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American Journal of Physiology. Renal... Apr 2021Urinary continence is maintained in the lower urinary tract by the contracture of urethral sphincters, including smooth muscle of the internal urethral sphincter. These... (Review)
Review
Urinary continence is maintained in the lower urinary tract by the contracture of urethral sphincters, including smooth muscle of the internal urethral sphincter. These contractions occlude the urethral lumen, preventing urine leakage from the bladder to the exterior. Over the past 20 years, research on the ionic conductances that contribute to urethral smooth muscle contractility has greatly accelerated. A debate has emerged over the role of interstitial cell of Cajal (ICC)-like cells in the urethra and their expression of Ca-activated Cl channels encoded by anoctamin-1 [Ano1; transmembrane member 16 A () gene]. It has been proposed that Ano1 channels expressed in urethral ICC serve as a source of depolarization for smooth muscle cells, increasing their excitability and contributing to tone. Although a clear role for Ano1 channels expressed in ICC is evident in other smooth muscle organs, such as the gastrointestinal tract, the role of these channels in the urethra is unclear, owing to differences in the species (rabbit, rat, guinea pig, sheep, and mouse) examined and experimental approaches by different groups. The importance of clarifying this situation is evident as effective targeting of Ano1 channels may lead to new treatments for urinary incontinence. In this review, we summarize the key findings from different species on the role of ICC and Ano1 channels in urethral contractility. Finally, we outline proposals for clarifying this controversial and important topic by addressing how cell-specific optogenetic and inducible cell-specific genetic deletion strategies coupled with advances in Ano1 channel pharmacology may clarify this area in future studies. Studies from the rabbit have shown that anoctamin-1 (Ano1) channels expressed in urethral interstitial cells of Cajal (ICC) serve as a source of depolarization for smooth muscle cells, increasing excitability and tone. However, the role of urethral Ano1 channels is unclear, owing to differences in the species examined and experimental approaches. We summarize findings from different species on the role of urethral ICC and Ano1 channels in urethral contractility and outline proposals for clarifying this topic using cell-specific optogenetic approaches.
Topics: Animals; Anoctamin-1; Calcium; Calcium Signaling; Humans; Interstitial Cells of Cajal; Muscle, Smooth; Myocytes, Smooth Muscle
PubMed: 33554780
DOI: 10.1152/ajprenal.00520.2020 -
Biomolecules Oct 2021(Ashwagandha) is used in Indian traditional medicine, Ayurveda, and is believed to have a variety of health-promoting effects. The molecular mechanisms and pathways...
(Ashwagandha) is used in Indian traditional medicine, Ayurveda, and is believed to have a variety of health-promoting effects. The molecular mechanisms and pathways underlying these effects have not yet been sufficiently explored. In this study, we investigated the effect of Ashwagandha extracts and their major withanolides (withaferin A and withanone) on muscle cell differentiation using C2C12 myoblasts. We found that withaferin A and withanone and Ashwagandha extracts possessing different ratios of these active ingredients have different effects on the differentiation of C2C12. Withanone and withanone-rich extracts caused stronger differentiation of myoblasts to myotubes, deaggregation of heat- and metal-stress-induced aggregated proteins, and activation of hypoxia and autophagy pathways. Of note, the Parkinson's disease model of Drosophila that possess a neuromuscular disorder showed improvement in their flight and climbing activity, suggesting the potential of Ashwagandha withanolides for the management of muscle repair and activity.
Topics: Animals; Cell Differentiation; Cell Line; Humans; Medicine, Ayurvedic; Mice; Muscle Cells; Parkinson Disease; Plant Extracts; Withanolides
PubMed: 34680087
DOI: 10.3390/biom11101454 -
FASEB Journal : Official Publication of... Nov 2021Aging exacerbates neointimal formation by reducing apoptosis of vascular smooth muscle cells (VSMCs) and induces inflammation within vascular wall. Prep1 is a...
Aging exacerbates neointimal formation by reducing apoptosis of vascular smooth muscle cells (VSMCs) and induces inflammation within vascular wall. Prep1 is a homeodomain transcription factor which stimulates the expression of proinflammatory cytokines in aortic endothelial cell models and plays a primary role in the regulation of apoptosis. In this study, we have investigated the role of Prep1 in aorta of Prep1 hypomorphic heterozygous mice (Prep1 ) and in VSMCs, and its correlation with aging. Histological analysis from Prep1 aortas revealed a 25% reduction in medial smooth muscle cell density compared to WT animals. This result paralleled higher apoptosis, caspase 3, caspase 9 and p53 levels in Prep1 mice and lower Bcl-xL. Prep1 overexpression in VSMCs decreased apoptosis by 25% and caspase 3 and caspase 9 expression by 40% and 37%. In parallel, Bcl-xL inhibition by BH3I-1 and p53 induction by etoposide reverted the antiapoptotic effect of Prep1. Experiments performed in aorta from 18 months old WT mice showed a significant increase in Prep1, p16 , p21 and interleukin 6 (IL-6) compared to youngest animals. Similar results have been observed in H O -induced senescent VSMCs. Interestingly, the synthetic Prep1 inhibitory peptide Prep1 (54-72) reduced the antiapoptotic effects mediated by IL-6, particularly in senescent VSMCs. These results indicate that IL-6-Prep1 signaling reduces apoptosis, by modulating Bcl-xL and p53 both in murine aorta and in VSMCs. In addition, age-dependent increase in IL-6 and Prep1 in senescent VSMCs and in old mice may be involved in the aging-related vascular dysfunction.
