Skeletal Muscle Abnormalities Research Articles

Subacute cadmium exposure changes different metabolic functions, leading to type 1 and 2 diabetes mellitus features in female rats.

Cadmium (Cd) is a heavy metal that acts as endocrine disrupting chemical (EDC). Few studies have investigated the effects of Cd exposure on metabolic dysfunctions, such as type 1 and 2 diabetes mellitus (T1DM and T2DM). Thus, we assessed whether subacute Cd exposure at occupational levels causes abnormalities in white adipose tissue (WAT), liver, pancreas, and skeletal muscle. We administered cadmium chloride (CdCl2) (100 ppm in drinking water for 30 days) to female rats and evaluated Cd levels in serum and metabolic organs, morphophysiology, inflammation, oxidative stress, fibrosis, and gene expression. High Cd levels were found in serum, WAT, liver, pancreas, and skeletal muscle. Cd-exposed rats showed low adiposity, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress compared to controls. Cd exposure reduced adipocyte size, hyperleptinemia, increased cholesterol levels, inflammation, apoptosis and fibrosis in WAT. Cd-exposed rats had increased liver cholesterol levels, insulin receptor beta (IRβ) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1α) expression, karyomegaly, inflammation, and fibrosis. Cd exposure reduced insulin levels and pancreatic islet size and increased inflammation and fibrosis. Cd exposure reduced skeletal muscle fiber diameter and increased IR expression and inflammation. Finally, strong positive correlations were observed between serum, tissue Cd levels, abnormal morphology, tissue inflammation and fibrosis. Thus, these data suggest that subacute Cd exposure impairs WAT, liver, pancreas and skeletal muscle function, leading to T1DM and T2DM features and other complications in female rats.

Quantitative ultrasonography reveals skeletal muscle abnormalities in carriers of DMD pathogenic variants.

Carriers of DMD pathogenic variants may become symptomatic and develop muscle-related manifestations. Despite that, few studies have attempted to characterize changes in the muscles of these carriers using imaging tools, particularly muscle ultrasound (MUS). The aim of this study was to compare lower limb MUS findings in carriers of DMD pathogenic variants (cDMD) vs healthy controls. Twenty-eight women (15 cDMD and 13 controls) underwent clinical evaluation and MUS. We collected information about muscle-related symptoms and assessed muscle strength. MUS was performed by a single physician (blind to the genetic status of subjects). The following muscles were assessed: rectus femoris, sartorius, tibialis anterior, and medial gastrocnemius. For each site, we computed data on muscle thickness, cross-sectional area, sound attenuation index, and elastography. Between-group comparisons were assessed using nonparametric tests and p-values <.05 were deemed significant. None of the subjects had objective muscle weakness, but exercise intolerance/fatigue was reported by four cDMDs and only one control. Regarding MUS, sound attenuation indices were significantly higher among carriers for all muscles tested. Longitudinal and axial deep echo intensities for the rectus femoris and tibialis anterior were also higher in the cDMD group compared with controls. No significant between-group differences were noted for elastography values, muscle area, or mean echo intensities. cDMD have skeletal muscle abnormalities that can be detected using quantitative MUS. Further studies are needed to determine whether such abnormalities are related to muscle symptoms in these patients.

Preventive education on adolescent idiopathic scoliosis in junior high school students at Surakarta

Adolescent idiopathic scoliosis (AIS) is a structural disorder of the vertebrae characterized by vertebral curvature exceeding 10°, commonly identified in children aged 10-18 years. Several contributing factors for AIS include genetic factors, abnormalities in connective tissue and skeletal muscles, biomechanical factors, and the use of school bags with associated weight. The primary issue identified from the preliminary study is the relatively high AIS rate, reaching 10.2%, with no previous preventive education programs implemented for students. The targeted participants for this program are students from Muhammadiyah Middle School 5 and Muhammadiyah Middle School 7 in Surakarta. The team conducted AIS prevention health education sessions in April-May 2023 for students aged 12-15 years. The educational activities involved the use of informative materials such as pocket books and videos, covering topics like the definition of Adolescent Idiopathic Scoliosis, physical examination methods for AIS, and preventive measures through posture correction exercises and the proper use of school bags.Results from the influence test, employing the Paired Sample T-Test, indicate a Sig. (2-tailed) value of 0.023. This implies a significant difference in the average knowledge level before and after receiving education on AIS prevention.

Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function

Tauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.

P301L‐Tau Expression Induces Skeletal Muscle Abnormalities in Mouse Model of Tauopathy

AbstractBackgroundPatients suffering from Alzheimer’s disease (AD) and related tauopathies often report signs of muscle weakness. The pathological accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD, yet it is unclear whether pathological tau impacts skeletal muscle. Proper muscle function is necessary for movement and consequently impacts quality of life in tauopathy patients, while concurrently contributing to the physiological maintenance of whole‐body endocrine and metabolic homeostasis. Skeletal muscle crosstalks with other organ systems; therefore, disruption of skeletal muscle health impacts whole‐body processes, such as the formation of pathological tau. The objective of this study was to determine the links between tauopathy and muscle function.MethodI performed intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (N = 4 females, 7 males) or a control plasmid (empty or a yellow fluorescent protein construct) (N = 5 females, 6 males). At 3 months, I measured grip strength. I harvested the brain, soleus, and tibialis anterior (TA) muscles at 15 months, and measured muscle mechanics concurrently in the soleus and extensor digitorum longus (EDL) muscles. I biochemically detected soluble tau and visualized TA structure immunohistochemically.ResultsGrip strength was reduced at 3 months in the P301L tau‐expressing mice of both sexes. The intrinsic force production of the soleus, but not the EDL, was reduced in P301L tau‐expressing males at 15 months. At this same time point, soluble tau accumulated in the cortex but not the soleus. Aggregation of nuclei were found histologically in the TA of P301L tau expressing mice but not in controls.ConclusionChanges in grip strength preceded insoluble tau accumulation and cognitive decline typical of this model. Reductions in the soleus force production indicate that P301L tau overexpression in the brain impacts intrinsic muscle strength, and occurs independently of innervation. The nuclear clumps detected in the TA of P301L tau‐expressing mice suggest that AAV‐P301L‐tau injections in the brain promote an inflammatory response in muscle. Together these data suggest that pathological tau species that are expressed in the brain reach peripheral tissues and exert deleterious consequences such as skeletal muscle abnormalities.

ASSESSMENT OF ABNORMAL SKELETAL MUSCLE PERFUSION BY CONTRAST-ENHANCED ULTRASOUND WITH PARAMETRIC IMAGING IN RATS AFTER SEVERE INJURY, HEMORRHAGIC SHOCK, AND WHOLE BLOOD RESUSCITATION.

Background: After severe injury, optical measures of microvascular blood flow (MBF) decrease and do not normalize with resuscitation to normal blood pressure. These changes are associated with organ dysfunction, coagulopathy, and death. However, the pathophysiology is not well understood. Several possible pathways could also contribute to the development of trauma-induced coagulopathy (TIC). A small-animal model of trauma-related MBF derangement that persists after resuscitation and includes TIC would facilitate further study. Parametric contrast-enhanced ultrasound (CEUS) is particularly advantageous in this setting, because it noninvasively assesses MBF in large, deep vascular beds. We sought to develop such a model, measuring MBF with CEUS. Methods: Sixteen male Sprague-Dawley rats were anesthetized, ventilated, and cannulated. Rats were subjected to either no injury (sham group) or a standardized polytrauma and pressure-targeted arterial catheter hemorrhage with subsequent whole blood resuscitation (trauma group). At prespecified time points, CEUS measurements of uninjured quadriceps muscle, viscoelastic blood clot strength, and complete blood counts were taken. Results: After resuscitation, blood pressure normalized, but MBF decreased and remained low for the rest of the protocol. This was primarily driven by a decrease in blood volume with a relative sparing of blood velocity. Viscoelastic blood clot strength and platelet count also decreased and remained low throughout the protocol. Conclusion: We present a rat model of MBF derangement in uninjured skeletal muscle and coagulopathy after polytrauma that persists after resuscitation with whole blood to normal macrohemodynamics. Parametric CEUS analysis shows that this change is primarily due to microvascular obstruction. This platform can be used to develop a deeper understanding of this important process.

