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Project description:Lung Cancer Cell-Mediated Skeletal Muscle Mitochondrial Dysfunction is Mitigated by 1a,25-Dihydroxyvitamin D3
| PRJNA401645 | ENA
Project description:Cancer cachexia is associated with muscle weakness and atrophy. We investigated whether 1?,25-dihydroxyvitamin D3 (1?,25(OH)2D3), which has previously been shown to increase skeletal myoblast oxygen consumption rate, could reverse the deleterious effects of tumor cell conditioned medium on myoblast function. Conditioned medium from Lewis lung carcinoma (LLC1) cells inhibits oxygen consumption, increases mitochondrial fragmentation, inhibits pyruvate dehydrogenase activity, and enhances proteasomal activity in human skeletal muscle myoblasts. 1?,25(OH)2D3 reverses the tumor cell-mediated changes in mitochondrial oxygen consumption and proteasomal activity, without changing pyruvate dehydrogenase activity. 1?,25(OH)2D3 might be useful in treatment of weakness seen in association with CC.
| S-EPMC5812288 | biostudies-literature
Project description:Muscle weakness and myopathy are observed in vitamin D deficiency and chronic renal failure, where concentrations of the active vitamin D3 metabolite, 1?,25-dihydroxyvitamin D3 (1?,25(OH)2D3), are low. To evaluate the mechanism of action of 1?,25(OH)2D3 in skeletal muscle, we examined mitochondrial oxygen consumption, dynamics, and biogenesis and changes in expression of nuclear genes encoding mitochondrial proteins in human skeletal muscle cells following treatment with 1?,25(OH)2D3. The mitochondrial oxygen consumption rate (OCR) increased in 1?,25(OH)2D3-treated cells. Vitamin D3 metabolites lacking a 1?-hydroxyl group (vitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) decreased or failed to increase OCR. 1?-Hydroxyvitamin D3 did not increase OCR. In 1?,25(OH)2D3-treated cells, mitochondrial volume and branching and expression of the pro-fusion protein OPA1 (optic atrophy 1) increased, whereas expression of the pro-fission proteins Fis1 (fission 1) and Drp1 (dynamin 1-like) decreased. Phosphorylated pyruvate dehydrogenase (PDH) (Ser-293) and PDH kinase 4 (PDK4) decreased in 1?,25(OH)2D3-treated cells. There was a trend to increased PDH activity in 1?,25(OH)2D3-treated cells (p = 0.09). 83 nuclear mRNAs encoding mitochondrial proteins were changed following 1?,25(OH)2D3 treatment; notably, PDK4 mRNA decreased, and PDP2 mRNA increased. MYC, MAPK13, and EPAS1 mRNAs, which encode proteins that regulate mitochondrial biogenesis, were increased following 1?,25(OH)2D3 treatment. Vitamin D receptor-dependent changes in the expression of 1947 mRNAs encoding proteins involved in muscle contraction, focal adhesion, integrin, JAK/STAT, MAPK, growth factor, and p53 signaling pathways were observed following 1?,25(OH)2D3 treatment. Five micro-RNAs were induced or repressed by 1?,25(OH)2D3. 1?,25(OH)2D3 regulates mitochondrial function, dynamics, and enzyme function, which are likely to influence muscle strength.
| S-EPMC4714233 | biostudies-literature
Project description:Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3), but not inactive 25-hydroxyvitamin D3 (25OHD3), correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02), velocity (Vmax, rho = 0.40, p = 0.02) and jump height (rho = 0.36, p = 0.04). Lean mass correlated positively with 1α,25(OH)2D3 (rho = 0.47, p = 0.02), in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively). Serum 25OHD3 and 24,25(OH)2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR) mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH)2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH)2D3 has limited effects on muscle gene expression, but is associated with increased muscle strength and lean mass in women. These pleiotropic effects of the vitamin D 'metabolome' on muscle function indicate that future supplementation studies should not be restricted to conventional analysis of the major circulating form of vitamin D, 25OHD3.
| S-EPMC5310904 | biostudies-literature
Project description:Vitamin D receptors (VDR) are abundantly expressed in developing zebrafish as early as 48 hours post-fertilization, and prior to the development of a mineralized skeleton, and mature intestine and kidney. We probed the role of VDR in zebrafish biology by examining changes in expression of RNA by whole transcriptome shotgun sequencing (RNA-seq) in fish treated with picomolar concentrations of the VDR ligand and hormonal form of vitamin D3, 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3). We observed significant changes in RNAs encoding proteins of fatty acid, amino acid, and xenobiotic metabolism pathways, and RNAs of transcription factors, leptin, peptide hormones, receptor-activator of NFkB ligand (RANKL), and calcitonin-like ligand receptor pathways. Early small, and subsequent massive changes in >10% of expressed cellular RNAs were observed. At day 2 (24h 1a,25(OH)2D3-treatment), only 5 RNAs were differentially expressed (hormone vs. vehicle). On day 4 (72h-treatment), 78 RNAs; on day 6 (120h-treatment) 1040 RNAs; and on day 7 (144h-treatment), 1755 RNAs were differentially expressed in response to 1a,25(OH)2D3. Fewer RNAs (n = 482) were altered in day 7 embryos treated for 24h with 1a,25(OH)2D3 vs. those treated with hormone for 144h. At 7 days, in 1a,25(OH)2D3-treated embryos, pharyngeal cartilage was larger and mineralization was greater. Changes in expression of RNAs for transcription factors, peptide hormones, and RNAs encoding proteins integral to fatty acid, amino acid, leptin, calcitonin-like ligand receptor, RANKL and xenobiotic metabolism pathways, demonstrate heretofore unrecognized mechanisms by which 1a,25(OH)2D3 functions in vivo in developing eukaryotes.