Topics: Aging; Animals; Apoptosis; Cells, Cultured; Homeodomain Proteins; Interleukin-6; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
PubMed: 34679197
DOI: 10.1096/fj.202100943R -
European Journal of Applied Physiology Jun 2022Skeletal muscle strength, mass, and function should be carefully monitored for signs of decline with advanced adult age. An understanding of the pathophysiology and... (Review)
Review
Skeletal muscle strength, mass, and function should be carefully monitored for signs of decline with advanced adult age. An understanding of the pathophysiology and severity of sarcopenia can be improved with the exploration of changes in muscle fiber properties. Furthermore, although functional decline with increase age is a well-known phenomenon, the mechanisms underlying this decline, and the features that characterize it, are complex and variable. The age-related decline of muscle function is a result of not only a decrease of muscle mass but also a decline in the intrinsic properties of muscle fibers that are independent of size. We believe it is important to understand changes in muscle quality (force adjusted for size), and not to focus solely on muscle mass, because muscle quality is closely related to measurements of function and could potentially predict clinical outcomes such as morbidity, disability, and mortality. Neurological and metabolic mechanisms contribute to muscle quality, but the intrinsic properties of muscle cells are central to the maintenance of force-generating capacity. Muscle quality can be evaluated with the assessment of morphological, physiological, and mechanical properties in single permeabilized or skinned fibers. This approach excludes the influence of the nervous system, tendons, and the extracellular matrix. In this review, we summarized the changes in active and passive mechanical properties at the single muscle cell level in older skeletal muscles. We argue that intrinsic mechanical changes in human single muscle fibers are useful biomarkers and indicators of muscle quality.
Topics: Adult; Aged; Aging; Biomarkers; Humans; Muscle Contraction; Muscle Fibers, Skeletal; Muscle, Skeletal
PubMed: 35249139
DOI: 10.1007/s00421-022-04924-4 -
Biomaterials Apr 2021A major obstacle for using human pluripotent stem cells (hPSCs) derived vascular cells for cell therapy is the lack of simple, cost-saving, and scalable methods for cell...
A major obstacle for using human pluripotent stem cells (hPSCs) derived vascular cells for cell therapy is the lack of simple, cost-saving, and scalable methods for cell production. Here we described a simplified and chemically defined medium (AATS) for endothelial cells (ECs) and smooth muscle cells (SMCs) differentiation. AATS medium does not contain insulin, enabling the rapid and highly efficient vascular mesoderm formation through accelerating metabolic and autophagy-enhanced mesoderm induction. Transcriptome profiling confirmed that hPSC-derived ECs and SMCs in the AATS medium closely resembled primary ECs and SMCs formed in vivo. ECs appeared to adhere and grow better in the AATS medium over other cell types, which allowed the purification of CD31CD144 double-positive cells. Furthermore, the AATS medium was compatible with 3D microscaffold (MS) culture, which may facilitate large-scale bioproduction of ECs. HPSC-derived ECs and SMCs in the AATS medium exhibited strong revascularization potential in treating murine ischemic models. Our study provided a cost-effective and efficient medium system to manufacture GMP compatible, off-the-shelf ECs, and SMCs to model human diseases and vascular repair.
Topics: Animals; Cell Differentiation; Endothelial Cells; Humans; Mice; Muscle, Smooth; Myocytes, Smooth Muscle; Pluripotent Stem Cells
PubMed: 33618219
DOI: 10.1016/j.biomaterials.2021.120713 -
Expert Opinion on Therapeutic Targets Feb 2020: The incidence of age-related vascular diseases such as arterial stiffness, hypertension and atherosclerosis, is rising dramatically and is substantially impacting... (Review)
Review
: The incidence of age-related vascular diseases such as arterial stiffness, hypertension and atherosclerosis, is rising dramatically and is substantially impacting healthcare systems. Mounting evidence suggests that there is an important role for autophagy in maintaining (cardio)vascular health. Impaired vascular autophagy has been linked to arterial aging and the initiation of vascular disease.: The function and implications of autophagy in vascular smooth muscle cells and endothelial cells are discussed in healthy blood vessels and arterial disease. Furthermore, we discuss current treatment options for vascular disease and their links with autophagy. A literature search was conducted in PubMed up to October 2019.: Although the therapeutic potential of inducing autophagy in age-related vascular pathologies is considerable, several issues should be addressed before autophagy induction can be clinically used to treat vascular disease. These issues include uncertainty regarding the most effective drug target as well as the lack of potency and selectivity of autophagy inducing drugs. Moreover, drug tolerance or autophagy mediated cell death have been reported as possible adverse effects. Special attention is required for determining the cause of autophagy deficiency to optimize the treatment strategy.
