understood. The aim of this systematic review is to summarize the current evidence on molecular changes in the skeletal muscle of humans and rodents with CKD and to assess the strength of such evidence.MethodsThe PubMed and EMBASE databases were searched using three main themes: messenger ribonucleic acid/protein/microRNA expression, skeletal muscle and CKD. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) standards.ResultsA total of 98 studies were included in the systematic review, comprising 26 prospective human clinical studies, four human and rodent studies, and 68 rodent‐only studies (32 mouse and 36 rat models respectively). The sample sizes of human studies were largely small (40% of studies had ≤20 participants). Qualitative polymerase chain reaction (qPCR) was the most commonly used method for gene expression and none of the studies fulfilled the Minimum Information for Publication of qPCR Experiments criteria for quality assessment. Majority of the studies investigated only a few genes or a specific signalling pathway. FBXO32, TRIM63, MSTN, IL6, TNF and IGF1 were the most investigated genes. The identified differentially expressed genes and proteins belonged to eight major pathways, including apoptosis, autophagy, inflammation, insulin/insulin‐like growth factor 1 signalling, lipid metabolism, mitochondrial function, muscle cell growth and differentiation, and protein degradation, similar to other chronic disease states.ConclusionsThe current evidence regarding molecular alterations in the skeletal muscle in CKD is largely derived from small and heterogenous studies. Markedly similar modifications in the major biological pathways between CKD and other chronic diseases supports shared deleterious molecular mechanisms producing muscle atrophy, irrespective of the underlying specific disease.

Abstract BackgroundIt is unknown to what degree of sarcopenia related to heart failure (HF) is reversible with resolution of the HF syndrome. We evaluated whether (1) weight loss prior to left ventricular assist device (LVAD) is associated with pre‐operative sarcopenia as quantified on pre‐operative chest CTs and (2) determine the relationship between weight recovery (increase) after LVAD implantation and reduction of NT‐proBNP levels.MethodsIn a large single‐centre cohort (n = 502), CT measures of sarcopenia (pectoralis muscle mass indexed to body surface area and tissue attenuation) were correlated with pre‐LVAD BMI trend (n = 190). BMI and NT‐proBNP trends before and after LVAD implantation were evaluated (n = 403). Linear effects modelling was performed to test the association between NT‐proBNP and BMI trends.ResultsA downtrending BMI prior to LVAD was associated with pectoralis muscle tissue attenuation (P < 0.05). BMI declined prior to LVAD, declined further early post‐implant, and then increased between 100 and 300 days post‐implant (average per cent change in BMI in Year 1, 7.6%, 95% CI: 6.3–8.8%). NT‐proBNP decreased during the first 100 post LVAD days (−5.4%, 95% CI: −6.6 to −4.2%). Post‐LVAD NT‐proBNP and BMI trends were significantly associated, with a decrease of 1 unit log NT‐proBNP associated with an increase in BMI of 0.81 kg/m2 (CI: 0.53–1.09, P < .001). The rise in post‐LVAD BMI occurred after the reduction in NT‐proBNP levels. Patients who failed to gain weight post‐LVAD had the highest 6‐month post‐LVAD natriuretic peptides (lowest per cent BMI gain tertile NT‐proBNP: 2208 vs. highest 1635 pg/mL, P < 0.001).ConclusionsWeight recovery during LVAD support occurs after the reduction in natriuretic peptide levels. Failure to gain weight during LVAD support was associated with persistently elevated natriuretic peptide levels. These data collectively suggest that recovery of body mass may be dependent upon recovery of the HF syndrome.

Abstract BackgroundPatients with pancreatic cancer often lose weight during chemotherapy with associated changes in body composition. The goal of the present analysis was to describe changes in body composition in pancreatic cancer patients on an exercise regimen. The long‐term goal is to determine whether an exercise intervention may attenuate changes in body composition and function.MethodsTwenty‐two pancreatic cancer patients of all stages who were to receive chemotherapy were recruited into a pre‐post exercise intervention study. A standard exercise prescription was individualized to include aerobic, resistance, stretch, and balance exercises. Pre‐ and post‐intervention computed tomography‐derived measures of body composition [skeletal muscle index (SMI), skeletal muscle density, visceral fat area, and subcutaneous fat area] and physical function measures (grip strength, timed up and go, 30‐s chair stand, and tandem balance stand) were evaluated using pairedt‐tests, χ2tests, and Pearson correlation coefficients.ResultsThe subjects were, on average, 62 years of age, 55% were female, 95% non‐Hispanic White, and 45% were Stage IV. Body composition changes included a median 4.6% decrease in SMI (P = 0.04), 7.91% increase in skeletal muscle density (P = 0.05), 25.07% decrease in visceral fat area (P = 0.0001), and 22.08% decrease in subcutaneous fat area (P = 0.001). Adherence to aerobic and strength exercise was 65% and 57%, respectively. Some physical function measures improved, though not significantly: chair stands increased from a mean of 11.5 to 13.0 (P = 0.59) and timed up and go improved from a mean of 11.7 to 10.3 (P = 0.26). Change in right hand grip strength was marginally positively associated with changes in SMI (r = 0.53,P = 0.06). Improvements in skeletal muscle density were seen in 63% of patients, including Stage IV patients but did not correlate with change in function.ConclusionsExercise is feasible during neoadjuvant chemotherapy for pancreatic cancer patients of all stages and may assist with maintaining physical function and improving body composition. Further research is needed.