title: 1α,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells.
abstract: Muscle weakness and myopathy are observed in vitamin D deficiency and chronic renal failure, where concentrations of the active vitamin D3 metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are low. To evaluate the mechanism of action of 1α,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 1α,25(OH)2D3. The mitochondrial oxygen consumption rate (OCR) increased in 1α,25(OH)2D3-treated cells. Vitamin D3 metabolites lacking a 1α-hydroxyl group (vitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) decreased or failed to increase OCR. 1α-Hydroxyvitamin D3 did not increase OCR. In 1α,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 1α,25(OH)2D3-treated cells. There was a trend to increased PDH activity in 1α,25(OH)2D3-treated cells (p = 0.09). 83 nuclear mRNAs encoding mitochondrial proteins were changed following 1α,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 1α,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 1α,25(OH)2D3 treatment. Five micro-RNAs were induced or repressed by 1α,25(OH)2D3. 1α,25(OH)2D3 regulates mitochondrial function, dynamics, and enzyme function, which are likely to influence muscle strength.
authors.affiliation: From the Departments of Medicine.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Ryan
authors.affiliation: From the Departments of Medicine.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Craig
authors.affiliation: From the Departments of Medicine.
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Folmes
authors.affiliation: Health Sciences Research.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Departments of Medicine.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Lanza
authors.affiliation: Physiology and Biomedical Engineering, and.
authors.forename: Niccole S
authors.initials: NS
authors.lastname: Schaible
authors.affiliation: Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Salisbury
authors.affiliation: From the Departments of Medicine.
authors.forename: K Sreekumaran
authors.initials: KS
authors.lastname: Nair
authors.affiliation: From the Departments of Medicine.
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.affiliation: Physiology and Biomedical Engineering, and.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
authors.affiliation: From the Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905 rkumar@mayo.edu.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D002117:Calcitriol / Q000031:analogs & derivatives / Q000378:metabolism*; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D035683:MicroRNAs; C000631432:PDK4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018167:Receptors, Calcitriol; D011993:Recombinant Fusion Proteins; C579457:VDR protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D002117:Calcitriol
keywords: 1,25-dihydroxyvitamin D3; RNA-seq; WTSS; cell signaling; gene expression; mitochondria; oxygen consumption; skeletal muscle; vitamin D