Aronsen, J. M. | Search bioRxiv

bioRxiv2020

MSK phosphorylation of H3S28 is required for immediate early gene induction and cardiac hypertrophy

Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not yet resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the Mitogen and Stress activated protein Kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights and highlight the role of signalling to the epigenome in gene expression regulation during cardiac hypertrophy. Brief summary one sentenceMSK1/2 phosphorylation of Histone 3 Serine 28 couples MAPK signalling with chromatin remodelling and immediate early gene expression to induce pro-hypertrophic cardiac transcriptional responses.

molecular biology↗

bioRxiv2020

Syndecan-4-/- mice have smaller muscle fibers, increased Akt/mTOR/S6K1 and Notch/HES-1 pathways, and alterations in extracellular matrix components

BackgroundExtracellular matrix (ECM) remodeling is essential for skeletal muscle development and adaption in response to environmental cues such as exercise and injury. The cell surface proteoglycan syndecan-4 has been reported to be essential for muscle differentiation, but few molecular mechanisms are known. Syndecan-4-/- mice are unable to regenerate damaged muscle, and display deficient satellite cell activation, proliferation, and differentiation. A reduced myofiber basal lamina has also been reported in syndecan-4-/- muscle, indicating possible defects in ECM production. To get a better understanding of the underlying molecular mechanisms, we have here investigated the effects of syndecan-4 genetic ablation on molecules involved in ECM remodeling and muscle growth, both under steady state conditions and in response to exercise. MethodsTibialis anterior (TA) muscles from sedentary and exercised syndecan-4-/- and WT mice were analyzed by immunohistochemistry, real-time PCR and western blotting. ResultsCompared to WT, we found that syndecan-4-/- mice had reduced body weight, reduced muscle weight, muscle fibers with a smaller cross-sectional area, and reduced expression of myogenic regulatory transcription factors. Sedentary syndecan-4-/- had also increased mRNA levels of syndecan-2, decorin, collagens, fibromodulin, biglycan, and LOX. Some of these latter ECM components were reduced at protein level, suggesting them to be more susceptible to degradation or less efficiently translated when syndecan-4 is absent. At the protein level, TRPC7 was reduced, whereas activation of the Akt/mTOR/S6K1 and Notch/HES-1 pathways were increased. Finally, although exercise induced upregulation of several of these components in WT, a further upregulation of these molecules was not observed in exercised syndecan-4-/- mice. ConclusionsAltogether our data suggest an important role of syndecan-4 in muscle development.

cell biology↗