Cardiovascular phenotype of the duchenne muscular dystrophy carrier female rat

Abstract Background Duchenne muscular dystrophy (DMD) is a lethal, severely progressive muscle-wasting disease. It is an X-linked recessive disease caused by mutations in the DMD gene encoding dystrophin protein and consequently the absence of dystrophin protein synthesis. Besides the skeletal muscle abnormalities, DMD patients are often suffering cardiovascular symptoms include cardiac fibrosis, dilated cardiomyopathy, arrhythmia, and congestive heart failure. Heterozygous female DMD carriers rarely acquire skeletal muscle symptoms, however the cardiac abnormalities are often underrepresented. There are few studies to date characterizing cardiovascular abnormalities in female DMD carriers and the mechanisms underlying the cardiac manifestations are still not fully known. Aims and Methods: Therefore, the aim of this study was to investigate the cardiovascular phenotype of 9 months old female DMD carrier rats and compare with age-matched wildtype rats. Objectives included assessment of cardiac function via transthoracic echocardiography, vascular function using wire myography, cardiac fibrosis and dystrophin via histology, mRNA expression of inflammatory markers via RT-qPCR, measurements of ACE1 and ACE2 activity, as well as expression of dystrophin, SERCA, sarcolipin, BAG3, and Connexin43 (Cx43) using western blotting. The cardiac function, vascular endothelial function, ACE1 and ACE2 activity, and collagen deposition in cardiac tissue were similar between the female DMD carrier and wildtype rats. The echocardiography data revealed thinning of the left-ventricular posterior wall indicating trend towards cardiac atrophy and dysfunction (p&amp;lt;0.05). Wire myography data showed trends of impaired endothelium-independent relaxation and hypercontractility, suggesting the potential vascular abnormalities. Histological analysis showed thickening of intima-media layer in coronary arteries, addition to reduced dystrophin staining, further affirming dystrophin loss impairs smooth muscle cell function (p&amp;lt;0.05, respectively). Protein expression of dystrophin, SERCA2, and BAG3 was decreased in female DMD carrier rats in the myocardium. We also found decreased levels of Cx43 at the intercalated discs, with a concomitant increase in the phosphorylation of Serine368 on Cx43 that very often precedes ubiquitination and degradation of Cx43 channels. In agreement, higher levels of the ubiquitin ligase Nedd4 were observed in hearts of female DMD carrier rats, implicating Cx43 degradation in cardiac dysfunction observed in these animals. Conclusions These findings indicate that female DMD carrier rats do not develop severe cardiac systolic dysfunction nor dilated cardiomyopathy at the age of 9 months unlike male DMD rats as previously described(1). However, the female DMD carrier rats begin to manifest tendencies towards cardiac and vascular dysfunction in association with a changes of calcium handling protein and Cx 43 expression in the heart.

Identification of Genetic Variants Associated with Severe Myocardial Bridging through Whole-Exome Sequencing.

Myocardial bridging (MB) is a congenital coronary artery anomaly and an important cause of angina. The genetic basis of MB is currently unknown. This study used a whole-exome sequencing technique and analyzed genotypic differences. Eight coronary angiography-confirmed cases of severe MB and eight age- and sex-matched control patients were investigated. In total, 139 rare variants that are potentially pathogenic for severe MB were identified in 132 genes. Genes with multiple rare variants or co-predicted by ClinVar and CADD/REVEL for severe MB were collected, from which heart-specific genes were selected under the guidance of tissue expression levels. Functional annotation indicated significant genetic associations with abnormal skeletal muscle mass, cardiomyopathies, and transmembrane ion channels. Candidate genes were reviewed regarding the functions and locations of each individual gene product. Among the gene candidates for severe MB, rare variants in DMD, SGCA, and TTN were determined to be the most crucial. The results suggest that altered anchoring proteins on the cell membrane and intracellular sarcomere unit of cardiomyocytes play a role in the development of the missed trajectory of coronary vessels. Additional studies are required to support the diagnostic application of cardiac sarcoglycan and dystroglycan complexes in patients with severe MB.

