Muscle Wasting Research Articles

UNDERSTANDING THE MANAGEMENT OF DUCHENNE MUSCULAR DYSTROPHY AS PER AYURVEDA

The muscular dystrophies are genitacally determined,progressive,primary disorders of muscle.Common presenting symptoms include delayed mile stones,abnormal mode of walking,difficulty in running,climbing stairs and getting up from floor,frequent falls,weakness of arms or face,ocular symptoms,enlargement or wasting of muscles and recurrent chest infections.The symptoms are progressive and a family history of similar illness may be obtained.Duchenne muscular dystrophy(D.M.D) is a severe muscle wasting disorder,resulting in early confinement to wheel chair and often death by the age of 20 years. There is no cure available for this disorder at present,prevention & treatment of complications is of prime importance as per modern medicine, but Ayurvedic treatments show significant results in all signs and symptoms of disease.

KLF10: a point of convergence in cancer cachexia.

Cancer-associated cachexia is a wasting syndrome entailing loss in body mass and a shortened life expectancy. There is currently no effective treatment to abrogate this syndrome, which leads to 20-30% of deaths in patients with cancer. While there have been advancements in defining signaling factors/pathways in cancer-induced muscle wasting, targeting the same in the clinic has not been as successful. Krüppel-like factor 10 (KLF10), a transcription factor implicated in muscle regulation, is regulated by the transforming growth factor-beta signaling pathway. This review proposes KLF10 as a potential convergence point of diverse signaling pathways involved in muscle wasting. KLF10 was discovered as a target of transforming growth factor-beta decades ago but more recently it has been shown that deletion of KLF10 rescues cancer-induced muscle wasting. Moreover, KLF10 has also been shown to bind key atrophy genes associated with muscle atrophy in vitro . There is an elevated need to explore targets in cachexia, which will successfully translate into the clinic. Investigating a convergence point downstream of multiple signaling pathways might hold promise in developing effective therapies for cachexia.

The therapeutic effect of NRF2 activator, ezetimibe, in cardiac cachexia.

Heart failure (HF) is caused by functional and structural irregularity leading to impaired ejection or filling capacity of the heart. HF leads to chronic inflammatory conditions in the heart leads to weight loss, anorexia, and muscle atrophy known as cachexia. The present study was carried out to investigate the role of Ezetimibe, an NRF2 activator, in cardiac cachexia and to develop a treatment strategy for cardiac cachexia. Balb/c mice of either sex at 6-8 weeks of age were given 2 mg/kg of doxorubicin in 0.9% sodium chloride solution intraperitoneally (i.p.) for the alternate days for the first week and then once a week for the next 4 weeks. After induction of cardiac atrophy, treatment with Ezetimibe (1.5 mg/kg, p.o) was given for the next 4 weeks. In the cardiac cachectic animals, a significant decrease in body weight, food, and water intake was observed. Cardiac cachectic animals showed a significant increase in serum glucose, total cholesterol, LDL, triglyceride, VLDL, CK-MB, LDH, and CRP levels. Cardiac atrophic index, heart weight to body weight ratios (HW/BW), right ventricular weight to heart weight ratios (RV/HW), and left ventricular weight to heart weight ratios (LV/HW), were significantly decreased in cardiac cachectic animals. The weights of the skeletal muscles such as EDL, gastrocnemius, soleus, tibialis anterior, and quadriceps muscles, and the weight of adipose tissue such as subcutaneous, visceral, perirenal, and brown adipose tissue were significantly decreased in the cardiac cachectic group relative to the normal group. Treatment with ezetimibe improves body weight, food intake, and water intake. Ezetimibe decreases serum glucose, total cholesterol, LDL, triglyceride, VLDL, CK-MB, LDH and CRP levels. Cardiac atrophic markers such as HW/BW, RV/HW, and LV/HW were improved. The weight of skeletal muscles and adipose tissue was increased after treatment with ezetimibe. Our data showed that the NRF2 activator, Ezetimibe produces a beneficial effect on cardiac cachexia in the doxorubicin-induced cardiac cachexia model. Ezetimibe was successful to reduce the levels of inflammatory cytokines, ameliorate the effects on cardiac muscle wasting, lipid levels, fat tissues, and skeletal muscles.

Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism.

Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics. Lewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption. Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P=0.0207) in these mice. A total of 12335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase-signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation. This study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.

SMCHD1 activates the expression of genes required for the expansion of human myoblasts.

SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4. Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression.

The "Sunshine Vitamin" and Its Antioxidant Benefits for Enhancing Muscle Function.

Pathological states marked by oxidative stress and systemic inflammation frequently compromise the functional capacity of muscular cells. This progressive decline in muscle mass and tone can significantly hamper the patient's motor abilities, impeding even the most basic physical tasks. Muscle dysfunction can lead to metabolic disorders and severe muscle wasting, which, in turn, can potentially progress to sarcopenia. The functionality of skeletal muscle is profoundly influenced by factors such as environmental, nutritional, physical, and genetic components. A well-balanced diet, rich in proteins and vitamins, alongside an active lifestyle, plays a crucial role in fortifying tissues and mitigating general weakness and pathological conditions. Vitamin D, exerting antioxidant effects, is essential for skeletal muscle. Epidemiological evidence underscores a global prevalence of vitamin D deficiency, which induces oxidative harm, mitochondrial dysfunction, reduced adenosine triphosphate production, and impaired muscle function. This review explores the intricate molecular mechanisms through which vitamin D modulates oxidative stress and its consequent effects on muscle function. The aim is to evaluate if vitamin D supplementation in conditions involving oxidative stress and inflammation could prevent decline and promote or maintain muscle function effectively.

Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

Restoring Skeletal Muscle Health through Exercise in Breast Cancer Patients and after Receiving Chemotherapy.

Breast cancer (BC) stands out as the most commonly type of cancer diagnosed in women worldwide, and chemotherapy, a key component of treatment, exacerbates cancer-induced skeletal muscle wasting, contributing to adverse health outcomes. Notably, the impact of chemotherapy on skeletal muscle seems to surpass that of the cancer itself, with inflammation identified as a common trigger for muscle wasting in both contexts. In skeletal muscle, pro-inflammatory cytokines modulate pathways crucial for the delicate balance between protein synthesis and breakdown, as well as satellite cell activation and myonuclear accretion. Physical exercise consistently emerges as a crucial therapeutic strategy to counteract cancer and chemotherapy-induced muscle wasting, ultimately enhancing patients' quality of life. However, a "one size fits all" approach does not apply to the prescription of exercise for BC patients, with factors such as age, menopause and comorbidities influencing the response to exercise. Hence, tailored exercise regimens, considering factors such as duration, frequency, intensity, and type, are essential to maximize efficacy in mitigating muscle wasting and improving disease outcomes. Despite the well-established anti-inflammatory role of aerobic exercise, resistance exercise proves equally or more beneficial in terms of mass and strength gain, as well as enhancing quality of life. This review comprehensively explores the molecular pathways affected by distinct exercise regimens in the skeletal muscle of cancer patients during chemotherapy, providing critical insights for precise exercise implementation to prevent skeletal muscle wasting.

Involvement of the gut microbiota in cancer cachexia.

Cancer cachexia, or the unintentional loss of body weight in patients with cancer, is a multiorgan and multifactorial syndrome with a complex and largely unknown etiology; however, metabolic dysfunction and inflammation remain hallmarks of cancer-associated wasting. Although cachexia manifests with muscle and adipose tissue loss, perturbations to the gastrointestinal tract may serve as the frontline for both impaired nutrient absorption and immune-activating gut dysbiosis. Investigations into the gut microbiota have exploded within the past two decades, demonstrating multiple gut-tissue axes; however, the link between adipose and skeletal muscle wasting and the gut microbiota with cancer is only beginning to be understood. Furthermore, the most used anticancer drugs (e.g. chemotherapy and immune checkpoint inhibitors) negatively impact gut homeostasis, potentially exacerbating wasting and contributing to poor patient outcomes and survival. In this review, we 1) highlight our current understanding of the microbial changes that occur with cachexia, 2) discuss how microbial changes may contribute to adipose and skeletal muscle wasting, and 3) outline study design considerations needed when examining the role of the microbiota in cancer-induced cachexia.

