The Vitamin D Receptor (VDR) Regulates Mitochondrial Function in C2C12 Myoblasts
Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity however, the mechanistic basis of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1a,25(OH)2D3 to the regulation of skeletal muscle mitochondrial function in vitro however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we utilised lentiviral mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared to shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes (P < 0.001). VDR-KD myoblasts displayed a 30%, 30% and 36% reduction in basal, coupled and maximal respiration respectively (P < 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33% and 48% reduction in basal, coupled and maximal respiration (P < 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATPOx) was reduced by 20% suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content as well as markers of mitochondrial fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.
|ISBN||1522-1563 (Electronic) 0363-6143 (Linking)|
|Authors||Ashcroft, S. P.; Bass, J. J.; Kazi, A. A.; Atherton, P. J.; Philp, A.|
|Responsible Garvan Author|
|Publisher Name||AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/31940245|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/15290|