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. 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.