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Research Square Jun 2024Interstitial cells of Cajal (ICC) and PDGFRα cells regulate smooth muscle motility in the gastrointestinal (GI) tract. However, their role(s) in esophageal motility...
Interstitial cells of Cajal (ICC) and PDGFRα cells regulate smooth muscle motility in the gastrointestinal (GI) tract. However, their role(s) in esophageal motility are still unclear. The mouse esophagus has traditionally been described as almost entirely skeletal muscle in nature though ICC have been identified along its entire length. The current study evaluated the distribution of skeletal and smooth muscle within the esophagus using a mouse selectively expressing eGFP in smooth muscle cells (SMCs). The relationship of SMCs to ICC and PDGFRα cells was also examined. SMCs declined in density in the oral direction however SMCs represented ~ 25% of the area in the distal esophagus suggesting a likeness to the transition zone observed in humans. ANO1 intramuscular ICC (ICC-IM) were distributed along the length of the esophagus though like SMCs, declined proximally. ICC-IM were closely associated with SMCs but were also found in regions devoid of SMCs. Intramuscular and submucosal PDGFRα cells were densely distributed throughout the esophagus though only intramuscular PDGFRα cells within the LES and distal esophagus highly expressed SK3. ICC-IM and PDGFRα cells were closely associated with nNOS , VIP , VAChT and TH neurons throughout the LES and distal esophagus. GFAP cells resembling intramuscular enteric glia were observed within the muscle and were closely associated with ICC-IM and PDGFRα cells, occupying a similar location to motor nerve fibers. These data suggest that the mouse esophagus is more similar to the human than thought previously and thus set the foundation for future functional and molecular studies using transgenic mice.
PubMed: 38947055
DOI: 10.21203/rs.3.rs-4474290/v1 -
Diabetes, Metabolic Syndrome and... 2024Growing evidence indicates that there is a close relationship between type 2 diabetes mellitus (T2DM) and sarcopenia, and T2DM patients are often accompanied by obesity....
Importance of Assessing Sarcopenia in Patients with Type 2 Diabetes Mellitus Based on Body Fat Percentage Measured by Dual-Energy X-Ray Absorptiometry in Different Genders.
BACKGROUND
Growing evidence indicates that there is a close relationship between type 2 diabetes mellitus (T2DM) and sarcopenia, and T2DM patients are often accompanied by obesity. However, research exploring the connection between body fat percentage (BFP) and sarcopenia is currently limited.
METHODS
This was a cross-sectional study that included 676 patients with T2DM over 50 years old. The appendicular skeletal muscle mass index (ASMI), handgrip strength, and 5-time chair stand test (5-TCST) were measured, and sarcopenia was diagnosed according to the Asian Working Group on Sarcopenia (AWGS). Spearman's coefficient was used to evaluate the correlation of BFP and body mass index (BMI) with the diagnostic elements of sarcopenia, and BFP and other relevant covariates were included in the binary logistic regression model. The subgroup performed an interaction test for statistically significant population baseline information.
RESULTS
The prevalence of sarcopenia was 18.0% in males and 11.6% in females. Spearman correlation analysis showed that BFP was positively correlated with ASMI in women (=0.107, =0.029), but not in men. BFP was negatively correlated with grip strength (male: = -0.187, =0.003; female: =-0.108, =0.029). There was a positive correlation between BFP and 5-TCST (male: =0.199, =0.001; female: =0.144, =0.003). After adjusting for confounding factors, BFP was an independent risk factor for sarcopenia (men, OR: 1.33, 95% CI: 1.15-1.54; women, OR: 1.26, 95% CI: 1.13-1.41). This correlation was generally consistent, as demonstrated in further subgroup analyses.
CONCLUSION
High BFP was significantly associated with sarcopenia risk, and this association was independent of gender, age, and BMI.
PubMed: 38946913
DOI: 10.2147/DMSO.S461748 -
Analytical Cellular Pathology... 2024Osteochondral defects (OCDs) are localized areas of damaged cartilage and underlying subchondral bone that can produce pain and seriously impair joint function....
