The vitamin D receptor (VDR) autonomously regulates skeletal muscle mass

Vitamin D (VitD) deficiency is estimated to affect ~40% of the world's population. Notably, VitD deficiency has been associated with impaired muscle maintenance and insulin resistance. VitD exerts its actions through the ubiquitous Vitamin D-receptor (VDR), the expression of which was recently confirmed in fully-differentiated muscle. To seek a possible autonomous role of the VDR in skeletal muscle, we first generated stable VDR-knockdown cells, which exhibited impaired myogenesis (i.e. cell-cycling, differentiation and myotube formation). In vivo VDR-knockdown in rat hind-limbs elicited myofibre atrophy and triggered autophagy pathways. In contrast, in vivo VDR-overexpression yielded myofibre hypertrophy; enhancing translational efficiency (e.g. mTOR-signaling), ribosomal biogenesis and satellite cell content. Neither VDR-knockdown nor overexpression impacted muscle glucose uptake. Crucially, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise training, but not aspects of insulin sensitivity. The VDR autonomously regulates muscle mass, acting reciprocally to limit atrophy and promote hypertrophy. Overall design: In vivo electroporation was used to knock out (ko) or knock in (ki) the vitmain D receptor in the tibialis anterior muscle of one hindlimb in rats. VDR-KD groups received VDR shRNA (Table S1) in right leg TAM and scramble shRNA in left leg TAM. VDR-OE groups received pCAGGS-mVDR in right leg TAM, and empty pCAGGS controls in left leg TAM. Immediately following, one HV (900 V/cm, 100 µ-sec pulse), and four LV (90 V/cm, 100 m-sec) pulses were administered across the distal limb via tweezer-electrodes attached to an ECM-830 electroporator (BTX, Holliston, MA). Animals subsequently received a subcutaneous injection of carprofen (50mg/kg), before recovery from anesthesia. RNA-seq was carried out with the contrast of interest being either ko v control limb or ki v control limb.