SAT639 Electronic Cigarettes-exposed Mice Have Impairments In Skeletal Muscle Mediated By Impaired Ampk Activation

Abstract Disclosure: J. Rivera: None. J. Espinoza-Derout: None. K.M. Hasan: None. C. Lao: None. J.B. Wilson: None. X.M. Shao: None. Y. Tintut: None. M. Jordan: None. K.P. Roos: None. A.P. Sinha-Hikim: None. T.C. Friedman: None. Electronic cigarettes (E-Cig) are a relatively new way to deliver nicotine (Nic). E-Cigs are gaining popularity, especially among youth and young adults, who do not realize their harmful health effects. Our laboratory has been a pioneer in demonstrating the adverse effects of E-Cigs on the liver and the heart. Skeletal muscle is a bigger tissue with physical and metabolic importance fundamental for human health. We previously reported that IP injection of Nic with a “second-hit” such as a high-fat diet (HFD) caused skeletal muscle damage. This study evaluated the detrimental effects of E-Cigs administration on skeletal muscle. We used an E-Cig inhalation model to deliver Nic in a similar way to humans. C57BL6 mice were fed with an HFD, divided into three groups, and exposed to a saline solution (control group), commercially available E-Cig (bluCig) in absence of Nic (E-Cig 0%), or E-Cig with the presence of Nic (E-Cig 2.4%) for 12 weeks. Results showed that the skeletal muscle exposed to E-Cig 2.4% had a reduction of the phosphorylation of the metabolic regulator, AMPK, and the pro-lipolytic enzyme ATGL as measured by western blot analyses in relation to control saline and E-Cig 0% groups. This metabolic impairment was accompanied by a reduction of the homeostatic mechanism, autophagy by a decrease of the ratio LC3II/LC3I, in the group exposed to E-Cig 2.4% in relation to the saline group. Electron microscopy showed intramyofibrillar mitochondrial with cristolysis, vacuolization, and intramyocellular lipid deposits in the E-Cig 2.4% group. Additionally, we observed an increase in oxidative stress suggested by the increase of the antioxidant enzyme HO-1 in the E-Cig 2.4%, and the reduction of the protein levels of SOD1 and SOD2. Finally, the previous changes trigger the activation of cellular stress pathways such as the phosphorylation of p38 and the increase in inflammasome protein, Nrlp3 in the E-Cig 2.4% compared to the saline group. This study suggests skeletal muscle abnormalities in mice vaping E-Cig 2.4% can alter muscle health. We believe these abnormalities will have important consequences in the skeletal muscle considering the early life stage of the consumers. Presentation: Saturday, June 17, 2023

P128 Quantitative ultrasonography reveals skeletal muscle abnormalities in female carriers of DMD pathogenic variants

P128 Quantitative ultrasonography reveals skeletal muscle abnormalities in female carriers of DMD pathogenic variants

The Effect of SERCA Activation on Functional Characteristics and Signaling of Rat Soleus Muscle upon 7 Days of Unloading.

Skeletal muscle abnormalities and atrophy during unloading are accompanied by the accumulation of excess calcium in the sarcoplasm. We hypothesized that calcium accumulation may occur, among other mechanisms, due to the inhibition of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity. Consequently, the use of the SERCA activator will reduce the level of calcium in the sarcoplasm and prevent the negative consequences of muscle unloading. Wistar rats were randomly assigned into one of three groups (eight rats per group): control rats with placebo (C), 7 days of unloading/hindlimb suspension with placebo (7HS), and 7 days of unloading treated with SERCA activator CDN1163 (7HSC). After seven days of unloading the soleus muscle, the 7HS group displayed increased fatigue in the ex vivo test, a significant increase in the level of calcium-dependent CaMK II phosphorylation and the level of tropomyosin oxidation, as well as a decrease in the content of mitochondrial DNA and protein, slow-type myosin mRNA, and the percentage of slow-type muscle fibers. All of these changes were prevented in the 7HSC group. Moreover, treatment with CDN1163 blocked a decrease in the phosphorylation of p70S6k, an increase in eEF2 phosphorylation, and an increase in MuRF-1 mRNA expression. Nevertheless, there were no differences in the degree of fast and slow muscle fiber atrophy between the 7HS and 7HSC groups. Conclusion: SERCA activation during 7 days of unloading prevented an increase in soleus fatigue, the decrease of slow-type myosin, mitochondrial markers, and markers of calcium homeostasis but had no effect on muscle atrophy.

AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice.

Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness affecting infants, children, and adults with different severity, is caused by a deficiency of lysosomal glycogen-degrading enzyme acid α-glucosidase (GAA). Here, we demonstrated that adeno-associated virus-mediated (AAV-mediated) systemic gene transfer reversed glycogen storage in all key therapeutic targets - skeletal and cardiac muscles, the diaphragm, and the central nervous system - in both young and severely affected old Gaa-knockout mice. Furthermore, the therapy reversed secondary cellular abnormalities in skeletal muscle, such as those in autophagy and mTORC1/AMPK signaling. We used an AAV9 vector encoding a chimeric human GAA protein with enhanced uptake and secretion to facilitate efficient spread of the expressed protein among multiple target tissues. These results lay the groundwork for a future clinical development strategy in Pompe disease.

Effects of a Mitochondrial Targeted Ubiquinol (MitoQ) on Vascular Function and Exercise Capacity in Chronic Kidney Disease: A Randomized Controlled Pilot Study.

Mitochondrial derived oxidative stress is implicated in vascular and skeletal muscle abnormalities in chronic kidney disease (CKD). The purpose of this study was to investigate the effects of a mitochondrial targeted ubiquinol (MitoQ) on vascular function and exercise capacity in CKD. In this randomized controlled trial, 18 patients with CKD (Mean±SEM: Age, 62±3years; eGFR, 45±3ml/min/1.732) received 4 weeks of 20mg/day MitoQ (MTQ) or placebo (PLB). Outcomes assessed at baseline and follow up included macrovascular function measured by flow mediated dilation; microvascular function assessed by laser Doppler flowmetry combined with intradermal microdialysis; aortic hemodynamics assessed by oscillometery; and exercise capacity by cardiopulmonary exercise testing. Compared to PLB, MTQ improved flow mediated dilation (baseline vs follow up: MTQ, 2.4±0.3 vs. 4.0±0.9%; PLB, 4.2±1.0 vs. 2.5±1.0%; p=0.04). MTQ improved microvascular function (DCVC: MTQ, 4.50 ± 2.57 vs. PLB -2.22 ± 2.67%; p=0.053). Central aortic systolic and pulse pressures were unchanged, however, MTQ prevented increases in augmentation pressures that were observed in the PLB group (p=0.026). MTQ did not affect exercise capacity. This study demonstrates potential for a mitochondrial targeted ubiquinol to improve vascular function in CKD. The findings hold promise for future investigations of mitochondrial targeted therapies in CKD.

Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy.

Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has not been extensively explored. We previously showed that global deletion of the muscle-specific nuclear envelope protein NET39 in mice leads to neonatal lethality due to skeletal muscle dysfunction. To study the potential role of the Net39 gene in adulthood, we generated a muscle-specific conditional knockout (cKO) of Net39 in mice. cKO mice recapitulated key skeletal muscle features of EDMD, including muscle wasting, impaired muscle contractility, abnormal myonuclear morphology, and DNA damage. The loss of Net39 rendered myoblasts hypersensitive to mechanical stretch, resulting in stretch-induced DNA damage. Net39 was downregulated in a mouse model of congenital myopathy, and restoration of Net39 expression through AAV gene delivery extended life span and ameliorated muscle abnormalities. These findings establish NET39 as a direct contributor to the pathogenesis of EDMD that acts by protecting against mechanical stress and DNA damage.