Topics: Aging; Animals; Autophagy; Endothelial Cells; Humans; Molecular Targeted Therapy; Myocytes, Smooth Muscle; Vascular Diseases
PubMed: 31985292
DOI: 10.1080/14728222.2020.1723079 -
International Journal of Molecular... Sep 2021Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid... (Review)
Review
Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid artery facilitates elastin to degradation by MMPs, exposing vascular cells to greater mechanical stress and triggering signaling mechanisms that only exacerbate aging, creating a self-sustaining inflammatory environment that also promotes vascular calcification. In this review, we highlight the role of crosstalk between smooth muscle cells and the vascular extracellular matrix (ECM) and how aging promotes smooth muscle cell phenotypes that ultimately lead to mechanical impairment of aging arteries. Understanding the underlying mechanisms and the role of associated changes in ECM during aging may contribute to new approaches to prevent or delay arterial aging and the onset of cardiovascular diseases.
Topics: Aging; Animals; Extracellular Matrix; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
PubMed: 34576337
DOI: 10.3390/ijms221810175 -
JCI Insight May 2021Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane...
Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane receptors, play a crucial role in SMC biology by binding to the extracellular matrix protein with the actin cytoskeleton within the SMC. Integrin α9 plays an important role in cell motility and autoimmune diseases; however, its role in SMC biology and remodeling remains unclear. Herein, we demonstrate that stimulated human coronary SMCs upregulate α9 expression. Targeting α9 in stimulated human coronary SMCs, using anti-integrin α9 antibody, suppresses synthetic phenotype and inhibits SMC proliferation and migration. To provide definitive evidence, we generated an SMC-specific α9-deficient mouse strain. Genetic ablation of α9 in SMCs suppressed synthetic phenotype and reduced proliferation and migration in vitro. Mechanistically, suppressed synthetic phenotype and reduced proliferation were associated with decreased focal adhesion kinase/steroid receptor coactivator signaling and downstream targets, including phosphorylated ERK, p38 MAPK, glycogen synthase kinase 3β, and nuclear β-catenin, with reduced transcriptional activation of β-catenin target genes. Following vascular injury, SMC-specific α9-deficient mice or wild-type mice treated with murine anti-integrin α9 antibody exhibited reduced injury-induced neointimal hyperplasia at day 28 by limiting SMC migration and proliferation. Our findings suggest that integrin α9 regulates SMC biology, suggesting its potential therapeutic application in vascular remodeling.
Topics: Animals; Female; Integrin alpha Chains; Male; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Phenotype; Vascular Remodeling
PubMed: 34027892
DOI: 10.1172/jci.insight.147134 -
The Journal of General Physiology Jul 2021The July 2021 issue of is a collection of peer-reviewed articles focused on the function and dynamic regulation of contractile systems in muscle and non-muscle cells.
The July 2021 issue of is a collection of peer-reviewed articles focused on the function and dynamic regulation of contractile systems in muscle and non-muscle cells.
Topics: Myofibrils
PubMed: 34170286
DOI: 10.1085/jgp.202112972 -
Cells Dec 2023Synaptopodin-2 (SYNPO2) is a protein associated with the Z-disc in striated muscle cells. It interacts with α-actinin and filamin C, playing a role in Z-disc...
Synaptopodin-2 (SYNPO2) is a protein associated with the Z-disc in striated muscle cells. It interacts with α-actinin and filamin C, playing a role in Z-disc maintenance under stress by chaperone-assisted selective autophagy (CASA). In smooth muscle cells, SYNPO2 is a component of dense bodies. Furthermore, it has been proposed to play a role in tumor cell proliferation and metastasis in many different kinds of cancers. Alternative transcription start sites and alternative splicing predict the expression of six putative SYNPO2 isoforms differing by extended amino- and/or carboxy-termini. Our analyses at mRNA and protein levels revealed differential expression of SYNPO2 isoforms in cardiac, skeletal and smooth muscle cells. We identified synemin, an intermediate filament protein, as a novel binding partner of the PDZ-domain in the amino-terminal extension of the isoforms mainly expressed in cardiac and smooth muscle cells, and demonstrated colocalization of SYNPO2 and synemin in both cell types. A carboxy-terminal extension, mainly expressed in smooth muscle cells, is sufficient for association with dense bodies and interacts with α-actinin. SYNPO2 therefore represents an additional and novel link between intermediate filaments and the Z-discs in cardiomyocytes and dense bodies in smooth muscle cells, respectively. In pathological skeletal muscle samples, we identified SYNPO2 in the central and intermediate zones of target fibers of patients with neurogenic muscular atrophy, and in nemaline bodies. Our findings help to understand distinct functions of individual SYNPO2 isoforms in different muscle tissues, but also in tumor pathology.
Topics: Humans; Actinin; Myocytes, Cardiac; Myocytes, Smooth Muscle; Protein Isoforms; Sarcomeres
PubMed: 38201288
DOI: 10.3390/cells13010085