Synergistic Effects of Icariin and Extracellular Vesicles Derived from Rabbit Synovial Membrane-Derived Mesenchymal Stem Cells on Osteochondral Repair via the Wnt/-Catenin Pathway.
OBJECTIVES
Osteochondral defects (OCDs) are localized areas of damaged cartilage and underlying subchondral bone that can produce pain and seriously impair joint function. Literature reports indicated that icariin (ICA) has the effect of promoting cartilage repair. However, its mechanism remains unclear. Here, we explored the effects of icariin and extracellular vesicles (EVs) from rabbit synovial-derived mesenchymal stem cells (rSMSCs) on repairing of OCDs.
MATERIALS AND METHODS
Rabbit primary genicular chondrocytes (rPGCs), knee skeletal muscle cells (rSMCKs), and rSMSCs, and extracellular vesicles derived from the latter two cells (rSMCK-EVs and rSMSC-EVs) were isolated and identified. The rPGCs were stimulated with ICA, rSMSC-EVs either separately or in combination. The rSMCK-EVs were used as a control. After stimulation, chondrogenic-related markers were analyzed by quantitative RT-PCR and western blotting. Cell proliferation was determined by the CCK-8 assay. The preventative effects of ICA and SMSC-EVs were determined by H&E and toluidine blue staining. Immunohistochemical analyses were performed to evaluate the levels of COL2A1 and -catenin . , the proliferation of rPGCs was markedly increased by ICA treatment in a dose-dependent manner. When compared with ICA or rSMSC-EVs treatment alone, combined treatment with ICA and SMSC-EVs produced stronger stimulative effects on cell proliferation. Moreover, combined treatment with ICA and rSMSC-EVs promoted the expression of chondrogenic-related gene, including COL2A1, SOX-9, and RUNX2, which may be via the activation of the Wnt/-catenin pathway. , combined treatment with rSMSC-EVs and ICA promoted cartilage repair in joint bone defects. Results also showed that ICA or rSMSC-EVs both promoted the COL2A1 and -catenin protein accumulation in articular cartilage, and that was further enhanced by combined treatment with rSMSC-EVs and ICA.
CONCLUSION
Our findings highlight the promising potential of using combined treatment with ICA and rSMSC-EVs for promoting osteochondral repair.
Topics: Animals; Rabbits; Flavonoids; Mesenchymal Stem Cells; Wnt Signaling Pathway; Extracellular Vesicles; Chondrocytes; Synovial Membrane; Chondrogenesis; Cell Proliferation; beta Catenin; Cartilage, Articular
PubMed: 38946863
DOI: 10.1155/2024/1083143 -
Journal of Hepatocellular Carcinoma 2024The impact of visceral adiposity on overall survival (OS) in hepatocellular carcinoma (HCC) receiving immunotherapy was unclear. We aimed to determine how visceral...
PURPOSE
The impact of visceral adiposity on overall survival (OS) in hepatocellular carcinoma (HCC) receiving immunotherapy was unclear. We aimed to determine how visceral adiposity affected OS and explore the interrelationships between visceral adiposity, body mass index (BMI), and other body compositions.
PATIENTS AND METHODS
Data from three centers were retrospectively analyzed. Skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI) were used to define each body composition. The BMI subgroups included the underweight, the normal weight, and the obesity. The Log rank test compared survival curves calculated by the Kaplan-Meier method. The relationships between body compositions and BMI with OS were examined using Cox proportional risk regression models.
RESULTS
A total of 305 patients who met the criteria were included. Patients with low VATI had significantly worse OS ( = 0.001). The protections of VATI ( = 0.011) on OS were independent of covariates. However, after additional adjustment of SMI, the effect of VATI on OS disappeared ( = 0.146), but the effect of SMD on OS did not ( = 0.021). BMI has a significant U-shaped relationship with OS, and the effect of BMI on OS equally disappeared after additional adjustment by SMI.
CONCLUSION
This study first demonstrated that high VATI and mid-level BMI were protective for the survival of patients with HCC receiving immunotherapy. Skeletal muscle status (including SMI and SMD) may be the better predictor for outcomes of patients with HCC receiving immunotherapy.
