Prediction of lymph node metastasis in T1 colorectal cancer based on combination of body composition and vascular invasion.

OBJECTIVES: Lymph node metastasis (LNM) in colorectal cancer (CRC) patients is not only associated with the tumor's local pathological characteristics but also with systemic factors. This study aims to assess the feasibility of using body composition and pathological features to predict LNM in early stage colorectal cancer (eCRC) patients. METHODS: A total of 192 patients with T1 CRC who underwent CT scans and surgical resection were retrospectively included in the study. The cross-sectional areas of skeletal muscle, subcutaneous fat, and visceral fat at the L3 vertebral body level in CT scans were measured using Image J software. Logistic regression analysis were conducted to identify the risk factors for LNM. The predictive accuracy and discriminative ability of the indicators were evaluated using receiver operating characteristic (ROC) curves. Delong test was applied to compare area under different ROC curves. RESULTS: LNM was observed in 32 out of 192 (16.7%) patients with eCRC. Multivariate analysis revealed that the ratio of skeletal muscle area to visceral fat area (SMA/VFA) (OR = 0.021, p = 0.007) and pathological indicators of vascular invasion (OR = 4.074, p = 0.020) were independent risk factors for LNM in eCRC patients. The AUROC for SMA/VFA was determined to be 0.740 (p < 0.001), while for vascular invasion, it was 0.641 (p = 0.012). Integrating both factors into a proposed predictive model resulted in an AUROC of 0.789 (p < 0.001), indicating a substantial improvement in predictive performance compared to relying on a single pathological indicator. CONCLUSION: The combination of the SMA/VFA ratio and vascular invasion provides better prediction of LNM in eCRC.

Skeletal muscle desmin alterations following revascularization in peripheral artery disease claudicants.

Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function.

miR-27b-3p reduces muscle fibrosis during chronic skeletal muscle injury by targeting TGF-ßR1/Smad pathway.

BACKGROUND: Fibrosis is a significant pathological feature of chronic skeletal muscle injury, profoundly affecting muscle regeneration. Fibro-adipogenic progenitors (FAPs) have the ability to differentiate into myofibroblasts, acting as a primary source of extracellular matrix (ECM). the process by which FAPs differentiate into myofibroblasts during chronic skeletal muscle injury remains inadequately explored. METHOD: mouse model with sciatic nerve denervated was constructed and miRNA expression profiles between the mouse model and uninjured mouse were analyzed. qRT/PCR and immunofluorescence elucidated the effect of miR-27b-3p on fibrosis in vivo and in vitro. Dual-luciferase reporter identified the target gene of miR-27b-3p, and finally knocked down or overexpressed the target gene and phosphorylation inhibition of Smad verified the influence of downstream molecules on the abundance of miR-27b-3p and fibrogenic differentiation of FAPs. RESULT: FAPs derived from a mouse model with sciatic nerves denervated exhibited a progressively worsening fibrotic phenotype over time. Introducing agomiR-27b-3p effectively suppressed fibrosis both in vitro and in vivo. MiR-27b-3p targeted Transforming Growth Factor Beta Receptor 1 (TGF-ßR1) and the abundance of miR-27b-3p was negatively regulated by TGF-ßR1/Smad. CONCLUSION: miR-27b-3p targeting the TGF-ßR1/Smad pathway is a novel mechanism for regulating fibrogenic differentiation of FAPs. Increasing abundance of miR-27b-3p, suppressing expression of TGF-ßR1 and inhibiting phosphorylation of smad3 presented potential strategies for treating fibrosis in chronic skeletal muscle injury.

Progressive sarcopenia and myosteatosis predict prognosis of advanced HCC patients treated with immune checkpoint inhibitors.

