Oral Presentation ESA-SRB-AOTA 2019

Mice with myocyte-deletion of vitamin D receptor (VDR) have sarcopenia and impaired muscle function (#91)

Jennifer Chen 1 , Christian Girgis 1 2 3 , Kuan M Cha 1 , Benjamin So 1 4 , Michael Tsang 1 , Peter J Houweling 5 6 , Aaron Schindeler 2 7 , Rebecca Stokes 1 , Michael M Swarbrick 1 2 , Frances J Evesson 2 8 , Sandra T Cooper 2 8 , Jenny E Gunton 1 2 3
  1. The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
  2. Faculty of Health and Medicine, University of Sydney, Sydney, NSW, Australia
  3. Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW, Australia
  4. Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  5. Murdoch Children's Research Institute, Melbourne, VIC, Australia
  6. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
  7. Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, NSW, Australia
  8. Kids Neuroscience Centre, The Children's Hospital at Westmead, University of Sydney, Children's Medical Research Institute, Westmead, NSW, Australia

Vitamin D deficiency has been linked to decreased muscle strength, and falls. Previous work on the whole-body vitamin D receptor knockout mouse model (VDRKO) found that these mice had reduced grip strength. Whether vitamin D has direct effects in muscle is very controversial.

In normal muscle, the VDR is present in very low levels. In this study, we used mice with myocyte-specific deletion of VDR (mVDR) to clarify whether vitamin D has a direct role in muscle function. Floxed VDR mice were interbred with human skeletal actin (HSA)-Cre mice to generate mVDR mice, and muscle physiology was assessed by grip strength tests and Promethion metabolic cages.

Compared to their floxed control siblings, mVDR mice had reduced grip strength (7-16% decrease, P=0.008), voluntary wheel running distance (22% decrease, P=0.009) and average wheel running speed. mVDR mice had significantly lower lean mass, measured by DEXA. At sacrifice, their muscles were significantly smaller. There were fewer, but larger myocytes in the quadriceps as well as increased proportions of small angular fibres with central nuclei indicating ongoing regeneration. The expression of endoplasmic reticulum genes which regulate calcium levels such as Serca2b, Serca3, and the cytosolic Ca2+ buffer Calbindin-D28k, both implicated in muscle relaxation, was reduced in mVDR mice. Downregulation of cell cycle progression genes such as CyclinD1, CyclinD2, CyclinD3, Cdk2 and Cdk4 may have contributed to the reduced muscle mass.

Together, our results suggest myocyte VDR deletion perturbs normal muscle function in mice. These findings demonstrate that vitamin D signalling has functional effects in muscle, where normal vitamin D signalling is important for maintaining muscle function and mass despite the low levels of VDR protein normally found.