Exercise helps one age gracefully, study

Reduced Satellite Cell Numbers and Myogenic Capacity in Aging Can Be Alleviated by Endurance Exercise. Muscle regeneration depends on satellite cells, myogenic stem cells that reside on the myofiber surface. Reduced numbers and/or decreased myogenic aptitude of these cells may impede proper maintenance and contribute to the age-associated decline in muscle mass and repair capacity. Endurance exercise was shown to improve muscle performance; however, the direct impact on satellite cells in aging was not yet thoroughly determined. Here, we focused on characterizing the effect of moderate-intensity endurance exercise on satellite cell, as possible means to attenuate adverse effects

of aging. Young and old rats of both genders underwent 13 weeks of treadmill-running or remained sedentary. Gastrocnemius muscles were assessed for the effect of age, gender and exercise on satellite-cell numbers and myogenic capacity. Satellite cells were identified in freshly isolated myofibers based on Pax7 immunostaining (i.e., ex-vivo). The capacity of individual myofiber-associated cells to produce myogenic progeny was determined in clonal assays (in-vitro). We show an age-associated decrease in satellite-cell numbers and in the percent of myogenic clones in old sedentary rats. Upon exercise, there was an increase in myofibers that contain higher numbers of satellite cells in both young and old rats, and an increase in the percent of myogenic clones derived from old rats. Changes at the satellite cell level in old rats were accompanied with positive effects on the lean-to-fat Gast muscle composition and on spontaneous locomotion levels. The significance of these data is that they suggest that the endurance exercise-mediated boost in both satellite numbers and myogenic properties may improve myofiber maintenance in aging.  – Prof. Dafna Benayahu; Research interests: Differentiation of mesenchymal stem cells.The research focuses on the role of marrow stroma stem cells (MSC) progenitors differentiation and function in skeletal formation and

maintenance. The study elaborates on different aspects of marrow stromal cells from mice, rat and human source. The knowledge on the role of marrow stromal cells is fundamental to better understand the skeletal physiology and hemopoiesis. The main focus of the study is the involvement of stromal stem cells towards skeletal [bone and muscle] formation.The goals of the research in my laboratory are to understand the molecular mechanism and biological function of marrow stem cells’ differentiation. We use adult stem cells’ model to follow their differentiation to a variety of lineage-specific committed progenitors [osteogenic, muscle and fibroblasts]. The MSCs are derived from the primitive mesenchymal cells. The osteoprogenitors differentiate to osteoblasts, the cells that form the bone. It has been suggested that progenitor cells differentiate also to skeletal and smooth muscle. In the study, we focused on the molecular biology of the osteoblast cell lineage. We compared the function and gene expression by osteoprogenitors and mature differentiated osteoblasts. We have found that osteoblasts function is controlled by hormonal regulation [using steroid hormones and PTH] that was analyzed by a variety of cellular functions.The significance of understanding the cellular

differentiation on the molecular level paves the way for exploring physiological changes. We studied such changes in animal model of ovariectomiezed (mice/rat) that were treated with replacement therapies. Other human bone pathologies studied are localized and followed changes in the mastoid bone structure or cases of bone cancer. Molecular alterations were observed in bone cancer, osteosarcoma or in metastasis to bone that occurred due to secreted factors by stromal osetobalsts.Our group has the advantage and experience of studying the stromal cells differentiation. The lack of valuable markers along the differentiation pathway of bone forming cells that represent at different stages of differentiation led us to develop such an approach. The present and future focus of the research effort is concentrated to identify the novel genes that have been cloned by us. We are active in characterizing the novel genes cloned both for their structure and function. Exploring these genes will enable us to characterize the MSC progenitors on the molecular level.The study on the cloned genes is based on high throughput bioinformatic computer analysis [including sequence homology searches, profile searches, alignment to the available genomic sequence, detection of ORFs, and domains]. The families of proteins for which new genes were identified include surface markers, transcription activators as hNRNP, kinesin related protein (KRP) and ChroM, a chromatin remodeling