Background: Immunotherapy stands as a pivotal modality in the therapeutic landscape for the treatment of advanced hepatocellular carcinoma, yet responses vary among patients. This study delves into the potential impact of sarcopenia, myosteatosis and adiposity indicators, as well as their changes during immunotherapy, on treatment response and prognosis in patients with advanced hepatocellular carcinoma treated with immune checkpoint inhibitors. Methods: In this retrospective analysis, 116 patients with advanced hepatocellular carcinoma receiving immune checkpoint inhibitors were recruited. Skeletal muscle, intramuscular, subcutaneous, and visceral adipose tissue were assessed by computed tomography at the level of the third lumbar vertebrae before and after 3 months of treatment. Sarcopenia and myosteatosis were evaluated by skeletal muscle index and mean muscle density using predefined threshold values. Patients were stratified based on specific baseline values or median values, along with alterations observed during the treatment course. Overall survival (OS) and progression-free survival (PFS) were compared using the log-rank test and a multifactorial Cox proportional risk model. Results: A total of 116 patients were recruited and divided into two cohorts, 81 patients for the training set and 35 patients for the validating set. In the overall cohort, progressive sarcopenia (P=0.021) and progressive myosteatosis (P=0.001) were associated with objective response rates, whereas progressive myosteatosis (P<0.001) was associated with disease control rates. In the training set, baseline sarcopenia, myosteatosis, and subcutaneous and visceral adipose tissue were not significantly associated with PFS and OS. In multivariate analysis adjusting for sex, age, and other factors, progressive sarcopenia(P=0.002) and myosteatosis (P=0.018) remained independent predictors of PFS. Progressive sarcopenia (P=0.005), performance status (P=0.006) and visceral adipose tissue index (P=0.001) were all independent predictors of OS. The predictive models developed in the training set also had good feasibility in the validating set. Conclusion: Progressive sarcopenia and myosteatosis are predictors of poor clinical outcomes in patients with advanced hepatocellular carcinoma receiving immune checkpoint inhibitors, and high baseline visceral adiposity is associated with a poorer survival.

A therapeutic leap: how myosin inhibitors moved from cardiac interventions to skeletal muscle myopathy solutions.

The myosin inhibitor mavacamten has transformed the management of obstructive hypertrophic cardiomyopathy (HCM) by targeting myosin ATPase activity to mitigate cardiac hypercontractility. This therapeutic mechanism has proven effective for patients with HCM independent of having a primary gene mutation in myosin. In this issue of the JCI, Buvoli et al. report that muscle hypercontractility is a mechanism of pathogenesis underlying muscle dysfunction in Laing distal myopathy, a disorder characterized by mutations altering the rod domain of ß myosin heavy chain. The authors performed detailed physiological, molecular, and biomechanical analyses and demonstrated that myosin ATPase inhibition can correct a large extent of muscle abnormalities. The findings offer a therapeutic avenue for Laing distal myopathy and potentially other myopathies. This Commentary underscores the importance of reevaluating myosin activity's role across myopathies in general for the potential development of targeted myosin inhibitors to treat skeletal muscle disorders.

A Laing distal myopathy-associated proline substitution in the ß-myosin rod perturbs myosin cross-bridging activity.

Proline substitutions within the coiled-coil rod region of the ß-myosin gene (MYH7) are the predominant mutations causing Laing distal myopathy (MPD1), an autosomal dominant disorder characterized by progressive weakness of distal/proximal muscles. We report that the MDP1 mutation R1500P, studied in what we believe to be the first mouse model for the disease, adversely affected myosin motor activity despite being in the structural rod domain that directs thick filament assembly. Contractility experiments carried out on isolated mutant muscles, myofibrils, and myofibers identified muscle fatigue and weakness phenotypes, an increased rate of actin-myosin detachment, and a conformational shift of the myosin heads toward the more reactive disordered relaxed (DRX) state, causing hypercontractility and greater ATP consumption. Similarly, molecular analysis of muscle biopsies from patients with MPD1 revealed a significant increase in sarcomeric DRX content, as observed in a subset of myosin motor domain mutations causing hypertrophic cardiomyopathy. Finally, oral administration of MYK-581, a small molecule that decreases the population of heads in the DRX configuration, significantly improved the limited running capacity of the R1500P-transgenic mice and corrected the increased DRX state of the myofibrils from patients. These studies provide evidence of the molecular pathogenesis of proline rod mutations and lay the groundwork for the therapeutic advancement of myosin modulators.

Muscle mass as a modifier of stress response in acute ischemic stroke patients.