PubMed: 38946842
DOI: 10.2147/JHC.S453262 -
Frontiers in Cell and Developmental... 2024Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic...
INTRODUCTION
Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic inflammation during growth, resulting in progressive generalized weakness of the skeletal and cardiac muscles. We previously demonstrated the therapeutic effects of systemic administration of dental pulp mesenchymal stromal cells (DPSCs) in a DMD animal model. We showed preservation of long-term muscle function and slowing of disease progression. However, little is known regarding the effects of cell therapy on the metabolic abnormalities in DMD. Therefore, here, we aimed to investigate the mechanisms underlying the immunosuppressive effects of DPSCs and their influence on DMD metabolism.
METHODS
A comprehensive metabolomics-based approach was employed, and an ingenuity pathway analysis was performed to identify dystrophy-specific metabolomic impairments in the mice to assess the therapeutic response to our established systemic DPSC-mediated cell therapy approach.
RESULTS AND DISCUSSION
We identified DMD-specific impairments in metabolites and their responses to systemic DPSC treatment. Our results demonstrate the feasibility of the metabolomics-based approach and provide insights into the therapeutic effects of DPSCs in DMD. Our findings could help to identify molecular marker targets for therapeutic intervention and predict long-term therapeutic efficacy.
PubMed: 38946797
DOI: 10.3389/fcell.2024.1363541 -
Journal of Experimental Zoology. Part... Jul 2024Vertebrate animals that run or jump across sparsely vegetated habitats, such as horses and jerboas, have reduced the number of distal limb bones, and many have lost most...
Vertebrate animals that run or jump across sparsely vegetated habitats, such as horses and jerboas, have reduced the number of distal limb bones, and many have lost most or all distal limb muscle. We previously showed that nascent muscles are present in the jerboa hindfoot at birth and that these myofibers are rapidly and completely lost soon after by a process that shares features with pathological skeletal muscle atrophy. Here, we apply an intra- and interspecies differential RNA-Seq approach, comparing jerboa and mouse muscles, to identify gene expression differences associated with the initiation and progression of jerboa hindfoot muscle loss. We show evidence for reduced hepatocyte growth factor and fibroblast growth factor signaling and an imbalance in nitric oxide signaling; all are pathways that are necessary for skeletal muscle development and regeneration. We also find evidence for phagosome formation, which hints at how myofibers may be removed by autophagy or by nonprofessional phagocytes without evidence for cell death or immune cell activation. Last, we show significant overlap between genes associated with jerboa hindfoot muscle loss and genes that are differentially expressed in a variety of human muscle pathologies and rodent models of muscle loss disorders. All together, these data provide molecular insight into the process of evolutionary and developmental muscle loss in jerboa hindfeet.
PubMed: 38946691
DOI: 10.1002/jez.b.23268 -
Physiological Reports Jul 2024Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle...
Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.
Topics: Animals; Cachexia; Sirtuin 1; Muscle Fibers, Skeletal; Mice; Oxidative Stress; Mice, Inbred C57BL; Carcinoma, Lewis Lung; Male; Heterocyclic Compounds, 4 or More Rings; Mitochondria, Muscle; Cell Line; Niacin; Mitochondria; Reactive Oxygen Species
PubMed: 38946587
DOI: 10.14814/phy2.16103 -
Circulation Research Jul 2024Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise...
BACKGROUND
Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism.
OBJECTIVE
To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac and skeletal myopathy.
METHODS AND RESULTS
High glucose promoted translocation of MondoA into the nucleus, which upregulated transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial expression in multiple types of mouse models of diabetes. We then analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. However, deletion of augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that -knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type (WT) animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression (beyond levels observed during diabetes) using adenoassociated virus suggests that high levels of myocardial have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1.
CONCLUSIONS
ARRDC4 serves as a regulator of hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.
PubMed: 38946541
DOI: 10.1161/CIRCRESAHA.123.323158 -
Free Radical Research Jul 2024It is well known that the adaptations of muscular antioxidant system to aerobic exercise depend on the frequency, intensity, duration, type of the exercise. Nonetheless,...