Unveiling the detrimental vicious cycle linking skeletal muscle and COVID-19: A systematic review and meta-analysis.

Skeletal muscle catabolism supports multiple organs and systems during severe trauma and infection, but its role in COVID-19 remains unclear. This study investigates the interactions between skeletal muscle and COVID-19. The PubMed, EMbase, and The Cochrane Library databases were systematically searched from January 2020 to August 2023 for cohort studies focusing on the impact of skeletal muscle on COVID-19 prevalence and outcomes, and longitudinal studies examining skeletal muscle changes caused by COVID-19. Skeletal muscle quantity (SMQN) and quality (SMQL) were assessed separately. The random-effect model was predominantly utilized for statistical analysis. Seventy studies with moderate to high quality were included. Low SMQN/SMQL was associated with an increased risk of COVID-19 infection (OR=1.62, p<0.001). Both the low SMQN and SMQL predicted COVID-19-related mortality (OR=1.53, p=0.016; OR=2.18, p=0.001, respectively). Mortality risk decreased with increasing SMQN (OR=0.979, p=0.009) and SMQL (OR=0.972, p=0.034). Low SMQN and SMQL were also linked to the need for intensive care unit/mechanical ventilation, increased COVID-19 severity, and longer hospital stays. Significant skeletal muscle wasting, characterized by reduced volume and strength, was observed during COVID-19 infection and the pandemic. This study reveals a detrimental vicious circle between skeletal muscle and COVID-19. Effective management of skeletal muscle could be beneficial for treating COVID-19 infections and addressing the broader pandemic. These findings have important implications for the management of future virus pandemics. PROSPERO CRD42023395476.

Dystrophin S3059 phosphorylation partially attenuates denervation atrophy in mouse tibialis anterior muscles.

The dystrophin protein has well-characterized roles in force transmission and maintaining membrane integrity during muscle contraction. Studies have reported decreased expression of dystrophin in atrophying muscles during wasting conditions, and that restoration of dystrophin can attenuate atrophy, suggesting a role in maintaining muscle mass. Phosphorylation of S3059 within the cysteine-rich region of dystrophin enhances binding between dystrophin and β-dystroglycan, and mimicking phosphorylation at this site by site-directed mutagenesis attenuates myotube atrophy invitro. To determine whether dystrophin phosphorylation can attenuate muscle wasting invivo, CRISPR-Cas9 was used to generate mice with whole body mutations of S3059 to either alanine (DmdS3059A) or glutamate (DmdS3059E), to mimic a loss of, or constitutive phosphorylation of S3059, on all endogenous dystrophin isoforms, respectively. Sciatic nerve transection was performed on these mice to determine whether phosphorylation of dystrophin S3059 could attenuate denervation atrophy. At 14 days post denervation, atrophy of tibialis anterior (TA) but not gastrocnemius or soleus muscles, was partially attenuated in DmdS3059E mice relative to WT mice. Attenuation of atrophy was associated with increased expression of β-dystroglycan in TA muscles of DmdS3059E mice. Dystrophin S3059 phosphorylation can partially attenuate denervation-induced atrophy, but may have more significant impact in less severe modes of muscle wasting.

Management of cervical spondylotic amyotrophy (Bahushosha) through customized Ayurvedic approaches: An experience

Cervical Spondylotic Amyotrophy (CSA) is a rare clinical syndrome in cervical spondylosis characterized by weakness and atrophy of the upper extremities with no or insignificant sensory deficit or paraparesis in the lower extremities. The clinical presentation of CSA can be correlated with Bahushosha (~wasting of arms), a condition explained under Vataja nanatmaja vikaras (~diseases due only to vitiated Vata). In all the Vataja variety of diseases enumerated, even when the inherent properties of Vata are manifested partially, these are diagnosed and treated as disorders of Vata. The present study is about managing a 46-year-old male patient with difficulty in uplifting both hands associated with weakness, stiffness, and muscle wasting. The patient is presented with Vataja lakshanas (~symptoms of Vata), and Panchakarma therapy was adopted with Vatahara (~pacifies vitiated Vata) and Brimhana (~nourishing) as the line of management, along with Shamana aushadha (~palliative medicines). Significant improvement was observed by the end of the treatment, inferring adopting Ayurveda approaches in the management of such pathologies. The absence of specific therapy for CSA also makes it even more important to consider such approaches that can add quality of life in suffering individuals.

