Dietary vitamin D3 supplementation at 50× the adequate intake decreases calbindin d28k and endoplasmic reticulum stress and increases apoptosis, suggesting toxicity, in the female transgenic G93A mouse model of amyotrophic lateral sclerosis

Background We previously showed that dietary vitamin D 3 (D 3 ) at 50× the adequate intake increased functional capacity in the transgenic G93A mouse model of amyotrophic lateral sclerosis (ALS), with females exhibiting signs of D 3 toxicity. ALS is a progressive neuromuscular disease resulting in the death of upper and lower motor neurons. Objective In this pilot study, we analyzed the quadriceps of G93A mice following dietary D 3 supplementation at 50× the AI for vitamin D receptor and markers of intracellular calcium trafficking (calbindin d28k, calretinin), endoplasmic reticulum (ER) stress (SERCA2, CHOP) and apoptosis (bax/bcl2 ratio, caspase 12 cleaved/pro ratio). Methods Beginning at age 25 d, 41 G93A mice were provided food ad libitum with either adequate (AI; 1 IU D 3 /g feed; 12 M, 11 F) or high (HiD; 50 IU D 3 /g feed; 10 M, 8 F) D 3 . At age 113 d, the quadriceps were analyzed for protein content. Differences were considered significant at P ≤ 0.10. Results In females, HiD had 33% lower calbindin d28k (P = 0.066), 68% lower CHOP (P = 0.074), and 242% higher bax/bcl2 ratio (P = 0.080) vs. AI. HiD males showed no significant differences vs. AI. Conclusion Dietary D 3 at 50× the AI decreases ER stress in the quadriceps of female G93A mice, but increases apoptosis, which could be due to D 3 toxicity. We hypothesize a dynamic crosstalk between ER stress and calcium trafficking. (Supported by NSERC and Faculty of Health, York University) Grant Funding Source : NSERC and Faculty of Health, York University