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Physiology & Behavior Feb 2024This study aimed to examine the effects of 12 weeks of resistance training (RT) and vitamin D (VitD) supplementation on muscle strength and C-terminal agrin fragment... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This study aimed to examine the effects of 12 weeks of resistance training (RT) and vitamin D (VitD) supplementation on muscle strength and C-terminal agrin fragment (CAF) and Neurotrophin-3 (NT-3) concentrations as potential biomarkers in postmenopausal women.
METHODS
This was a randomized double-blind placebo-controlled study. Forty-four healthy postmenopausal women (55.84 ± 4.70 years and 29.61 ± 4.26 kg/m2) were randomly assigned into four groups: (1) Resistance training + placebo (RT + PLA), (2) Vitamin D supplementation (VitD), (3) Resistance training + vitamin D (RT + VitD), and (4) Placebo (PLA). VitD was supplemented as an oral capsule containing 50000 IU of cholecalciferol every two weeks. RT involved leg press, chest press, leg extension, leg curl, and shoulder press exercises, performed with 3-4 sets at 70-85 % of 1RM, three times a week.
RESULTS
Circulating levels of CAF and NT-3 did not significantly change following the intervention period in the study groups (p > 0.05). There were significant increases in upper and lower body muscle strength and power for RT + VitD and RT + PLA ( < 0.05), but not for VitD or PLA (p > 0.05). The muscle function gains for RT + VitD and RT + PLA were higher than those for VitD and PLA but did not differ between them.
CONCLUSION
12-week of RT interventions resulted in significant increases in muscle strength and power in postmenopausal women. However, VitD supplementation did not result in any additional benefits. The positive changes in muscle function promoted by RT do not seem to be associated with changes in the neuromuscular joint via the CAF or NT-3 as potential biomarkers.
Topics: Humans; Female; Vitamin D; Postmenopause; Resistance Training; Muscle Strength; Dietary Supplements; Biomarkers; Polyesters; Double-Blind Method; Muscle, Skeletal
PubMed: 38036018
DOI: 10.1016/j.physbeh.2023.114419 -
Science Advances Dec 2023Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells...
Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells promote cardiomyocyte cell cycle reentry and myocardial repair, but the mechanisms responsible for promoting an injury microenvironment conducive to regeneration remain incompletely defined. Here, we identify the matrix metalloproteinase Mmp14b as an essential regulator of heart regeneration. We identify a TEAD-dependent endothelial enhancer induced by heart injury in zebrafish and mice, and we show that the enhancer is required for regeneration, supporting a role for Hippo signaling upstream of . Last, we show that MMP-14 function in mice is important for the accumulation of Agrin, an essential regulator of neonatal mouse heart regeneration. These findings reveal mechanisms for extracellular matrix remodeling that promote heart regeneration.
Topics: Animals; Mice; Zebrafish; Endothelial Cells; Myocardium; Myocytes, Cardiac; Cell Proliferation; Regeneration; Mammals
PubMed: 38019918
DOI: 10.1126/sciadv.adh5313 -
BioRxiv : the Preprint Server For... Oct 2023The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly considered, the function of the NMJ is to transduce a nerve action potential...
The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly considered, the function of the NMJ is to transduce a nerve action potential into a muscle fiber action potential (MFAP). Efficient information transfer requires both cholinergic signaling, responsible for the generation of endplate potentials (EPPs), and excitation, the activation of postsynaptic voltage-gated sodium channels (Nav1.4) to trigger MFAPs. In contrast to the cholinergic apparatus, the signaling pathways that organize Nav1.4 and muscle fiber excitability are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as an agrin-LRP4 receptor, is also a BMP co-receptor that binds BMPs via its Ig3 domain and shapes BMP-induced signaling and transcriptional output. Here we probed the function of the MuSK-BMP pathway at the NMJ using mice lacking the MuSK Ig3 domain ('ΔIg3-MuSK'). Synapses formed normally in ΔIg3-MuSK animals, but the postsynaptic apparatus was fragmented from the first weeks of life. Anatomical denervation was not observed at any age examined. Moreover, spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable to WT. However, trains of nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal as revealed by increased jitter and blocking in single fiber electromyography. Further, nerve-evoked compound muscle action potentials (CMAPs), as well as twitch and tetanic muscle torque force production, were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK synapses but not at the extrajunctional sarcolemma, indicating that the observed excitability defects are the result of impaired localization of this voltage-gated ion channel at the NMJ. We propose that MuSK plays two distinct roles at the NMJ: as an agrin-LRP4 receptor necessary for establishing and maintaining cholinergic signaling, and as a BMP co-receptor required for maintaining proper Nav1.4 density, nerve-evoked muscle excitability and force production. The MuSK-BMP pathway thus emerges as a target for modulating excitability and functional innervation, which are defective in conditions such as congenital myasthenic syndromes and aging.