The Role of SOCS3 in Regulating Meat Quality in Jinhua Pigs

Meat quality is an important economic trait that influences the development of the pig industry. Skeletal muscle development and glycolytic potential (GP) are two crucial aspects that significantly impact meat quality. It has been reported that abnormal skeletal muscle development and high glycogen content results in low meat quality. However, the genetic mechanisms underlying these factors are still unclear. Compared with intensive pig breeds, Chinese indigenous pig breeds, such as the Jinhua pig, express superior meat quality characteristics. The differences in the meat quality traits between Jinhua and intensive pig breeds make them suitable for uncovering the genetic mechanisms that regulate meat quality traits. In this study, the Jinhua pig breed and five intensive pig breeds, including Duroc, Landrace, Yorkshire, Berkshire, and Pietrain pig breeds, were selected as experimental materials. First, the FST and XP-EHH methods were used to screen the selective signatures on the genome in the Jinhua population. Then, combined with RNA-Seq data, the study further confirmed that SOCS3 could be a key candidate gene that influences meat quality by mediating myoblast proliferation and glycometabolism because of the down-regulated expression of SOCS3 in Jinhua pigs compared with Landrace pigs. Finally, through SOCS3 knockout (KO) and overexpression (OE) experiments in mouse C2C12 cells, the results showed that SOCS3 regulated the cell proliferation of myoblasts. Moreover, SOCS3 is involved in regulating glucose uptake by the IRS1/PI3K/AKT signaling pathway. Overall, these findings provide a basis for the genetic improvement of meat quality traits in the pig industry.

Relationship between circulating tumour DNA and skeletal muscle stores at diagnosis of pancreatic ductal adenocarcinoma: a cross-sectional study

Low skeletal muscle index (SMI) and low skeletal muscle radiodensity (SMD) are associated with reduced survival time in pancreatic ductal adenocarcinoma (PDAC). The negative prognostic impact of low SMI and low SMD is often reported as independent of cancer stage when using traditional clinical staging tools. Therefore, this study sought to explore the relationship between a novel marker of tumour burden (circulating tumour DNA) and skeletal muscle abnormalities at diagnosis of PDAC. A retrospective cross-sectional study was conducted in patients who had plasma and tumour tissue samples stored in the Victorian Pancreatic Cancer Biobank (VPCB) at diagnosis of PDAC, between 2015 and 2020. Circulating tumour DNA (ctDNA) of patients with G12 and G13 KRAS mutations was detected and quantified. Pre-treatment SMI and SMD derived from analysis of diagnostic computed tomography imaging was tested for its association to presence and concentration of ctDNA, as well as conventional staging, and demographic variables. The study included 66 patients at PDAC diagnosis; 53% female, mean age 68.7 years (SD ± 10.9). Low SMI and low SMD were present in 69.7% and 62.1% of patients, respectively. Female gender was an independent risk factor for low SMI (OR 4.38, 95% CI 1.23–15.55, p = 0.022), and older age an independent risk factor for low SMD (OR 1.066, 95% CI 1.002–1.135, p = 0.044). No association between skeletal muscle stores and concentration of ctDNA (SMI r = − 0.163, p = 0.192; SMD r = 0.097, p = 0.438) or stage of disease according to conventional clinical staging [SMI F(3, 62) = 0.886, p = 0.453; SMD F(3, 62) = 0.717, p = 0.545] was observed. These results demonstrate that low SMI and low SMD are highly prevalent at diagnosis of PDAC, and suggest they are comorbidities of cancer rather than related to the clinical stage of disease. Future studies are needed to identify the mechanisms and risk factors for low SMI and low SMD at diagnosis of PDAC to aid screening and intervention development.

#5042 ASSOCIATIONS BETWEEN SARCOPAENIA, CARDIOVASCULAR HEALTH AND HABITUAL PHYSICAL ACTIVITY IN PATIENTS ON HAEMODIALYSIS

