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FRIMEDBIO-Fri prosj.st. med.,helse,biol

The muscle excitation-transcription coupling

Awarded: NOK 6.2 mill.

The composition of muscle is related to the risk of developing life style diseases such as obesity and type II diabetes. Muscle is a permanent tissue, but the phenotype can nevertheless be changed by changing the pattern of activity such as by exercise. C hanges in the pattern of action potentials leads to a different set of genes being expressed in pre-existing fibres, and this will change physiological properties such as contraction speed and metabolism (glycolytic/oxidative). Recent evidence suggests th at a multitude of activity-correlates can serve as signals in this excitation-transcription coupling. We will study some of the putative pathways such as negative regulation of fast myosin heavy chain isoforms by the transcription factor NFAT; how calcium regulate phosphorylation of muscle specific factors such as myogenin and myoD regulate myson heavy chain and metabolism; effects of lipid sensors such as PPARd; and factors related to low oxygen levels such as Hif-1a. We will also by genomics and proteom ics search for new pathways. The understanding of the signalling pathways related to activity opens up the possibility for drug intervention, and for one of the pathways (PPARd), we will test drug candidates directly. We will use several advanced special methods that have been established in the lab such as somatic gene transfer, electrical stimulation with implanted electrodes and in vivo time lapse imaging of single cells over days and weeks in the intact animal.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

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