Assessment of Nutritional Intake in Patients With Kidney Failure Treated by Haemodialysis on Dialysis and Non-dialysis Days

Introduction/Aims/ObjectiveInadequate nutritional intake in haemodialysis (HD) patients increases the risk of muscle wasting, nutrient deficiencies, leading to an increased risk of additional morbidity and mortality. We aimed to assess nutritional intake on the dialysis and non-dialysis day of patients established on HD. MethodsWe employed a two-day dietary record, one on the day of dialysis and one on the non-dialysis day, and then determined nutritional intake using the Nutritics software. Muscle strength was assessed by hand grip strength (HGS) and body composition determined using multifrequency bioelectrical impedance recorded post-dialysis. ResultsWe recruited 51 established HD patients dialysing between May-July 2022, mean age 60±15 years, 52.9% male, and 51% diabetic. Only 25% achieved the calorie and protein intake recommended by Kidney Disease Outcomes Quality Initiative (KDOQI). Most patients had inadequate consumtion of fibre (96%), calcium (86%), iron (80%), zinc (82%), selenium (92%), folate (82%), vitamin A (88%), and (100%) vitamin D. On the other hand, the great majority followed the restriction guidelines for potassium (96%), phosphorus (86%), and sodium (84%), repectively. However, consumption was greater for potassium (P=0.007), phosphorus (P=0.015), and zinc (P=0.032) on non-dialysis vs dialysis days, but there was no difference in protein or calorie intake between days. ConclusionOur results suggest that many of our HD patients do not achieve the recommended nutritional targets. Patient compliance with restricting sodium, potassium and phosphate limits protein and calorie intake. HD patients are at increased risk of sarcopenia, so failure to achieve dietary protein intake will further increase this risk.

The role of zinc and matrix metalloproteinases in myofibrillar protein degradation in critical illness myopathy

Due to an unexpected activation of different zinc (Zn) transporters in a recent prospective clinical study, we have revisited the role of Zn homeostasis and the activation of matrix metalloproteinases (MMPs) in skeletal muscle exposed to the intensive care unit (ICU) condition (immobilization and mechanical ventilation). ICU patients exposed to 12 days ICU condition were followed longitudinally with six repeated muscle biopsies while they showed a progressive preferential myosin loss, i.e., the hallmark of Critical Illness Myopathy (CIM), in parallel with the activation of Zn-transporters. In this study, we have revisited the expression of Zn-transporters and the activation of MMPs in clinical as well as in experimental studies using an established ICU model. MMPs are a group Zn-dependent endopeptidases which do not only target and cleave extracellular proteins but also intracellular proteins including multiple sarcomeric proteins. MMP-9 is of specific interest since the hallmark of CIM, the preferential myosin loss, has also been reported in dilated cardiomyopathy and coupled to MMP-9 activation. Transcriptional activation of Zn-transporters was observed in both clinical and experimental studies as well as the activation of MMPs, in particular MMP-9, in various limb and respiratory muscles in response to long-term exposure to the ICU condition. The activation of Zn-transporters was paralleled by increased Zn levels in skeletal muscle which in turn showed a negative linear correlation with the preferential myosin loss associated with CIM, offering a potential intervention strategy. Thus, activation of Zn-transporters, increased intramuscular Zn levels, and activation of the Zn-dependent MMPs are forwarded as a probable mechanism involved in CIM pathophysiology. These effects were confirmed in different rat strains subjected to a model of CIM and exacerbated by old age. This is of specific interest since old age and muscle wasting are the two factors most strongly associated with ICU mortality.