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) show skeletal muscle abnormalities such as sarcopenia (presence of low muscle mass, strength, and physical performance). Severe sarcopenia and its components are associated with poor clinical outcomes, decreased quality of life (QoL), and mortality. The direction of the relationships between sarcopenia and cardiovascular disease are less clear as are the impact of exercise interventions in patients with severe sarcopenia. Method This is a post-hoc analysis of the CYCLE-HD study, which was a randomised controlled trial assessing the effects of a 6-month structured intradialytic cycling intervention on cardiovascular health in those on haemodialysis. Presence of sarcopenia was established using the European Working Group of Sarcopenia in Older People (EWGSOP) definition. A cut off of &amp;lt;17.5 kg/m2 in men and &amp;lt;14.5 kg/m2 in women were used for fat free mass to establish muscle quantity using bioimpedance. The cut off of 15 seconds on the sit to stand 5 tests was used to establish muscle strength and a score of ≤8 on the short physical performance battery was used to assess physical performance. If all three criteria were met, severe sarcopenia was confirmed. Accelerometery assessed habitual physical activity (PA) and the general practice physical activity questionnaire assessed self-reported PA. Magnetic resonance imaging (MRI) measured left ventricular mass, pulse wave velocity, and global native T1 mapping (measure of myocardial fibrosis). Mann - Whitney U or unpaired t-tests explored differences in cardiac MRI, and physical activity (PA) outcomes between sarcopenic and non-sarcopenic patients. Linear regressions were used to investigate whether sarcopenia or its components predict cardiovascular health, and habitual PA outcomes cross-sectionally at baseline and following the 6-month programme of intradialytic exercise. Multinomial regressions were used to explore if sarcopenia or its components predicted self-reported PA. Results 130 patients (57 [±15] years, 95 [73.08%] male) were included in the analysis of whom 65 patients underwent the intradialytic cycling intervention. 31 (23.85%) patients had severe sarcopenia. 107(82.31%) had low muscle mass, 92(70.77%) had low strength, and 48 (36.92%) had low physical performance. Severe sarcopenia was a significant predictor for self-reported PA status (p = .042, Pseudo R2 = 0.043) at baseline but not for any other outcomes. However, low muscle mass was a significant predictor for LV mass (p = .014, R2 = 0.04, Β = -6.76). Low muscle strength was a significant predictor for higher pulse wave velocity (p = .010, R2 = 0.056, Β = 2.57) and global native T1 (p = .001, R2 = 0.091, Β = 26.79). Low fat mass (p = .005, R2 = 0.07, Β = -2198.63) and physical performance were significant predictors for mean steps (p&amp;lt;.001, R2 = 0.12, Β = -209.16). Baseline severe sarcopenia or its components were not predictors for cardiovascular or habitual PA changes following intradialytic exercise. Conclusion Severe sarcopenia was present in nearly quarter of the participants, but the majority showed at least one muscle health related abnormality (low muscle mass, strength or physical performance). These markers of sarcopenia showed associations with habitual PA and structural markers of cardiovascular disease. However, the presence of sarcopenia may not limit the benefits offered by intradialytic exercise. Patients with sarcopenic traits should be encouraged to participate in appropriate interventions to improve health and wellbeing.

Association between sarcopenia and exercise capacity in patients with pulmonary hypertension without left heart disease

BackgroundPulmonary hypertension (PH) has recently been described as a complex clinical syndrome affecting multiple organ systems, including the heart, lungs, and skeletal muscle, each of which plays an important role in exercise capacity. However, the relationship between exercise capacity and skeletal muscle abnormalities in patients with PH has not been fully elucidated. MethodsWe retrospectively analysed the exercise capacity and measures of skeletal muscle of 107 patients with PH without left heart disease (mean age 63 ± 15 years, 32.7% males, n = 30/6/66/5 in the clinical classification Group 1/3/4/5). ResultsSarcopenia, low appendicular skeletal muscle mass index, low grip strength, and slow gait speed, determined by international criteria, were found in 15 (14.0%), 16 (15.0%), 62 (57.9%), and 41 (38.3%) patients, respectively. The mean 6-min walk distance of all patients was 436 ± 134 m and was independently associated with sarcopenia (standardised β = −0.292, p < 0.001). All patients with sarcopenia showed reduced exercise capacity defined as 6-min walk distance < 440 m. Multivariable logistic regression analysis showed that each of the components of sarcopenia was associated with reduced exercise capacity (adjusted odds ratio and 95% confidence interval of appendicular skeletal muscle mass index: 0.39 [0.24–0.63] per 1 kg/m2, p = 0.006, grip strength: 0.83 [0.74–0.94] per 1 kg, p = 0.003, and gait speed: 0.31 [0.18–0.51] per 0.1 m/s, p < 0.001). ConclusionsSarcopenia and its components are associated with reduced exercise capacity in patients with PH. A multifaceted evaluation may be important in the management of reduced exercise capacity in patients with PH.

