Vitamin D3 at 50x AI Attenuates the Decline in Paw Grip Endurance, but Not Disease Outcomes, in the G93A Mouse Model of ALS, and Is Toxic in Females

Abstract

BackgroundWe previously demonstrated that dietary vitamin D3 at 10x the adequate intake (AI) attenuates the decline in functional capacity in the G93A mouse model of ALS. We hypothesized that higher doses would elicit more robust changes in functional and disease outcomes.ObjectiveTo determine the effects of dietary vitamin D3 at 50xAI on functional outcomes (motor performance, paw grip endurance) and disease severity (clinical score), as well as disease onset, disease progression and lifespan in the transgenic G93A mouse model of ALS.MethodsStarting at age 25 d, 100 G93A mice (55 M, 45 F) were provided ad libitum with either an adequate (AI; 1 IU D3/g feed) or high (HiD; 50 IU D3/g feed) vitamin D3 diet.ResultsHiD females consumed 9% less food corrected for body weight vs. AI females (P = 0.010). HiD mice had a 12% greater paw grip endurance over time between age 60–141 d (P = 0.015), and a 37% greater score during disease progression (P = 0.042) vs. AI mice. Although HiD females had a non-significant 31% greater CS prior to disease onset vs. AI females, they exhibited a significant 20% greater paw grip endurance AUC (P = 0.020) when corrected for clinical score.ConclusionDietary D3 supplementation at 50x the adequate intake attenuated the decline in paw grip endurance, but did not influence age at disease onset, hindlimb paralysis or endpoint in the transgenic G93A mouse model of ALS. Furthermore, females may have reached the threshold for vitamin D3 toxicity as evidence by reduced food intake and greater disease severity prior to disease onset.

Dietary Vitamin D3 Supplementation at 10× the Adequate Intake Improves Functional Capacity in the G93A Transgenic Mouse Model of ALS, a Pilot Study

“…Furthermore, we found that when corrected for disease severity HiD mice had 5% greater ATM versus AI mice, and HiD males had 81% greater MP versus AI males. Indeed, we observed similar functional and disease outcomes in a much larger, higher dose follow-up study using the same mouse model [20]. For humans, this would indicate that vitamin D 3 supplementation far above the adequate intake may improve ambulation at the same stage of disease versus no supplementation.…”

“…20 20 Fat (%) 7 7 Vitamin D 3 (IU/g) 1 a 10 a,b Calcium (%) 0.5 c 0.5 c Vitamin mix V10037 (mg/g) 10 10 Mineral mix S100022G (mg/g) 35 35 Diets provided by Research Diets (based on AIN-93G; New Brunswick, NJ; AI product # D10012G; HiD product # D08080101). a included in vitamin mix V10037.…”

“…Beginning at age 60 days, PaGE was measured twice per week using the modified hanging wire test [7,8,19,20,22,23].…”

Vitamin D is Not a Protective Factor in ALS

“…Some studies suggest that vitamin D could ameliorate pathological mechanisms [15] and that supplementation could slow the disease course [12,16]. On the other hand, reports from a high copy SOD1 G93A-mutated transgenic mouse model of ALS suggest that administration of vitamin D could alter dopaminergic activity in the brain [16], which may be toxic to female pups [14] and, when deficient, may delay onset and attenuate early disease severity [17]. In one study, vitamin D supplementation in rodents did not produce beneficial effects on age of onset or disease duration [15].…”

Vitamin D in amyotrophic lateral sclerosis

“…Several studies have analyzed vitamin D status in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease (Buell et al, 2010;Gianforcaro and Hamadeh, 2012). Recent studies on the G93A transgenic mouse model of ALS showed improved functional outcome compared to control mice after supplementation of vitamin D Hamadeh, 2012, Solomon et al, 2011;Gianforcaro et al, 2013). Moreover, vitamin D applied on motoneurons cultured in vitro seems to potentiate the effects of glial-and brainderived neurotrophic growth factors, protecting cells from Fas-induced cell death (Camu et al, 2014).…”