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.
Highlights
Dietary 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 Amyotrophic lateral sclerosis (ALS)
Females may have reached the threshold for vitamin D3 toxicity as evidence by reduced food intake and greater disease severity prior to disease onset
Amyotrophic lateral sclerosis (ALS; known as Lou Gehrig’s disease) is a neurodegenerative/neuromuscular disease characterized by progressive degeneration of motor neurons in the central nervous system (CNS), resulting in muscle weakness followed by paralysis [1]
Summary
Amyotrophic lateral sclerosis (ALS; known as Lou Gehrig’s disease) is a neurodegenerative/neuromuscular disease characterized by progressive degeneration of motor neurons in the central nervous system (CNS), resulting in muscle weakness followed by paralysis [1]. The pathophysiology is multi-faceted and involves oxidative stress, inflammation, glutamate excitotoxicity, and neurodegeneration [3]. Vitamin D attenuates several mechanisms involved in ALS disease pathology, such as 1) oxidative stress (increased liver and kidney antioxidant enzyme activity by up to 4.4 fold, and decreased lipid peroxidation by up to 46%) [9], 2) inflammation (increased serum IL-10 by 43%, while inhibiting rise in TNF-a) [10], 3) glutamate excitotoxicity (increased neuronal survival in vitro by 17% and 50% with 10 nM and 100 nM calcitriol, respectively) [11] and 4) neuronal death while increasing expression of neurotrophic factors [12,13,14,15]. We hypothesized that higher doses would elicit more robust changes in functional and disease outcomes
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