protein. Heterogenous nuclear riboprotein – HNRNP- These proteins action in nuclear export of mRNA. The export of mRNA through nuclear pore complexes (NPC) is preceded by multiple and well coordinated steps, resulting in formation of an export competent ribonucleoprotein complex (mRNP). Numerous factors involved in the translocation of the mRNP through the NPC and their releases into the cytoplasm have been isolated mainly through genetic approaches in yeast, and functional homologues were found at high ordered mammalian. Understanding the mechanism of mRNA export relies, in part, on the functional characterization of these tissue specific factors and the establishment of a complete network of molecular interactions and implicated in the tissue specific export of an mRNA from the nucleus to the cytoplasm.Kinesin related protein (KRP) – The kinesin proteins super family has been shown to transport membranous organelles and protein complexes in a microtubule- and ATP-dependent manner. We have identified a novel protein that shared the N terminal with kinesin motor

domain, and is unique at the C terminal that have a steroid binding domain as was revealed based on a database search of the human genome. The biological function of KRP and its function in cellular transport require a highly complex intracellular system. It is becoming increasingly clear that the use of specific kinesin in the cell for the direction, destination, and transportation of various important functional molecules, is fundamentally in intracellular transport.A novel selectin – like protein – The selectins are cell surface lectins that have evolved to mediate the adhesion of white blood cells to cells in the microenvironment. Specifically these proteins are part of recognition and interaction with endothelial and platelets under flow. The selectins are physiologically important in inflammation, lymphocyte homing, immunological responses and homing of bone marrow stem cells. They play a role in arteriosclerosis, ischemia-reperfusion injury, inflammatory diseases and metastasis spreading of some cancers. The cloned gene shares at the C terminal structure of repeating motifs that relates them to the selectin family. The study involved with the bioinfomratics analysis from the gene to protein. We developed biological tools to study the message

expression and tissue distribution and an antibody to evaluate the protein expression profile on tissues and cells.The ChroM – a chromatin remodeling protein – In the eukaryotic cell nucleus, hundreds of millions of base pairs of DNA are assembled into chromosomes. Chromosomes dynamic varies in structure throughout the cell cycle and serves as the substrate for many nuclear processes such as DNA replication, recombination, repair and transcription. Chromatin, the central nucleoprotein filament of chromosomes, has many different forms, from euchromatin to heterochromatin. The packaging of DNA into chromatin provides the cell with the means to compact and to store its nuclear DNA and regulates the function of DNA binding factors. To counter balance the repressive nature of chromatin, a variety of chromatin remodeling factors use the energy of ATP hydrolysis to facilitate the interaction of proteins with nucleosomal DNA. The ability of these factors may play a role and participates in the tissue specific transcriptional regulation. To provide such perspective, we have identified a novel protein that functions as chromatin remodeling factor in processes of stromal progenitors proliferation and differentiation.The cloning of ChroM gene followed by revealing its genomic structure and alternative splice forms that are differential expressed in mesenchymal tissues. The protein posses’ chromodoamain, ATPase activity and DNA binding domain,

nuclear localization sites (NLS). The relation between ChroM and gene promoters activity are studied by ChIP technology to explore to which promoters the ChroM is binding too.Series of antibodies used to localize the ChroM protein expression along stages in mouse embryos during development, adult tissue expression and on tissue cultured cells. The ChroM appearance between normal and cancerous cells, osteosarcoma has a different cellular compartment distribution that led us to search for possible genetic alteration in osteosarcoma. The use of ChroM will enable us to monitor the cytotoxic effects of drugs on osteosarcoma cells.The significance of these studies is to enhance the understanding of the cellular and molecular levels of stormal cells’ regulation and function. They will enable us to bring better understanding to skeletal diseases that afflict a wide range of patients and have a major impact on the health care system. Youth suffer dysplatic disorders and benign or malignant tumors. Older individuals suffer age related bone disorders, such as osteoporosis. Bone disorders and genetic abnormalities are disfiguring, and many are associated with severe and increased mortality. Sources: PLoS ONE open access scientific journal published by Public Library of Science. &  Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University.

 

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