Vitamin D deficiency: A forgotten treatable cause of motor delay and proximal myopathy
Pediatric Neurology, Pediatric Subspecialties Service, Geneva Children's Hospital, Switzerland. Electronic address: .Brain & development (Impact Factor: 1.88). 12/2012; 36(1). DOI: 10.1016/j.braindev.2012.11.014
We report a four-year-old African boy referred for proximal muscle weakness, fatigability and episodic limb pain. Classical causes of structural and metabolic myopathy were initially considered before clinical and biological features of vitamin D deficiency rickets were identified. Prompt treatment with vitamin D and calcium supplementation led to a complete reversal of the muscle symptoms. Rickets-associated myopathy should be included in the differential diagnosis of proximal myopathy, especially in at-risk individuals. Vitamin D deficiency and its prevention remain important health issues in industrialized countries.
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ABSTRACT: OBJECTIVE:: To evaluate the impact of the active metabolite of vitamin D, 1α,25-dihydroxycholecalciferol (1,25D3), on nucleoside reverse transcriptase inhibitor (NRTI) induced mitochondrial DNA (mtDNA) depletion in human skeletal muscle myoblasts and myotubes. DESIGN:: mtDNA was quantified in human skeletal muscle myoblasts and myotubes following 1,25D3 and NRTI treatment using real-time PCR. METHODS:: Human skeletal muscle myoblasts and myotubes were treated with didanosine (ddI), stavudine (d4T), zidovudine (ZDV), lamivudine (3TC), and abacavir (ABC) alone or in combination either in the presence or absence of 1,25D3 for 5 days. Cells were harvested, DNA extracted and mtDNA quantified. RESULTS:: ddI and ddI-d4T significantly decreased both myoblast and myotube mtDNA in the absence of 1,25D3 compared to untreated controls (P ≤ 0.029). In addition, the ZDV-3TC combination resulted in a 47% decrease in myotube mtDNA (P = 0.005). 1,25D3 increased myotube mtDNA levels in ddI, ZDV, 3TC, ABC, ddI-d4T, d4T-3TC, ZDV-3TC, ZDV-ABC, and ZDV-3TC-ABC containing regimens and myoblast mtDNA levels in ddI, d4T, ZDV, 3TC, ddI-d4T, ZDV-3TC, ZDV-ABC containing regimens. Of note, 1,25D3 protected against myotube mtDNA depletion following ZDV-3TC treatment, rendering them similar to 1,25D3 untreated controls (P = 0.62), and increased both myotube and myoblast mtDNA 2-3-fold in ddI containing regimens (P < 0.05). CONCLUSIONS:: 1,25D3 confers a protective effect against NRTI-induced mitochondrial toxicity in skeletal muscle myoblasts and myotubes. These findings support a protective role for vitamin D in preventing mitochondrial toxicity and suggest that supplemental vitamin D may protect against NRTI-associated mitochondrial toxicity.
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ABSTRACT: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder affecting, among others, the endocrine system, with derangement of steroid hormones functions. Vitamin D is a steroid recognized for its role in calcium homeostasis. In addition, vitamin D influences muscle metabolism by genomic and non-genomic actions, including stimulation of the insulin-like-growth-factor 1 (IGF1), a major regulator of muscle trophism. To verify the presence of vitamin D deficit in DM1 and its possible consequences, serum 25-hydroxyvitamin D (25(OH)D), calcium, parathormone (PTH), and IGF1 levels were measured in 32 DM1 patients and in 32 age-matched controls. Bone mineral density (BMD) and proximal muscle strength were also measured by DXA and a handheld dynamometer, respectively. In DM1 patients, 25(OH)D levels were reduced compared to controls, and a significant decrease of IGF1 was also found. 25(OH)D levels inversely correlated with CTG expansion size, while IGF1 levels and muscle strength directly correlated with levels of 25(OH)D lower than 20 and 10 ng/ml, respectively. A significantly higher percentage of DM1 patients presented hyperparathyroidism as compared to controls. Calcium levels and BMD were comparable between the two groups. Oral administration of cholecalciferol in 11 DM1 patients with severe vitamin D deficiency induced a normal increase of circulating 25(OH)D, ruling out defects in intestinal absorption or hepatic hydroxylation. DM1 patients show a reduction of circulating 25(OH)D, which correlates with genotype and may influence IGF1 levels and proximal muscle strength. Oral supplementation with vitamin D should be considered in DM1 and might mitigate muscle weakness.
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ABSTRACT: Vitamin D deficiency is linked to a range of muscle disorders including myalgia, muscle weakness and falls. Humans with severe vitamin D deficiency and mice with transgenic VDR ablation have muscle fiber atrophy. However, molecular mechanisms by which vitamin D influences muscle function and fiber size remain unclear. A central question is whether the vitamin D receptor (VDR) is expressed in skeletal muscle and is able to regulate transcription at this site. To address this, we examined key molecular and morphologic changes in C2C12 cells treated with 25OHD and 1,25(OH)2D. As well as stimulating VDR expression, 25(OH)D and 1,25(OH)2D dose-dependently increased expression of the classic vitamin D target CYP24A1, demonstrating the presence of an auto-regulatory vitamin D-endocrine system in these cells. Luciferase reporter studies demonstrated that CYP27B1 was functional in these cells. Both 25OHD and 1,25(OH)2D altered C2C12 proliferation and differentiation. These effects were related to the increased expression of genes involved in G0/G1 arrest (Rb: 1.3-fold; ATM: 1.5-fold, both p<0.05), down-regulation of mRNAs involved in G1/S transition, including myc and Cyclin-D1 (0.7 and 0.8-fold, both p<0.05) and reduced phosphorylation of Rb protein (0.3-fold, p<0.005). Following serum depletion, 1,25(OH)2D (100nM) suppressed myotube formation with decreased mRNAs for key myogenic regulatory factors (myogenin: 0.5-fold; myf5: 0.4-fold, p<0.005) but led to 1.8-fold increase in cross-sectional size of individual myotubes associated with markedly decreased myostatin expression (0.2-fold, p<0.005). These data show that Vitamin D signaling alters gene expression in C2C12 cells, with effects on proliferation, differentiation and myotube size.
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