Stroke triggers a systemic inflammatory response over the ensuing days after the cerebral insult. The age and comorbidities of the stroke population make them a vulnerable population for low muscle mass and sarcopenia, the latter being another clinical condition that is closely associated with inflammation, as shown by increased levels of pro-inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR). In this study, we evaluated the relationship between post-stroke NLR changes and muscle mass in a prospective cohort of acute ischemic stroke patients (n = 102) enrolled in the Muscle Assessment in Stroke Study Turkey (MASS-TR). Admission lumbar computed tomography images were used to determine the cross-sectional muscle area of skeletal muscles at L3 vertebra level and calculate the skeletal muscle index (SMI). The median (IQR) SMI was 44.7 (39.1-52.5) cm2/m2, and the NLR at admission and follow-up were 4.2 (3.0-10.5) and 9.4 (5.7-16.2), respectively. While there was no relationship between SMI and admission NLR, a significant inverse correlation was observed between SMI and follow-up NLR (r = - 0.26; P = 0.007). Lower SMI remained significantly associated (P = 0.036) with higher follow-up NLR levels in multivariate analysis. Our findings highlight the importance of muscle mass as a novel factor related to the level of post-stroke stress response.

Electrical Stimulation-Based Twitch Exercise Suppresses Progression of Immobilization-Induced Muscle Fibrosis via Downregulation of PGC-1?/VEGF Pathway.

This study aimed to determine whether electrical stimulation-based twitch exercise is effective in inhibiting the progression of immobilization-induced muscle fibrosis. 19 Wistar rats were randomly divided into a control group (n=6), an immobilization group (n=6; with immobilization only), and a Belt group (n=7; with immobilization and twitch exercise through the belt electrode device, beginning 2 weeks after immobilization). The bilateral soleus muscles were harvested after the experimental period. The right soleus muscles were used for histological analysis, and the left soleus muscles were used for biochemical and molecular biological analysis. As a result, in the picrosirius red images, the perimysium and endomysium were thicker in both the immobilization and Belt groups compared to the control group. However, the perimysium and endomysium thickening were suppressed in the Belt group. The hydroxyproline content and alpha-SMA, TGF-beta1, and HIF-1alpha mRNA expressions were significantly higher in the immobilization and belt groups than in the control group. These expressions were significantly lower in the Belt group than in the immobilization group. The capillary-to-myofiber ratio and the mRNA expressions of VEGF and PGC-1alpha were significantly lower in the immobilization and belt groups than in the control group, these were significantly higher in the Belt group than in the immobilization group. From these results, Electrical stimulation-based twitch exercise using the belt electrode device may prevent the progression of immobilization-induced muscle fibrosis caused by downregulating PGC-1alpha/VEGF pathway, we surmised that this intervention strategy might be effective against the progression of muscle contracture. Keywords: Immobilization, Skeletal muscle, Fibrosis, Electrical stimulation-based twitch exercise, PGC-1alpha/VEGF pathway.

CaMKIIß deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I.

BACKGROUND: Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown. METHODS: We compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1. RESULTS: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIß/ßM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation. CONCLUSIONS: Our results indicate that CaMKIIß-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.

Low skeletal muscle mass predicts melanoma-specific survival in melanoma patients treated with adjuvant immune checkpoint blockade.

PURPOSE: Adjuvant immunotherapy with immune checkpoint blockade(ICB) has greatly reduced the risk of recurrence and metastatic spread in early and advanced melanoma. However, not all patients benefit from adjuvant treatment: many patients show disease recurrence despite therapy, while those without recurrence harbor the risk for potentially irreversible adverse events. Biomarkers to select patients benefitting most from adjuvant therapy are currently lacking. As body composition assessment using CT images has shown promising results as a prognostic biomarker in stage IV melanoma, we aim to study the applicability of body composition parameters also in adjuvant melanoma treatment. METHODS: We analyze body composition features via CT scans in a retrospective cohort of 109 patients with resected stage IIB-IV melanoma receiving an adjuvant first-line treatment with ICB in our department. In this analysis, we focus on the impact of body composition, especially the presence of low skeletal muscle mass (LSMM), on patients' survival and occurrence of adverse events (AEs). RESULTS: In uni- and multivariate analyses, we identify an association between CT-measured LSMM and melanoma-specific survival in patients treated with adjuvant ICB. Furthermore, LSMM is associated with a lower risk for therapy-related AEs, especially hypothyroidism, fatigue, and xerostomia. Conventional serological biomarkers e.g. S100 and LDH and measures of adipose tissue compartments did not show a correlation with survival or the occurrence of AEs. CONCLUSIONS: LSMM constitutes a novel biomarker for melanoma-specific survival in patients treated with adjuvant ICB.