Skeletal Muscle-Specific Bis Depletion Leads to Muscle Dysfunction and Early Death Accompanied by Impairment in Protein Quality Control.

Bcl-2-interacting cell death suppressor (BIS), also called BAG3, plays a role in physiological functions such as anti-apoptosis, cell proliferation, autophagy, and senescence. Whole-body Bis-knockout (KO) mice exhibit early lethality accompanied by abnormalities in cardiac and skeletal muscles, suggesting the critical role of BIS in these muscles. In this study, we generated skeletal muscle-specific Bis-knockout (Bis-SMKO) mice for the first time. Bis-SMKO mice exhibit growth retardation, kyphosis, a lack of peripheral fat, and respiratory failure, ultimately leading to early death. Regenerating fibers and increased intensity in cleaved PARP1 immunostaining were observed in the diaphragm of Bis-SMKO mice, indicating considerable muscle degeneration. Through electron microscopy analysis, we observed myofibrillar disruption, degenerated mitochondria, and autophagic vacuoles in the Bis-SMKO diaphragm. Specifically, autophagy was impaired, and heat shock proteins (HSPs), such as HSPB5 and HSP70, and z-disk proteins, including filamin C and desmin, accumulated in Bis-SMKO skeletal muscles. We also found metabolic impairments, including decreased ATP levels and lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the diaphragm of Bis-SMKO mice. Our findings highlight that BIS is critical for protein homeostasis and energy metabolism in skeletal muscles, suggesting that Bis-SMKO mice could be used as a therapeutic strategy for myopathies and to elucidate the molecular function of BIS in skeletal muscle physiology.

Contributory roles of sarcopenia and myosteatosis in development of overt hepatic encephalopathy and mortality after transjugular intrahepatic portosystemic shunt.

Skeletal muscle abnormalities, such as muscle mass depletion (sarcopenia) and fatty infiltration of the muscle (myosteatosis), are frequent complications in cirrhotic patients scheduled for transjugular intrahepatic portosystemic shunt (TIPS). To investigate the association and predictive value of sarcopenia and myosteatosis for overt hepatic encephalopathy (HE) and mortality after TIPS. The records of cirrhotic patients who underwent the TIPS procedure at our hospital between January 2020 and June 2021 were retrospectively retrieved. The transversal psoas muscle thickness (TPMT) and psoas muscle attenuation (PMA) measured from the unenhanced abdominal computed tomography (CT) at the level of the third lumbar vertebrae were used to analyze the sarcopenia and myosteatosis, respectively. The area under curve (AUC) was used to evaluate the discriminative power of TPMT, PMA, and relevant clinical parameters. Fur-thermore, log-rank test was performed to compare the incidence of overt HE and survival between the different groups, and the association of risk factors with overt HE and mortality was analyzed using Cox proportional hazards regression models. A total of 108 patients were collected. Among these patients, 45.4% of patients developed overt HE after TIPS treatment. Furthermore, 32.4% and 28.7% of these patients were identified to have myosteatosis and sarcopenia, respectively. Myosteatosis (51.0% vs 16.9%, P < 0.001) and sarcopenia (40.8 vs 18.6%, P = 0.011) were found to be more frequent in patients with overt HE, when compared to patients without overt HE. The receiver operating characteristics analysis indicated that the predictive power of TPMT and PMA in overt HE (AUC = 0.713 and 0.778, respectively) was higher when compared to the neutrophil lymphocyte ratio (AUC = 0.636). The cumulative incidence of overt HE was the highest in patients with concomitant sarcopenia and myosteatosis, followed by patients with myosteatosis or sarcopenia, while this was the lowest in patients without sarcopenia and myosteatosis. In addition, sarcopenia and myosteatosis were inde-pendently associated with overt HE and mortality after adjusting for confounding factors in post-TIPS patients. CT-based estimations for sarcopenia and myosteatosis can be used as reliable predictors for the risk of developing overt HE and mortality in cirrhotic patients after TIPS.