Poster Topical Area: Nutrient-Gene Interactions

Location: Hall D

Poster Board Number: 426

P17-003 - Autonomous modulation of skeletal muscle remodelling and energy metabolism genesets by the Vitamin D receptor

Sunday, Jun 10
8:00 AM – 6:00 PM

Objective
Vitamin D (VitD) deficiency is prevalent in ~25% of the population, and is proposed to have actions upon skeletal muscle metabolism and health. VitD regulates and exerts its effects through the ubiquitously expressed VitD receptor (VDR); a potent transcription factor, controlling the expression of multiple genes through modulation of Pol II pre-initiation complexes. Recent investigations have established a VDR autonomous role in muscle function and regeneration. Thus, we aimed to investigate whether VDR has a functional role in modulating key regulatory pathways/ genesets important to muscle growth and homeostasis.

Methods
To examine the role of VDR in muscle mass regulation, Tibialis Cranialis (TC) muscles of Wistar rats were electroporated (under 2.5% isofluorane, 50mg/kg carprofen) to continuously over-express (VDR-OE) or knockdown (VDR-KD) VDR by cDNA or shRNA lentiviral transfection; contralateral TC's were sham treated internal controls. RNA from muscles underwent RNA-Seq using the Illumina HiSeq system, before analysis of differential gene expression and geneset enrichment. False discovery rates were applied throughout.


Results
VDR-OE stimulated fibre hypertrophy (cross-sectional area (CSA) +17±7%, P<0.05) and enhanced muscle protein synthesis (+69±7%, P<0.05). This was matched by an upregulation in key growth related extracellular remodeling and integrin pathway genesets. Comparatively, VDR-KD induced myofibre atrophy (CSA -8±2%, P<0.001) and autophagy related processes (e.g. LC3B-II +84±43%, P<0.05). This was complemented by an upregulation in multiple lysosome and vesicle biogenesis genesets. Moreover, many energy metabolism related genes were downregulated, i.e. electron transport, oxidative phosphorylation, glycolysis and citric acid cycle genesets.



Conclusions
Thus, the VDR acts autonomously to regulate muscle mass; operating through alternate geneset modulation to facilitate hypertrophy through enhanced remodeling, whilst limiting atrophy by regulating energy metabolism and autophagy.







Funding Source: JJB was funded by the MRC doctoral training programme (MR/J500495/1.)

CoAuthors: Daniel Wilkinson – University of Nottingham; Kenneth Smith – University of Nottingham; Andrew Philp – University of Birmingham; Nathaniel Szewczyk – University of Nottingham; Mark Cleasby – Royal Veterinary College; Iain Gallagher – University of Stirling; Philip Atherton – University of Nottingham

Joseph J. Bass

Research Fellow
University of Nottingham
Derby, England, United Kingdom