The impact of skeletal muscle index at the third lumbar spine on nosocomial deterioration and short-term prognosis in acute pancreatitis: a retrospective observational study.

Objective: To investigate the impact of the third lumbar skeletal muscle index (L3-SMI) assessed by CT on the in-hospital severity and short-term prognosis of acute pancreatitis. Methods: A total of 224 patients with severe acute pancreatitis admitted to Yantaishan Hospital from January 2021 to June 2022 were selected as the subjects. Based on the in-hospital treatment outcomes, they were divided into a mortality group of 59 cases as well as a survival group of 165 cases. Upon admission, general information such as the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, along with the abdominal CT images of each patient, were analyzed. The L3-SMI was calculated, and the Modified CT Severity Index (MCTSI) and Balthazar CT grade were used to assess the severity of in-hospital complications of acute pancreatitis. The evaluation value of L3-SMI for the prognosis of severe acute pancreatitis was analyzed, as well as the factors influencing the prognosis of severe acute pancreatitis. Results: No statistically significant differences in gender, age, BMI, etiology, duration of anti-inflammatory drug use, and proportion of surgical patients between the survival and mortality groups were observed. But the mortality group showed higher proportions of patients with an elevated APACHE II score upon admission, mechanical ventilation, and renal replacement therapy, compared to the survival group, with statistically significant differences (P < 0.001). Furthermore, the mortality group had higher MCTSI scores (6.42 ± 0.69) and Balthazar CT grades (3.78 ± 0.45) than the survival group, with statistically significant differences (P < 0.001). The mortality group also had a lower L3-SMI (39.68 ± 3.25) compared to the survival group (42.71 ± 4.28), with statistically significant differences (P < 0.001). L3-SMI exhibited a negative correlation with MCTSI scores and Balthazar CT grades (r = -0.889, -0.790, P < 0.001). Logistic regression analysis, with mortality of acute pancreatitis patients as the dependent variable and MCTSI scores, Balthazar CT grades, L3-SMI, APACHE II score upon admission, mechanical ventilation, and renal replacement therapy as independent variables, revealed that MCTSI scores and L3-SMI were risk factors for mortality in acute pancreatitis patients (P < 0.001). Logistic regression analysis using the same variables confirmed that all these factors were risk factors for mortality in acute pancreatitis patients. Conclusion: This study confirmed that diagnosing muscle depletion using L3-SMI is a valuable radiological parameter for predicting in-hospital severity and short-term prognosis in patients with acute pancreatitis.

Association of low muscle mass with cognitive function and mortality in USA seniors: results from NHANES 1999-2002.