Clinical evaluation of AI-assisted muscle ultrasound for monitoring muscle wasting in ICU patients

Muscle ultrasound has been shown to be a valid and safe imaging modality to assess muscle wasting in critically ill patients in the intensive care unit (ICU). This typically involves manual delineation to measure the rectus femoris cross-sectional area (RFCSA), which is a subjective, time-consuming, and laborious task that requires significant expertise. We aimed to develop and evaluate an AI tool that performs automated recognition and measurement of RFCSA to support non-expert operators in measurement of the RFCSA using muscle ultrasound. Twenty patients were recruited between Feb 2023 and July 2023 and were randomized sequentially to operators using AI (n = 10) or non-AI (n = 10). Muscle loss during ICU stay was similar for both methods: 26 ± 15% for AI and 23 ± 11% for the non-AI, respectively (p = 0.13). In total 59 ultrasound examinations were carried out (30 without AI and 29 with AI). When assisted by our AI tool, the operators showed less variability between measurements with higher intraclass correlation coefficients (ICCs 0.999 95% CI 0.998–0.999 vs. 0.982 95% CI 0.962–0.993) and lower Bland Altman limits of agreement (± 1.9% vs. ± 6.6%) compared to not using the AI tool. The time spent on scans reduced significantly from a median of 19.6 min (IQR 16.9–21.7) to 9.4 min (IQR 7.2–11.7) compared to when using the AI tool (p < 0.001). AI-assisted muscle ultrasound removes the need for manual tracing, increases reproducibility and saves time. This system may aid monitoring muscle size in ICU patients assisting rehabilitation programmes.

Thrombospondin-4 deletion does not exacerbate muscular dystrophy in β-sarcoglycan-deficient and laminin α2 chain-deficient mice

Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or enhance the severity of a primary disease helps to understand mechanisms behind disease pathology and facilitates discovery of molecular targets for therapy. Several muscular dystrophies are caused by genetic defects in the components of the dystrophin-glycoprotein adhesion complex (DGC). Thrombospondin-4 overexpression has been shown to mitigate dystrophic disease in mouse models for Duchenne muscular dystrophy (dystrophin deficiency) and limb-girdle muscular dystrophy type 2F (LGMD2F, δ-sarcoglycan deficiency), while deletion of the thrombospondin-4 gene exacerbated the diseases. Hence, thrombospondin-4 has been considered a candidate molecule for therapy of muscular dystrophies involving the DGC. We have investigated whether thrombospondin-4 could act as a genetic modifier for other DGC-associated diseases: limb-girdle muscular dystrophy type 2E (LGMD2E, β-sarcoglycan deficiency) and laminin α2 chain-deficient muscular dystrophy (LAMA2-RD). Deletion of the thrombospondin-4 gene in mouse models for LGMD2E and LAMA2-RD, respectively, did not result in worsening of the dystrophic phenotype. Loss of thrombospondin-4 did not enhance sarcolemma damage and did not impair trafficking of transmembrane receptors integrin α7β1 and dystroglycan in double knockout muscles. Our results suggest that thrombospondin-4 might not be a relevant therapeutic target for all muscular dystrophies involving the DGC. This data also demonstrates that molecular pathology between very similar diseases like LGMD2E and 2F can differ significantly.

Acute Skeletal Muscle Wasting is Associated with Prolonged Hospital Stay in Critical Illness with Brain Injury.