PubMed: 37961580
DOI: 10.1101/2023.10.24.563837 -
Annals of Human Genetics Jan 2024Autosomal recessive polycystic kidney disease is an early onset inherited hepatorenal disorder affecting around 1 in 20,000 births with no approved specific therapies.... (Review)
Review
Autosomal recessive polycystic kidney disease is an early onset inherited hepatorenal disorder affecting around 1 in 20,000 births with no approved specific therapies. The disease is almost always caused by variations in the polycystic kidney and hepatic disease 1 gene, which encodes fibrocystin (FC), a very large, single-pass transmembrane glycoprotein found in primary cilia, urine and urinary exosomes. By comparison to proteins involved in autosomal dominant PKD, our structural and molecular understanding of FC has lagged far behind such that there are no published experimentally determined structures of any part of the protein. Bioinformatics analyses predict that the ectodomain contains a long chain of immunoglobulin-like plexin-transcription factor domains, a protective antigen 14 domain, a tandem G8-TMEM2 homology region and a sperm protein, enterokinase and agrin domain. Here we review current knowledge on the molecular function of the protein from a structural perspective.
Topics: Humans; Polycystic Kidney, Autosomal Recessive; Receptors, Cell Surface; RNA; Transcription Factors; Sperm Proteins; Protein Conformation
PubMed: 37905714
DOI: 10.1111/ahg.12535 -
Frontiers in Immunology 2023Systemic lupus erythematosus (SLE) is an autoimmune disease involving many systems and organs, and individuals with SLE exhibit unique cancer risk characteristics. The...
INTRODUCTION
Systemic lupus erythematosus (SLE) is an autoimmune disease involving many systems and organs, and individuals with SLE exhibit unique cancer risk characteristics. The significance of the basement membrane (BM) in the occurrence and progression of human autoimmune diseases and tumors has been established through research. However, the roles of BM-related genes and their protein expression mechanisms in the pathogenesis of SLE and pan-cancer development has not been elucidated.
METHODS
In this study, we applied bioinformatics methods to perform differential expression analysis of BM-related genes in datasets from SLE patients. We utilized LASSO logistic regression, SVM-RFE, and RandomForest to screen for feature genes and construct a diagnosis model for SLE. In order to attain a comprehensive comprehension of the biological functionalities of the feature genes, we conducted GSEA analysis, ROC analysis, and computed levels of immune cell infiltration. Finally, we sourced pan-cancer expression profiles from the TCGA and GTEx databases and performed pan-cancer analysis.
RESULTS
We screened six feature genes (AGRN, PHF13, SPOCK2, TGFBI, COL4A3, and COLQ) to construct an SLE diagnostic model. Immune infiltration analysis showed a significant correlation between AGRN and immune cell functions such as parainflammation and type I IFN response. After further gene expression validation, we finally selected AGRN for pan-cancer analysis. The results showed that AGRN's expression level varied according to distinct tumor types and was closely correlated with some tumor patients' prognosis, immune cell infiltration, and other indicators.
DISCUSSION
In conclusion, BM-related genes play a pivotal role in the pathogenesis of SLE, and AGRN shows immense promise as a target in SLE and the progression of multiple tumors.
Topics: Humans; Autoimmune Diseases; Computational Biology; DNA-Binding Proteins; Interferon Type I; Lupus Erythematosus, Systemic; Neoplasms; Proteoglycans; Risk Factors; Transcription Factors; Agrin
PubMed: 37841281
DOI: 10.3389/fimmu.2023.1231611 -
Oncology Letters Nov 2023Agrin (AGRN) is a matricellular glycoprotein involved in extracellular signal transduction. AGRN is involved in tumorigenesis and cancer progression; however, the role...