BACKGROUND: Sarcopenia and cognitive impairment have been linked in prior research, and both are linked to an increased risk of mortality in the general population. Muscle mass is a key factor in the diagnosis of sarcopenia. The relationship between low muscle mass and cognitive function in the aged population, and their combined impact on the risk of death in older adults, is currently unknown. This study aimed to explore the correlation between low muscle mass and cognitive function in the older population, and the relationship between the two and mortality in older people. METHODS: Data were from the National Health and Nutrition Examination Survey 1999-2002. A total of 2540 older adults aged 60 and older with body composition measures were included. Specifically, 17-21 years of follow-up were conducted on every participant. Low muscle mass was defined using the Foundation for the National Institute of Health and the Asian Working Group for Sarcopenia definitions: appendicular lean mass (ALM) (< 19.75 kg for males; <15.02 kg for females); or ALM divided by body mass index (BMI) (ALM: BMI, < 0.789 for males; <0.512 for females); or appendicular skeletal muscle mass index (ASMI) (< 7.0 kg/m2 for males; <5.4 kg/m2 for females). Cognitive functioning was assessed by the Digit Symbol Substitution Test (DSST). The follow-up period was calculated from the NHANES interview date to the date of death or censoring (December 31, 2019). RESULTS: We identified 2540 subjects. The mean age was 70.43 years (43.3% male). Age-related declines in DSST scores were observed. People with low muscle mass showed lower DSST scores than people with normal muscle mass across all age groups, especially in the group with low muscle mass characterized by ALM: BMI (60-69 years: p < 0.001; 70-79 years: p < 0.001; 80 + years: p = 0.009). Low muscle mass was significantly associated with lower DSST scores after adjusting for covariates (ALM: 43.56 ± 18.36 vs. 47.56 ± 17.44, p < 0.001; ALM: BMI: 39.88 ± 17.51 vs. 47.70 ± 17.51, p < 0.001; ASMI: 41.07 ± 17.89 vs. 47.42 ± 17.55, p < 0.001). At a mean long-term follow-up of 157.8 months, those with low muscle mass were associated with higher all-cause mortality (ALM: OR 1.460, 95% CI 1.456-1.463; ALM: BMI: OR 1.452, 95% CI 1.448-1.457); ASMI: OR 3.075, 95% CI 3.063-3.088). In the ALM: BMI and ASMI-defined low muscle mass groups, participants with low muscle mass and lower DSST scores were more likely to incur all-cause mortality ( ALM: BMI: OR 0.972, 95% CI 0.972-0.972; ASMI: OR 0.957, 95% CI 0.956-0.957). CONCLUSIONS: Low muscle mass and cognitive function impairment are significantly correlated in the older population. Additionally, low muscle mass and low DSST score, alone or in combination, could be risk factors for mortality in older adults.

Examining variations in body composition among patients with colorectal cancer according to site and disease stage.

Patients with colorectal cancer (CRC) often exhibit changes in body composition (BC) which are associated with poorer clinical outcomes. Many studies group colon and rectal cancers together, irrespective of staging, potentially affecting assessment and treatment strategies. Our study aimed to compare BC in patients with CRC focusing on tumor location and metastasis presence. A total of 635 individuals were evaluated, with a mean age of 61.8 ± 12.4 years and 50.2% female. The majority had rectal cancer as the primary cancer site (51.0%), and 23.6% had metastatic disease. The first regression model showed tumor site and metastasis as independent factors influencing skeletal muscle (SM), skeletal muscle index (SMI), and visceral adipose tissue variability (all p values < 0.05). The second model, adjusted for BMI, indicated tumor site as the primary factor affecting SMI variations (adjusted R2 = 0.50 p < 0.001), with colon tumors inversely associated with SM (standardized ß - 2.15(- 3.3; - 0.9) p < 0.001). A third model, considering all the confounders from the directed acyclic graphs, was constructed and the found association remained independent. Our findings highlight significant BC variations in patients with CRC, influenced by tumor location and metastases presence, underscoring the need for location-specific assessment in CRC management.

Decreased Left Ventricular Mass is Associated with Sarcopenia and its Severity in Elderly Inpatients.

Objective: Skeletal muscle mass and cardiac structure change with age. It is unclear whether the loss of skeletal muscle mass (SMM) is accompanied by a decrease in heart mass loss. The aim of this study is to investigate the relationship of left ventricular mass (LVM) with sarcopenia and its severity in elderly inpatients. Methods: Seventy-one sarcopenia subjects and 103 non-sarcopenia controls were enrolled in this study. Bioelectrical impedance analysis, handgrip strength, and 5-time chair stand test were used to evaluate SMM, muscle strength, and physical performance, respectively. Myocardial structure and function were assessed by echocardiography. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia criteria 2019. Results: Sarcopenic patients had smaller left ventricular sizes and LVM than non-sarcopenic controls. Severe sarcopenic patients had smaller left ventricular sizes and LVM than non-severe sarcopenic patients. In univariate regression analysis, body mass index (BMI), cardiac size, and LVM were positively correlated with SMM or SMI. In multivariate regression analysis, BMI and LVM were independently correlated with SMM and SMI. The combined measurement of LVM and BMI predicts sarcopenia with 66.0% sensitivity and 88.7% specificity (AUC: 0.825; 95% CI: (0.761, 0.889); p < 0.001). Conclusion: In hospitalized elderly patients, decreased left ventricular mass is associated with sarcopenia and its severity, and the combined measurement of LVM and BMI has a predictive value for sarcopenia.