Acute muscle wasting is common in critically ill patients, and this can lead to unfavorable clinical outcomes. The aim of this study was to identify factors associated with muscle wasting and to investigate the association between skeletal muscle wasting and prolonged hospital stay in critically ill patients with acute brain injury. This single-center prospective observational study was conducted in critically ill patients with acute brain injury who stayed in the intensive care unit for at least 1week. The rectus femoris cross-sectional area was measured via ultrasound at baseline and a week after the first assessment. Univariate and multivariate logistic regression analyses were performed to identify factors that predicted prolonged hospital stay. A total of 86 patients were included in the study. Their mean age was 49.4 ± 16.9years, 57% were male, and 46.5% had an admission diagnosis of subarachnoid hemorrhage. The percentage change in the rectus femoris cross-sectional area was 15.8% (95% confidence interval [CI] - 19.8% to - 12.0%; p < 0.001), and 57% of all patients had acute muscle wasting. According to the univariate analysis, there was a significant association between prolonged hospital stay and acute muscle wasting (odds ratio [OR] 3.677; 95% CI 1.487-9.043; p = 0.005), mechanical ventilation status (OR 3.600; 95% CI 1.455-8.904; p = 0.006), and Glasgow Coma Scale score (OR 0.888; 95% CI 0.808-0.976; p = 0.014) at intensive care unit admission. The multivariate analysis demonstrated that acute muscle wasting (OR 3.449; 95% CI 1.344-8.853; p = 0.010) was an independent risk factor for prolonged hospital stay. There was considerable muscle wasting in critically ill patients with brain injuries over a 1-week period. Acute muscle wasting was associated with prolonged hospital stay in critically ill patients with acute brain injury.

Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS

Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.

Comparative evaluation of screening tools for sarcopenia in patients with axial spondyloarthritis

Sarcopenia is linked to chronic inflammation and muscle wasting. This research aims to compare the screening accuracy of tools for sarcopenia in axial spondyloarthritis (axSpA). A cross-sectional study involving 104 axSpA patients was conducted at Phramongkutklao Hospital between January 2020 and February 2021. Sarcopenia was diagnosed according to the AWGS 2019 criteria. Appendicular skeletal muscle mass was measured using DXA. SARC-F, SARC-CalF, and SARC-F+EBM, muscle strength, and physical performance were assessed. The screening tests were evaluated using ROC curves. The optimal cutoffs were identified with the Youden index. Most patients were male (74%), with a mean (SD) age and disease duration of 42.6 (12.22) and 8.3 (8.5), respectively. The prevalence of sarcopenia was 22.1%. The AUCs (95% CI) for calf circumference, SARC-F, SARC-CalF, SARC-F+EBM, handgrip strength, chair stand time, gait speed, and time and go test were 0.830 (0.734, 0.925), 0.509 (0.373–0.645), 0.782 (0.670–0.894), 0.856 (0.758–0.954), 0.710 (0.594–0.825), 0.640 (0.508–0.772), 0.689 (0.539–0.839), and 0.711 (0.576–0.846), respectively. The optimal cutoffs for SARC-F, SARC-CalF, and SARC-F+EBM were 1, 10, and 10, with sensitivity/specificity of 81.0%/29.7%, 90.5%/68.9%, and 77.3%/87.2%, respectively. Calf circumference, SARC-CalF, and SARC-F+EBM had the best performance to screen for sarcopenia in axSpA patients. Lowering the thresholds would potentially enhance the performances of SARC-CalF and SARC-F+EBM.

In Vitro Models for Cancer-Associated Cachexia: The Complex Modelling of a Multiorgan Syndrome

Cancer-associated cachexia is a multifactorial syndrome characterised by systemic inflammation and hypermetabolism that affects different tissues and organs. Is characterised by progressive and irreversible weight loss, mainly due to skeletal muscle wasting and often accompanied by loss of fat mass. Due to its complexity, and lack of effective treatment, this syndrome is a sign of poor prognosis in cancer patients. Cellular models constitute a valuable and powerful tool offering insights into the molecular pathways and cellular responses associated with cancer cachexia. Currently, there are robust and widely used cell lines used to establish models to study the pathophysiology of muscle wasting and adipose tissue loss. Various methods can be used to induce the cachectic phenotype in the cells, utilising genetic engineering or different inducing agents such as hormones, inflammatory factors and chemotherapeutic drugs. The available experimental data on their metabolic properties and transcriptional and proteomic profiles allows the selection of the most suitable research model to replicate the relevant aspects of cachexia. In this review, we make an overview of the in vitro models used to study biological aspects of cancer-associated cachexia and analyse their strengths and limitations in replicating the complex physiological environment and pathological processes of the syndrome. Herein, we also briefly approach the difficulty of modelling the contribution of different organs and crosstalk between different tissues.