Agrin (AGRN) is a matricellular glycoprotein involved in extracellular signal transduction. AGRN is involved in tumorigenesis and cancer progression; however, the role of AGRN in thyroid cancer (TC) remains unclear. In the present study, using cell lines derived from various subtypes of TC including CGTH, FTC-133 and BcPAP and transcriptomic data from patients with TC, the role of AGRN in TC was analyzed by migration, invasion, viability and proliferation assays as well as Western blot with EMT markers. AGRN expression was significantly increased in thyroid tumors and cell lines derived from various TC subtypes. The highest AGRN expression was found in follicular and papillary thyroid carcinoma subtypes. Immunocytochemistry revealed nuclear AGRN localization in normal (NTHY) and TC cells. Silencing of AGRN decreased viability, proliferation, migration and invasion of TC cell lines by upregulating vimentin and downregulating N-cadherin and E-cadherin. Furthermore, the expression of AGRN was associated with neutrophil infiltration in thyroid tumors. In conclusion, the present results indicated that increased AGRN expression promoted tumorigenic phenotypes of TC cells, while AGRN expression was associated with immune infiltration in thyroid tumors. AGRN may represent a target for future cancer therapy and requires further evaluation.
PubMed: 37818129
DOI: 10.3892/ol.2023.14070 -
Journal of Applied Physiology... Nov 2023Skeletal muscle disuse atrophy can cause degenerative changes in neuromuscular junction morphology. Although Daurian ground squirrels () are a natural anti-disuse animal...
Skeletal muscle disuse atrophy can cause degenerative changes in neuromuscular junction morphology. Although Daurian ground squirrels () are a natural anti-disuse animal model for studying muscle atrophy during hibernation, little is known about the morphological and regulatory mechanisms of their neuromuscular junctions. Here, we found that morphological indices of the soleus muscle were significantly lower during hibernation (torpor and interbout arousal) compared with pre-hibernation but recovered during post-hibernation. In the extensor digitorum longus muscle, neuromuscular junction morphology did not change significantly during hibernation. Agrin-Lrp4-MuSK is a key pathway for the formation and maintenance of the neuromuscular junction. Our results showed that low-density lipoprotein receptor-associated protein 4 (Lrp4) expression in the soleus (slow muscle) decreased by 46.2% in the interbout arousal group compared with the pre-hibernation group ( = 0.019), with recovery in the post-hibernation group. Compared with the pre-hibernation group, agrin expression in the extensor digitorum longus (fast muscle) increased by 67.0% in the interbout arousal group ( = 0.016). In conclusion, periodic up-regulation in agrin expression during interbout arousal may be involved in the maintenance of neuromuscular junction morphology in the extensor digitorum longus muscle during hibernation. The degenerative changes in neuromuscular junction morphology and the periodic decrease in Lrp4 protein expression in the soleus during hibernation, these changes recovered to the pre-hibernation levels in the post-hibernation group, exhibiting significant plasticity. This plasticity may be one of the important mechanisms for resisting disuse atrophy in hibernating animals. This study is the first to explore the neuromuscular junction morphology of slow- and fast-twitch muscles in Daurian ground squirrels during different periods of hibernation. Results showed that the neuromuscular junction maintained stable morphology in the extensor digitorum longus muscle. The degenerative changes in neuromuscular junction morphology and the periodic decrease in Lrp4 protein expression in the soleus muscle during hibernation recovered in post-hibernation, exhibiting significant plasticity.
Topics: Animals; Sciuridae; Agrin; Muscle, Skeletal; Muscular Atrophy; Neuromuscular Junction; Transcription Factors; Muscular Disorders, Atrophic; Hibernation
PubMed: 37795532
DOI: 10.1152/japplphysiol.00334.2023 -
Archives of Medical Research Nov 2023Age-related muscle decline, called sarcopenia, and hypertension are commonly observed in patients with chronic obstructive pulmonary disease (COPD). Angiotensin receptor...
BACKGROUND
Age-related muscle decline, called sarcopenia, and hypertension are commonly observed in patients with chronic obstructive pulmonary disease (COPD). Angiotensin receptor blockers (ARBs) are common antihypertensive medications with muscle protective effects. However, the anti-sarcopenic potential and associated mechanisms of ARBs in hypertensive patients with COPD are unknown.