Comparison of different 2D muscle indexes measured at the level of the 3rd lumbar vertebra in survival prediction in patients with renal cell carcinoma.

BACKGROUND: Low computed tomography (CT)-determined muscle mass, commonly determined with height-adjusted muscle indexes (MIs), predicts worse survival in several cancers and has been suggested as a prognostic assessment tool. Although several MIs measured at the level of the 3rd lumbar vertebra (L3) are commonly used, it remains unestablished how different L3-determined MIs perform in survival prognostication compared to each other. The objective of this study was to investigate the performance of different MIs for survival prognostication in renal cell carcinoma (RCC). METHODS: We retrospectively enrolled 214 consecutive patients with RCC. We determined three L3-MIs (psoas muscle index (PMI), psoas muscle index and erector spinae index (PMI+ESI), and whole skeletal muscle index (SMI)) from preoperative CT scans. Categorization of those with low and normal muscle mass was based on the Youden Index sex-specific MI cut-offs. We determined sensitivity, specificity, and accuracy metrics for predicting 1-year, 5-year, and overall survival (OS) using Cox regression models. RESULTS: Low PMI, PMI+ESI, and SMI significantly predicted decreased 1-year, 5-year, and OS in uni- and multivariate models. PMI+ESI and SMI were more accurate than PMI in males, and PMI and PMI+ESI were more accurate than SMI in females in the prediction of 1-year survival. However, there were no differences in accuracies between MIs in 5-year and OS prediction. INTERPRETATION: PMI+ESI performed well overall in short-term prognostication, but there were no differences between the MIs in long-term prognostication. We recommend the use of PMI+ESI for muscle evaluation, particularly when SMI cannot be evaluated.

Systemic LPS Administration Stimulates the Activation of Non-Neuronal Cells in an Experimental Model of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deficiency of the survival motor neuron (SMN) protein. Although SMA is a genetic disease, environmental factors contribute to disease progression. Common pathogen components such as lipopolysaccharides (LPS) are considered significant contributors to inflammation and have been associated with muscle atrophy, which is considered a hallmark of SMA. In this study, we used the SMNΔ7 experimental mouse model of SMA to scrutinize the effect of systemic LPS administration, a strong pro-inflammatory stimulus, on disease outcome. Systemic LPS administration promoted a reduction in SMN expression levels in CNS, peripheral lymphoid organs, and skeletal muscles. Moreover, peripheral tissues were more vulnerable to LPS-induced damage compared to CNS tissues. Furthermore, systemic LPS administration resulted in a profound increase in microglia and astrocytes with reactive phenotypes in the CNS of SMNΔ7 mice. In conclusion, we hereby show for the first time that systemic LPS administration, although it may not precipitate alterations in terms of deficits of motor functions in a mouse model of SMA, it may, however, lead to a reduction in the SMN protein expression levels in the skeletal muscles and the CNS, thus promoting synapse damage and glial cells' reactive phenotype.

System-level analysis of genes mutated in muscular dystrophies reveals a functional pattern associated with muscle weakness distribution.

Muscular dystrophies (MDs) are inherited genetic diseases causing weakness and degeneration of muscles. The distribution of muscle weakness differs between MDs, involving distal muscles or proximal muscles. While the mutations in most of the MD-associated genes lead to either distal or proximal onset, there are also genes whose mutations can cause both types of onsets. We hypothesized that the genes associated with different MD onsets code proteins with distinct cellular functions. To investigate this, we collected the MD-associated genes and assigned them to three onset groups: genes mutated only in distal onset dystrophies, genes mutated only in proximal onset dystrophies, and genes mutated in both types of onsets. We then systematically evaluated the cellular functions of these gene sets with computational strategies based on functional enrichment analysis and biological network analysis. Our analyses demonstrate that genes mutated in either distal or proximal onset MDs code proteins linked with two distinct sets of cellular processes. Interestingly, these two sets of cellular processes are relevant for the genes that are associated with both onsets. Moreover, the genes associated with both onsets display high centrality and connectivity in the network of muscular dystrophy genes. Our findings support the hypothesis that the proteins associated with distal or proximal onsets have distinct functional characteristics, whereas the proteins associated with both onsets are multifunctional.

