PMID- 26601949 OWN - NLM STAT- MEDLINE DCOM- 20160602 LR - 20220321 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 291 IP - 3 DP - 2016 Jan 15 TI - 1alpha,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells. PG - 1514-28 LID - 10.1074/jbc.M115.684399 [doi] AB - Muscle weakness and myopathy are observed in vitamin D deficiency and chronic renal failure, where concentrations of the active vitamin D3 metabolite, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), are low. To evaluate the mechanism of action of 1alpha,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 1alpha,25(OH)2D3. The mitochondrial oxygen consumption rate (OCR) increased in 1alpha,25(OH)2D3-treated cells. Vitamin D3 metabolites lacking a 1alpha-hydroxyl group (vitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) decreased or failed to increase OCR. 1alpha-Hydroxyvitamin D3 did not increase OCR. In 1alpha,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 1alpha,25(OH)2D3-treated cells. There was a trend to increased PDH activity in 1alpha,25(OH)2D3-treated cells (p = 0.09). 83 nuclear mRNAs encoding mitochondrial proteins were changed following 1alpha,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 1alpha,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 1alpha,25(OH)2D3 treatment. Five micro-RNAs were induced or repressed by 1alpha,25(OH)2D3. 1alpha,25(OH)2D3 regulates mitochondrial function, dynamics, and enzyme function, which are likely to influence muscle strength. CI - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Ryan, Zachary C AU - Ryan ZC AD - From the Departments of Medicine. FAU - Craig, Theodore A AU - Craig TA AD - From the Departments of Medicine. FAU - Folmes, Clifford D AU - Folmes CD AD - From the Departments of Medicine. FAU - Wang, Xuewei AU - Wang X AD - Health Sciences Research. FAU - Lanza, Ian R AU - Lanza IR AD - From the Departments of Medicine. FAU - Schaible, Niccole S AU - Schaible NS AD - Physiology and Biomedical Engineering, and. FAU - Salisbury, Jeffrey L AU - Salisbury JL AD - Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905. FAU - Nair, K Sreekumaran AU - Nair KS AD - From the Departments of Medicine. FAU - Terzic, Andre AU - Terzic A AD - From the Departments of Medicine. FAU - Sieck, Gary C AU - Sieck GC AD - Physiology and Biomedical Engineering, and. FAU - Kumar, Rajiv AU - Kumar R AD - From the Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905 rkumar@mayo.edu. LA - eng GR - K99 HL121079/HL/NHLBI NIH HHS/United States GR - HL126451/HL/NHLBI NIH HHS/United States GR - AG009531/AG/NIA NIH HHS/United States GR - R01 HL126451/HL/NHLBI NIH HHS/United States GR - DK066013/DK/NIDDK NIH HHS/United States GR - UL1 TR000135/TR/NCATS NIH HHS/United States GR - R01 AG009531/AG/NIA NIH HHS/United States GR - R01 DK066013/DK/NIDDK NIH HHS/United States GR - U01 DK066013/DK/NIDDK NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151124 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (MicroRNAs) RN - 0 (PDK4 protein, human) RN - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase) RN - 0 (Receptors, Calcitriol) RN - 0 (Recombinant Fusion Proteins) RN - 0 (VDR protein, human) RN - 0 (enhanced green fluorescent protein) RN - 147336-22-9 (Green Fluorescent Proteins) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 3.1.3.43 (Pyruvate Dehydrogenase (Lipoamide)-Phosphatase) RN - EC 3.6.1.- (GTP Phosphohydrolases) RN - EC 3.6.1.- (OPA1 protein, human) RN - FXC9231JVH (Calcitriol) SB - IM MH - Calcitriol/analogs & derivatives/*metabolism MH - Cells, Cultured MH - GTP Phosphohydrolases/genetics/metabolism MH - Gene Expression Profiling MH - *Gene Expression Regulation MH - Green Fluorescent Proteins/genetics/metabolism MH - Humans MH - MicroRNAs/agonists/antagonists & inhibitors/metabolism MH - Mitochondria, Muscle/enzymology/*metabolism MH - *Mitochondrial Dynamics MH - Muscle, Skeletal/cytology/enzymology/*metabolism MH - *Oxidative Phosphorylation MH - Phosphorylation MH - Protein Processing, Post-Translational MH - Protein Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism MH - Pyruvate Dehydrogenase (Lipoamide)-Phosphatase/genetics/metabolism MH - Pyruvate Dehydrogenase Acetyl-Transferring Kinase MH - RNA Interference MH - Receptors, Calcitriol/*agonists/antagonists & inhibitors/genetics/metabolism MH - Recombinant Fusion Proteins/metabolism MH - Signal Transduction PMC - PMC4714233 OTO - NOTNLM OT - 1,25-dihydroxyvitamin D3 OT - RNA-seq OT - WTSS OT - cell signaling OT - gene expression OT - mitochondria OT - oxygen consumption OT - skeletal muscle OT - vitamin D EDAT- 2015/11/26 06:00 MHDA- 2016/06/03 06:00 PMCR- 2017/01/15 CRDT- 2015/11/26 06:00 PHST- 2015/08/10 00:00 [received] PHST- 2015/11/26 06:00 [entrez] PHST- 2015/11/26 06:00 [pubmed] PHST- 2016/06/03 06:00 [medline] PHST- 2017/01/15 00:00 [pmc-release] AID - S0021-9258(20)36181-0 [pii] AID - M115.684399 [pii] AID - 10.1074/jbc.M115.684399 [doi] PST - ppublish SO - J Biol Chem. 2016 Jan 15;291(3):1514-28. doi: 10.1074/jbc.M115.684399. Epub 2015 Nov 24.