OBJECTIVES
We aimed to investigate the potential contribution of neuromuscular junction (NMJ) stability as a driving mechanism of ARBs-induced muscle protection.
METHODS
We categorized 236 patients with COPD into normotensive (n = 79) and hypertensive, based on treatment with ARB (n = 82), and other antihypertensive drugs (n = 75). Hypertensive patients with COPD were evaluated at two time points one year apart. Handgrip strength (HGS), body composition, short physical performance battery (SPPB), and plasma c-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation were measured.
RESULTS
Patients with COPD exhibited reduced HGS and SPPB scores, and higher levels of CAF22 than controls, regardless of hypertension status. ARBs treatment improved HGS and gait speed and reduced plasma CAF22 levels in hypertensive patients with COPD (all p <0.05). ARBs also prevented the decline in SPPB components, including maintaining balance, gait speed, and the ability to rise from a chair in hypertensive patients with COPD (all p <0.05). We also found dynamic associations of plasma CAF22 with HGS, gait speed, and SPPB scores in hypertensive patients with COPD.
CONCLUSIONS
Altogether, ARB treatment preserves skeletal muscle health and functional capacity in hypertensive patients with COPD by reducing plasma CAF22 and possibly repairing NMJs.
Topics: Humans; Angiotensin Receptor Antagonists; Hand Strength; Muscle Strength; Angiotensin-Converting Enzyme Inhibitors; Pulmonary Disease, Chronic Obstructive; Muscle, Skeletal; Sarcopenia; Hypertension; Antihypertensive Agents
PubMed: 37741098
DOI: 10.1016/j.arcmed.2023.102890 -
Cell Reports. Medicine Sep 2023The tumor microenvironment (TME) is influenced by a "disorganized" extracellular matrix (ECM) that sensitizes cancer cells toward mechanical stress, signaling, and... (Review)
Review
The tumor microenvironment (TME) is influenced by a "disorganized" extracellular matrix (ECM) that sensitizes cancer cells toward mechanical stress, signaling, and structural alterations. In hepatocellular carcinoma (HCC), lack of knowledge about key ECM proteins driving the TME refractory to targeted therapies poses a barrier to the identification of new therapeutic targets. Herein, we discuss the contributions of various ECM components that impact hepatocytes and their surrounding support network during tumorigenesis. In addition, the underpinnings by which ECM proteins transduce mechanical signals to the liver TME are detailed. Finally, in view of the bidirectional feedback between the ECM, transformed hepatocytes, and immune cells, we highlight the potential role of the ECM disorganization process in shaping responses to immune checkpoint inhibitors and targeted therapies. Our comprehensive characterization of these ECM components may provide a roadmap for innovative therapeutic approaches to restrain HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Extracellular Matrix; Hepatocytes; Tumor Microenvironment
PubMed: 37652015
DOI: 10.1016/j.xcrm.2023.101170 -
Scientific Reports Aug 2023Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases due to mutations in neuromuscular junction (NMJ)...
Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases due to mutations in neuromuscular junction (NMJ) protein-coding genes. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and rare cases of CMS with mutations in LRP4 gene has been described so far. In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A > G; p.Thy607Cys) within the β1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential in spinal accessory nerves, associated with congenital agenesis of the hands and feet and renal malformation. Mechanistic expression studies show a significant decrease of AChR aggregation in cultured patient myotubes, as well as altered in vitro binding of agrin and Wnt11 ligands to the mutated β1 propeller domain of LRP4 explaining the dual phenotype characterized clinically and electoneuromyographically in the patient. These results expand the LRP4 mutations spectrum associated with a previously undescribed clinical association involving impaired neuromuscular transmission and limb deformities and highlighting the critical role of a yet poorly described domain of LRP4 at the NMJ. This study raises the question of the frequency of this rare neuromuscular form and the future diagnosis and management of these cases.
Topics: Humans; Myasthenic Syndromes, Congenital; Agrin; Mutation; Foot; LDL-Receptor Related Proteins
PubMed: 37640745
DOI: 10.1038/s41598-023-41008-5