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  1. Article ; Online: Genetic reduction of the extracellular matrix protein versican attenuates inflammatory cell infiltration and improves contractile function in dystrophic mdx diaphragm muscles

    Natasha L. McRae / Alex B. Addinsall / Kirsten F. Howlett / Bryony McNeill / Daniel R. McCulloch / Nicole Stupka

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 19

    Abstract: Abstract There is a persistent, aberrant accumulation of V0/V1 versican in skeletal muscles from patients with Duchenne muscular dystrophy and in diaphragm muscles from mdx mice. Versican is a provisional matrix protein implicated in fibrosis and ... ...

    Abstract Abstract There is a persistent, aberrant accumulation of V0/V1 versican in skeletal muscles from patients with Duchenne muscular dystrophy and in diaphragm muscles from mdx mice. Versican is a provisional matrix protein implicated in fibrosis and inflammation in various disease states, yet its role in the pathogenesis of muscular dystrophy is not known. Here, female mdx and male hdf mice (haploinsufficient for the versican allele) were bred. In the resulting F1 mdx-hdf male pups, V0/V1 versican expression in diaphragm muscles was decreased by 50% compared to mdx littermates at 20–26 weeks of age. In mdx-hdf mice, spontaneous physical activity increased by 17% and there was a concomitant decrease in total energy expenditure and whole-body glucose oxidation. Versican reduction improved the ex vivo strength and endurance of diaphragm muscle strips. These changes in diaphragm contractile properties in mdx-hdf mice were associated with decreased monocyte and macrophage infiltration and a reduction in the proportion of fibres expressing the slow type I myosin heavy chain isoform. Given the high metabolic cost of inflammation in dystrophy, an attenuated inflammatory response may contribute to the effects of versican reduction on whole-body metabolism. Altogether, versican reduction ameliorates the dystrophic pathology of mdx-hdf mice as evidenced by improved diaphragm contractile function and increased physical activity.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: CaMKK2 is not involved in contraction-stimulated AMPK activation and glucose uptake in skeletal muscle

    Florentina Negoita / Alex B. Addinsall / Kristina Hellberg / Conchita Fraguas Bringas / Paul S. Hafen / Tyler J. Sermersheim / Marianne Agerholm / Christopher T.A. Lewis / Danial Ahwazi / Naomi X.Y. Ling / Jeppe K. Larsen / Atul S. Deshmukh / Mohammad A. Hossain / Jonathan S. Oakhill / Julien Ochala / Jeffrey J. Brault / Uma Sankar / David H. Drewry / John W. Scott /
    Carol A. Witczak / Kei Sakamoto

    Molecular Metabolism, Vol 75, Iss , Pp 101761- (2023)

    2023  

    Abstract: Objective: The AMP-activated protein kinase (AMPK) gets activated in response to energetic stress such as contractions and plays a vital role in regulating various metabolic processes such as insulin-independent glucose uptake in skeletal muscle. The ... ...

    Abstract Objective: The AMP-activated protein kinase (AMPK) gets activated in response to energetic stress such as contractions and plays a vital role in regulating various metabolic processes such as insulin-independent glucose uptake in skeletal muscle. The main upstream kinase that activates AMPK through phosphorylation of α-AMPK Thr172 in skeletal muscle is LKB1, however some studies have suggested that Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) acts as an alternative kinase to activate AMPK. We aimed to establish whether CaMKK2 is involved in activation of AMPK and promotion of glucose uptake following contractions in skeletal muscle. Methods: A recently developed CaMKK2 inhibitor (SGC-CAMKK2-1) alongside a structurally related but inactive compound (SGC-CAMKK2-1N), as well as CaMKK2 knock-out (KO) mice were used. In vitro kinase inhibition selectivity and efficacy assays, as well as cellular inhibition efficacy analyses of CaMKK inhibitors (STO-609 and SGC-CAMKK2-1) were performed. Phosphorylation and activity of AMPK following contractions (ex vivo) in mouse skeletal muscles treated with/without CaMKK inhibitors or isolated from wild-type (WT)/CaMKK2 KO mice were assessed. Camkk2 mRNA in mouse tissues was measured by qPCR. CaMKK2 protein expression was assessed by immunoblotting with or without prior enrichment of calmodulin-binding proteins from skeletal muscle extracts, as well as by mass spectrometry-based proteomics of mouse skeletal muscle and C2C12 myotubes. Results: STO-609 and SGC-CAMKK2-1 were equally potent and effective in inhibiting CaMKK2 in cell-free and cell-based assays, but SGC-CAMKK2-1 was much more selective. Contraction-stimulated phosphorylation and activation of AMPK were not affected with CaMKK inhibitors or in CaMKK2 null muscles. Contraction-stimulated glucose uptake was comparable between WT and CaMKK2 KO muscle. Both CaMKK inhibitors (STO-609 and SGC-CAMKK2-1) and the inactive compound (SGC-CAMKK2-1N) significantly inhibited contraction-stimulated glucose uptake. ...
    Keywords Ca2+/calmodulin dependent protein kinase kinase 2 ; AMP-activated protein kinase ; SGC-CAMKK2-1 ; STO-609 ; Glucose uptake ; Internal medicine ; RC31-1245
    Language English
    Publishing date 2023-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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