Association between the skeletal muscle mass to visceral fat area ratio and metabolic dysfunction-associated fatty liver disease: A cross-sectional study of NHANES 2017-2018.

BACKGROUND AND AIMS: Previous studies have shown that sarcopenic obesity (SO) was associated with nonalcoholic fatty liver disease (NAFLD). However, research is limited in the context of the NAFLD renamed as metabolic dysfunction-associated steatotic liver disease (MASLD) defined by updated diagnostic criteria. The aim of this study was to use the index skeletal muscle mass to visceral fat area ratio (SVR) to describe SO in a large and representative US population (National Health and Nutrition Examination Survey 2017-2018) of adults and investigate their association with MASLD. METHODS: A total of 2087 individuals were included in the analysis. SVR was calculated according to the measurement of dual-energy x-ray absorptiometry and MASLD was diagnosed with controlled attenuation parameter scores and cardiometabolic risk factors. SVR was divided into tertiles. Logistic regression adjusted for confounders was used to evaluate the association between SVR and MASLD. Several sensitivity analyses were performed to test the robustness of our findings. RESULTS: In a multivariate logistic regression analysis, a significant association between SVR and MASLD was shown (odds ratio [OR]: 3.11, 95% confidence interval [CI]: 1.31-7.39, p = .010 for middle levels of SVR; OR: 3.82, 95% CI: 1.45-10.08, p = .007 for lowest levels of SVR). The sensitivity analyses confirmed that the association was robust. CONCLUSION: Our findings imply that decreased SVR is linked to MASLD.

Impairments in peroneal muscle size and activation in individuals with patellofemoral pain in weight-bearing position.

BACKGROUND: Patellofemoral pain (PFP) is characterized by chronic pain in the anterior aspect of the knee during loading activities. Many studies investigating muscle morphology changes for individuals with PFP focus on the proximal joints, however, few studies have investigated muscles of the foot and ankle complex. This study aimed to explore the differences in peroneal muscle size and activation between individuals with PFP and healthy controls using ultrasound imaging in weight-bearing. METHODS: A case-control study in a university lab setting was conducted. Thirty individuals with PFP (age: 20.23 ± 3.30 years, mass: 74.70 ± 27.63 kgs, height: 161.32 ± 11.72 cm) and 30 healthy individuals (age: 20.33 ± 3.37 years, mass: 64.02 ± 11.00 kgs, height: 169.31 ± 9.30 cm) participated. Cross-sectional area (CSA) images of the peroneal muscles were taken in non-weight bearing and weight-bearing positions. The functional activation ratio from lying to single-leg standing (SLS) was calculated. RESULTS: There was a statistically significant (p = 0.041) group (PFP, healthy) by position (non-weight-bearing, weight-bearing) interaction for the peroneal muscle CSA with a Cohen's d effect size of 0.2 in non-weight-bearing position and 0.7 in weight-bearing position. The functional activation ratio for the healthy group was significantly more (p = 0.01) than the PFP group. CONCLUSION: Peroneal muscles were found to be smaller in size in those with PFP compared to the healthy subjects in the weight-bearing SLS position. This study found that those with PFP have lower activation of peroneal muscles in functional position.

Failure of Autophagy in Pompe Disease.

Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles. The autophagic pathway is largely responsible for the delivery of cytosolic glycogen to the lysosome where it is degraded to glucose via acid α-glucosidase. Although the physiological role of lysosomal glycogenolysis is not fully understood, its significance is highlighted by the manifestations of Pompe disease, which is caused by a deficiency of this lysosomal enzyme. Pompe disease is a severe lysosomal glycogen storage disorder that affects skeletal and cardiac muscles most. In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. Finally, we outline how autophagic pathology in the diseased muscles can be used as a tool to fast track the efficacy of therapeutic interventions.