It is well known that the adaptations of muscular antioxidant system to aerobic exercise depend on the frequency, intensity, duration, type of the exercise. Nonetheless, the timing of aerobic exercise, related to circadian rhythms or biological clock, may also affect the antioxidant defense system, but its impact remains uncertain. Bain and muscle ARNT-like 1 (BMAL1) is the core orchestrator of molecular clock, which can maintain cellular redox homeostasis by directly controlling the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2). So, our research objective was to evaluate the impacts of aerobic exercise training at various time points of the day on BMAL1 and NRF2-mediated antioxidant system in skeletal muscle. C57BL/6J mice were assigned to the control group, the group exercising at Zeitgeber Time 12 (ZT12), and the group exercising at ZT24. Control mice were not intervened, while ZT12 and ZT24 mice were trained for four weeks at the early and late time point of their active phase, respectively. We observed that the skeletal muscle of ZT12 mice exhibited higher total antioxidant capacity and lower reactive oxygen species compared to ZT24 mice. Furthermore, ZT12 mice improved the colocalization of BMAL1 with nucleus, the protein expression of BMAL1, NRF2, NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, glutamate-cysteine ligase modifier subunit and glutathione reductase in comparison to those of ZT24 mice. In conclusion, the 4-week aerobic training performed at ZT12 is more effective for enhancing NRF2-mediated antioxidant responses of skeletal muscle, which may be attributed to the specific activation of BMAL1.
PubMed: 38946540
DOI: 10.1080/10715762.2024.2348789 -
European Review For Medical and... Jun 2024Sarcopenia is a condition characterized by muscle mass loss. Skeletal muscle is capable of producing and secreting different molecules called myokines, and apelin is one...
OBJECTIVE
Sarcopenia is a condition characterized by muscle mass loss. Skeletal muscle is capable of producing and secreting different molecules called myokines, and apelin is one of them. The literature contains contradictory data on the relationship between apelin and sarcopenia. We decided to investigate the role of apelin in sarcopenia in subjects with disease-related malnutrition (DRM), a group of patients with a high rate of sarcopenia.
PATIENTS AND METHODS
83 elderly patients with DRM assessed according to the Global Leadership Initiative on Malnutrition (GLIM) criteria were included in the study, with a mean age of 69.9±3.8 years. Anthropometric data, muscle mass by ultrasound at the rectus femoris quadriceps (RFQ) level, bioimpedance [skeletal muscle mass (SMM), appendicular SMM (aSMM) and aSMM index (aSMMI)], dynamometry, biochemical parameters, dietary intake, circulating apelin levels were determined in all patients.
RESULTS
a total of 33 patients (37.9%) were diagnosed with sarcopenia, while 54 patients did not present sarcopenia (60.1%). Body weight (-5.5±2.0 kg, p=0.01), calf circumference (-1.9±0.2 cm, p=0.02), phase angle (-0.6±0.2º, p=0.01), reactance (-6.8±2.3 Ohms, p=0.03), resistance (-38.8±12.3 Ohms, p=0.04), SMM (-2.2±0.3 kg, p=0.04), aSMM (-2.2±0.2 kg, p=0.03) and aSMMI (-0.6±0.2 kg, p=0.02), dominant muscle area (-0.6±0.2 cm2, p=0.04), dominant Y axis (-0.4±0.1 cm, p=0.03), dominant X/Y axis (1.1±0.3 cm, p=0.04), strength (-5.1±1.3 kg, p=0.01), albumin (-0.9±0.1 g/dl, p=0.02) and prealbumin (-4.6±0.7 mg/dl, p=0.02) were worse in patients with sarcopenia than non-sarcopenic patients. Circulating apelin levels were similar in both groups. No significant correlation of apelin levels was detected, either with bioimpedance data or with muscle ultrasonography data. The multivariant analysis did not detect a significant association of apelin with the presence of sarcopenia.
CONCLUSIONS
Our study shows a lack of association between apelin and sarcopenia in elderly malnourished patients.
Topics: Humans; Sarcopenia; Apelin; Aged; Malnutrition; Male; Female; Muscle, Skeletal
PubMed: 38946382
DOI: 10.26355/eurrev_202406_36461