&lt;b&gt;1α,25(OH)&lt;/b&gt;&lt;b&gt;&lt;sub&gt;2&lt;/sub&gt;&lt;/b&gt;&lt;b&gt;D&lt;/b&gt;&lt;b&gt;&lt;sub&gt;3&lt;/sub&gt;&lt;/b&gt;&lt;b&gt; downregulates gene expression levels of muscle ubiquitin ligases MAFbx and MuRF1 in human &lt;/b&gt;&lt;b&gt;myotubes &lt;/b&gt;

Hayakawa, Naohiko; Fukumura, Junko; Yasuno, Hideyuki; Fujimoto-Ouchi, Kaori; Kitamura, Hiroyuki

doi:10.2220/biomedres.36.71

Cited by 21 publications

(14 citation statements)

References 45 publications

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“…Decreases in Murf1 and Mafbx in mVDR mice would support better maintenance of fibre size with inhibition of the ubiquitin–proteosome pathway. Interestingly, these were also decreased in human myotubes treated with vitamin D, suggesting the possibility that in mVDR mice, the decrease could be mediated by effects of another cell type with intact vitamin D signalling.…”

Section: Discussionmentioning

confidence: 99%

Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function

Girgis

Minn

et al. 2019

J cachexia sarcopenia muscle

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BackgroundIt has long been recognized that vitamin D deficiency is associated with muscle weakness and falls. Vitamin D receptor (VDR) is present at very low levels in normal muscle. Whether vitamin D plays a direct role in muscle function is unknown and is a subject of hot debate. Myocyte‐specific deletion of VDR would provide a strategy to answer this question.MethodsMyocyte‐specific vitamin D receptor (mVDR) null mice were generated by crossing human skeletal actin‐Cre mice with floxed VDR mice. The effects of gene deletion on the muscle phenotype were studied in terms of body tissue composition, muscle tissue histology, and gene expression by real‐time PCR.ResultsUnlike whole‐body VDR knockout mice, mVDR mice showed a normal body size. The mVDR showed a distinct muscle phenotype featuring reduced proportional lean mass (70% vs. 78% of lean mass), reduced voluntary wheel‐running distance (22% decrease, P = 0.009), reduced average running speed, and reduced grip strength (7–16% reduction depending on age at testing). With their decreased voluntary exercise, and decreased lean mass, mVDR have increased proportional fat mass at 20% compared with 13%.Surprisingly, their muscle fibres showed slightly increased diameter, as well as the presence of angular fibres and central nuclei suggesting ongoing remodelling. There were, however, no clear changes in fibre type and there was no increase in muscle fibrosis. VDR is a transcriptional regulator, and changes in the expression of candidate genes was examined in RNA extracted from skeletal muscle. Alterations were seen in myogenic gene expression, and there was decreased expression of cell cycle genes cyclin D1, D2, and D3 and cyclin‐dependent kinases Cdk‐2 and Cdk‐4. Expression of calcium handling genes sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) Serca2b and Serca3 was decreased and Calbindin mRNA was lower in mVDR muscle.ConclusionsThis study demonstrates that vitamin D signalling is needed for myocyte function. Despite the low level of VDR protein normally found muscle, deleting myocyte VDR had important effects on muscle size and strength. Maintenance of normal vitamin D signalling is a useful strategy to prevent loss of muscle function and size.

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Section: Discussionmentioning

confidence: 99%

Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function

Girgis

Minn

et al. 2019

J cachexia sarcopenia muscle

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“…MAFbx and MuRF1 mRNA levels were not significantly different between rat skeletal muscle with and without infusion of IL-6 [ 13 ]. Although MAFbx mRNA was increased by 100 ng/mL of IL-6 and MuRF1 mRNA was significantly increased by 10 and 100 ng/mL IL-6, MAFbx mRNA was not increased by 1 or 10 ng/mL of IL-6 and MuRF1 mRNA was not increased by 1 ng/mL of IL-6 in human myocytes [ 25 ]. In this study, LPS increased IL-6 levels by up to approximately 0.94 ng/mL, which may be too low to increase MAFbx and MuRF1 protein levels.…”

Section: Discussionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 Inhibits Lipopolysaccharide-Induced Interleukin-6 Production by C2C12 Myotubes

et al. 2020

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Background and Objective. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits proinflammatory cytokines in microglial cells and monocytes. However, it is unclear whether 1,25(OH)2D3 inhibits proinflammatory cytokines in muscle cells. This study was conducted to investigate whether 1,25(OH)2D3 inhibits the production of proinflammatory cytokines, resulting in inhibition of the protein expression of E3 ubiquitin ligases and muscle protein loss. Materials and Methods. C2C12 myoblasts were proliferated in Dulbecco’s modified Eagle medium (DMEM) containing 10% fetal bovine serum, and myoblasts were differentiated into myotubes in DMEM containing 2% horse serum. Myotubes were treated with 1,25(OH)2D3 for 24 h, followed by lipopolysaccharide (LPS) stimulation for 48 h. Results. Interleukin (IL)-6 protein concentrations were higher in the culture supernatant following LPS stimulation compared to that without LPS stimulation (p < 0.001). However, the IL-6 concentration was significantly lower in C2C12 myotubes following 1,25(OH)2D3 treatment than in C2C12 myotubes without 1,25(OH)2D3 treatment (p < 0.001). The myosin heavy chain (MHC), muscle atrophy F-box, and muscle ring-finger protein-1 protein levels did not significantly differ (P = 0.324, 0.552, and 0.352, respectively). We could not compare tumor necrosis factor α (TNFα) protein levels because they were below the limit of detection of our assay in many supernatant samples, including in LPS-stimulated samples. Conclusions. 1,25(OH)2D3 inhibited increases in IL-6 protein concentrations in muscle cells stimulated by LPS, suggesting that 1,25(OH)2D3 inhibits inflammation in muscle cells. The findings suggest that 1,25(OH)2D3 can prevent or improve sarcopenia, which is associated with IL-6. The TNFα protein content could not be measured, and MHC was not decreased despite LPS stimulation of C2C12 myotubes. Further studies are needed to examine the effects of higher doses of LPS stimulation on muscle cells and use more sensitive methods for measuring TNFα protein to investigate the preventive effects of 1,25(OH)2D3 on increased TNFα and muscle proteolysis.

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“…Few studies have previously shown that vitamin D represses atrogene expression [ 16 ]. However, we have demonstrated for the first time that vitamin D represses the expression of MuRF1 and atrogin-1 in a mouse model of disuse-induced atrophy.…”

Section: Discussionmentioning

confidence: 99%

“…1,25(OH) 2 D 3 and other forms of vitamin D have been shown to repress IL-6 in vitro and in vivo [ 14 , 15 ]. One study has reported that 1,25(OH) 2 D 3 downregulated MuRF1 and atrogin-1 expression in human myotubes [ 16 ]. In this way, HMB and 1,25(OH) 2 D 3 have been supposed to possess both anti-atrophic effects and IL-6-repressing effects, but the relationship between these effects is unclear.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy

et al. 2018

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BackgroundInterleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear.MethodsTail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy.ResultsSerum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice.ConclusionSystemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy.

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<b>1α,25(OH)</b><b><sub>2</sub></b><b>D</b><b><sub>3</sub></b><b> downregulates gene expression levels of muscle ubiquitin ligases MAFbx and MuRF1 in human </b><b>myotubes </b>

Cited by 21 publications

References 45 publications

Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function

Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function

1,25-Dihydroxyvitamin D3 Inhibits Lipopolysaccharide-Induced Interleukin-6 Production by C2C12 Myotubes

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy

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