The vitamin D receptor regulates mitochondrial function in C2C12 myoblasts

Am J Physiol Cell Physiol. 2020 Mar 1;318(3):C536-C541. doi: 10.1152/ajpcell.00568.2019. Epub 2020 Jan 15.


Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity; however, the mechanistic bases of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1α,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 used lentivirus-mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared with an 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.

Keywords: adaptation; metabolism; mitochondria; skeletal muscle; vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Knockdown Techniques / methods
  • HEK293 Cells
  • Humans
  • Mice
  • Mitochondria / physiology*
  • Myoblasts / physiology*
  • Receptors, Calcitriol / deficiency
  • Receptors, Calcitriol / physiology*
  • Vitamin D Deficiency / metabolism


  • Receptors, Calcitriol
  • VDR protein, human