1α,25-dihydroxyvitamin D3 regulates mitochondrial oxygen consumption and dynamics in human skeletal muscle cells

Zachary C. Ryan, Theodore A. Craig, Clifford Folmes, Xuewei Wang, Ian R Lanza, Niccole S. Schaible, Jeffrey L Salisbury, K Sreekumaran Nair, Andre Terzic, Gary C Sieck, Rajiv Kumar

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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 (vitaminD3, 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 α 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.

Original languageEnglish (US)
Article number15
Pages (from-to)1514-1528
Number of pages15
JournalJournal of Biological Chemistry
Volume291
Issue number3
DOIs
StatePublished - Jan 15 2016

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Calcitriol
Oxygen Consumption
Muscle Cells
Muscle
Skeletal Muscle
Cells
Oxygen
Messenger RNA
Cholecalciferol
Mitochondrial Proteins
Metabolites
Pyruvic Acid
Oxidoreductases
Proteins
Dynamin I
Autosomal Dominant Optic Atrophy
Mitochondrial Dynamics
Mitochondrial Size
Calcifediol
Calcitriol Receptors

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

1α,25-dihydroxyvitamin D3 regulates mitochondrial oxygen consumption and dynamics in human skeletal muscle cells. / Ryan, Zachary C.; Craig, Theodore A.; Folmes, Clifford; Wang, Xuewei; Lanza, Ian R; Schaible, Niccole S.; Salisbury, Jeffrey L; Nair, K Sreekumaran; Terzic, Andre; Sieck, Gary C; Kumar, Rajiv.

In: Journal of Biological Chemistry, Vol. 291, No. 3, 15, 15.01.2016, p. 1514-1528.

Research output: Contribution to journalArticle

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AU - Schaible, Niccole S.

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