2012-06-29 | GSE38575 | GEO
Project description:Low serum levels or deficiency of 1α,25-dihydroxyvitamin D3 (VD3) are associated with a higher mortality in trauma patients with sepsis or acute respiratory distress syndrome, although the molecular mechanisms behind this observation are not yet understood. VD3 is known to stimulate lung maturity, alveolar type II cell differentiation and pulmonary surfactant synthesis. This study aims to expand the knowledge by quantitative characterization of NCI-H441 cells upon VD3 treatment at the proteome level.
2023-05-10 | PXD040622 | Pride
Project description:The extracellular matrix protein nephronectin (Npnt), also called POEM, is considered to play critical roles as an adhesion molecule in development and functions of various tissues, such as the kidneys, liver, and bone. In the present study, we examined the molecular mechanism of Npnt gene expression and found that vitamin D3 (1?,25-dihydroxyvitamin D3,VD 3) strongly enhanced Npnt mRNA expression in MC3T3-E1 cells from a mouse osteoblastic cell line. The VD 3-induced increase in Npnt expression is both time- and dose-dependent and is mediated by the vitamin D receptor (VDR).
| S-EPMC5011489 | biostudies-literature
Project description:In this study, we analysed the in-vitro modulation of the transcriptome of human PBMCs isolated from 14 individuals after 24 hours of stimunation with 10 nM 1α,25-dihydroxyvitamin D3 (1,25D)
2024-03-20 | GSE261699 | GEO
Project description:Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 μg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)2D3 in CKD mice. Repletion of 25(OH)D3 in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.
| S-EPMC8699879 | biostudies-literature
Project description:Vitamin D receptors (VDR) are abundantly expressed in developing zebrafish as early as 48 hours post-fertilization, and prior to the development of a mineralized skeleton, and mature intestine and kidney. We probed the role of VDR in zebrafish biology by examining changes in expression of RNA by whole transcriptome shotgun sequencing (RNA-seq) in fish treated with picomolar concentrations of the VDR ligand and hormonal form of vitamin D3, 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3). We observed significant changes in RNAs encoding proteins of fatty acid, amino acid, and xenobiotic metabolism pathways, and RNAs of transcription factors, leptin, peptide hormones, receptor-activator of NFkB ligand (RANKL), and calcitonin-like ligand receptor pathways. Early small, and subsequent massive changes in >10% of expressed cellular RNAs were observed. At day 2 (24h 1a,25(OH)2D3-treatment), only 5 RNAs were differentially expressed (hormone vs. vehicle). On day 4 (72h-treatment), 78 RNAs; on day 6 (120h-treatment) 1040 RNAs; and on day 7 (144h-treatment), 1755 RNAs were differentially expressed in response to 1a,25(OH)2D3. Fewer RNAs (n = 482) were altered in day 7 embryos treated for 24h with 1a,25(OH)2D3 vs. those treated with hormone for 144h. At 7 days, in 1a,25(OH)2D3-treated embryos, pharyngeal cartilage was larger and mineralization was greater. Changes in expression of RNAs for transcription factors, peptide hormones, and RNAs encoding proteins integral to fatty acid, amino acid, leptin, calcitonin-like ligand receptor, RANKL and xenobiotic metabolism pathways, demonstrate heretofore unrecognized mechanisms by which 1a,25(OH)2D3 functions in vivo in developing eukaryotes. Zebrafish embryos were obtained from mating of Segrest wild-type (SWT) parents under controlled barrier conditions, in the Mayo Clinic Zebrafish Core Facility, in Instant Ocean media . Zebrafish embryos (25-30) were placed in 20 mL embryo medium (pH 7.2) containing 1-phenyl-2-thiourea (PTU) (0.003% (w/v) and were maintained at 28-30 oC. At 24 hpf (1 day post fertilization, dpf), 10 microliters of 1a,25(OH)2D3 in ethanol was added to embryos maintained in 20 mL fresh embryo medium with PTU. The final concentration of 1a,25(OH)2D3 was 300 pM. Control zebrafish were treated with 10 microliters ethanol alone (vehicle controls). The medium containing either 300 pM 1a,25(OH)2D3 or vehicle was changed every 24 h . In experiment 1, at 2, 4, 6 and 7 dpf embryos/larvae were removed and immediately frozen at -80 0C for later RNA preparations. 25-30 embryos per set were used for preparation on RNA. At the same times, 7-12 embryos were fixed in 4% paraformaldehyde in 0.75 X DulbeccoM-bM-^@M-^Ys phosphate buffered saline (DPBS). In experiment 2, 6 dpf larvae were treated with 1a,25(OH)2D3 (300 pM) or vehicle for 24 h. RNA was prepared from three sets of larvae.
2012-06-28 | E-GEOD-38575 | biostudies-arrayexpress