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Steg A, Oczkowicz M, Świątkiewicz M. Effects of High-Dose Vitamin D3 Supplementation on Pig Performance, Vitamin D Content in Meat, and Muscle Transcriptome in Pigs. J Anim Physiol Anim Nutr (Berl) 2025; 109:560-573. [PMID: 39567837 DOI: 10.1111/jpn.14066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/02/2024] [Accepted: 10/19/2024] [Indexed: 11/22/2024]
Abstract
Vitamin D is known for its role in calcium homeostasis, bone health, and immune function. Recent research has explored its effects on muscle functionality and meat quality in pigs. This study examined high-dose vitamin D3 supplementation in pigs, focusing on growth, blood and tissue vitamin D3 levels, and muscle transcriptome changes. Thirty pigs were divided into three groups, given different amounts of oral supplementation: control, 5000 IU/kg and 10,000 IU/kg vitamin D3. Biochemical and haematological blood parameters, vitamin D content in blood and muscle, and kidney calcium content were evaluated. RNA-seq and qPCR analysed muscle transcriptome changes, while gene set enrichment analysis (GSEA) identified gene expression enrichments. Results showed that 5000 IU/kg vitamin D3 supplementation altered blood parameters like platelet anisocytosis and glucose levels but did not affect body weight, weight gain, or feed intake. Kidney calcium content increased with supplementation. The muscle (longissimus dorsi) vitamin D content increased, suggesting the potential for biofortified pork, although still not optimal as a dietary vitamin D source. Transcriptome analysis revealed minimal gene expression changes, with only the interferon-gamma receptor 2 (IFNGR2) gene differentially expressed at the highest dose. GSEA indicated enrichment in ATP metabolic processes and electron transport chain genes in the 5000 IU/kg group, and immune system, cholesterol, steroid, and fatty acid metabolism genes in the 10,000 IU/kg group. Despite literature suggesting a role for vitamin D in muscle gene expression and growth improvement, this study found its effects limited.
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Affiliation(s)
- Anna Steg
- Department of Animal Molecular Biology, National Research Institute of Animal Production, Krakowska, Poland
| | - Maria Oczkowicz
- Department of Animal Molecular Biology, National Research Institute of Animal Production, Krakowska, Poland
| | - Małgorzata Świątkiewicz
- Department of Animal Nutrition and Feed Science, National Research Institute of Animal Production, Krakowska, Poland
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Jiang W, Sang R, Zhang C, Yin R, Ouyang Z, Wei Y. Application of small interfering RNA technology in cytochrome P450 gene modulation. Drug Metab Dispos 2025; 53:100040. [PMID: 40010050 DOI: 10.1016/j.dmd.2025.100040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 02/28/2025] Open
Abstract
Cytochrome P450 plays key roles in the biotransformation of endogenous and exogenous chemicals including drugs and environmental pollutants. The inhibition and downregulation of P450s can have therapeutic effects, and/or modulate drug metabolism. P450s are largely inhibited by small molecules; however, this strategy is often hampered by intrinsic toxicity and drug-drug interactions. Furthermore, it is challenging for small molecules to exhibit high selectivity and inhibitory efficiencies. Recently, small interfering RNA (siRNA) technology has demonstrated the potential for P450 modulation. Examples of recent applications of siRNAs in P450 gene modulation, in vitro and in vivo, are highlighted in this review. The necessity of siRNA techniques and their advantages as P450 modulators are discussed, along with a review of current obstacles and a perspective on future advancements. SIGNIFICANCE STATEMENT: This article reviews studies on the application of small interfering RNA technology to cytochrome P450 gene modulation. The necessity of siRNA methods and the benefits of their use as P450 modulators have been suggested by comparison with small-molecule drugs. Additionally, the challenges that presently limit the broader implementation of this topic are examined, and a perspective for future developments is proposed.
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Affiliation(s)
- Wenzhao Jiang
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Ruoyao Sang
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Cai Zhang
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Zhen Ouyang
- School of Pharmacy, Jiangsu University, Zhenjiang, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhenjiang, China.
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Ewendt F, Drewitz F, Althammer M, Eichler C, Brandsch C, Brey S, Winkler TH, Wilkens MR, St-Arnaud R, Kreutz M, Stangl GI. Vitamin D stimulates Il-15 synthesis in rodent muscle. Biochem Biophys Rep 2025; 41:101925. [PMID: 40134939 PMCID: PMC11935148 DOI: 10.1016/j.bbrep.2025.101925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 12/24/2024] [Accepted: 01/19/2025] [Indexed: 03/27/2025] Open
Abstract
Besides its classical skeletal function, vitamin D plays a critical role in both skeletal muscle and the immune system. Interleukin-15 (IL-15), which is highly expressed, and secreted complexed with its receptor, IL-15Rα, by skeletal muscle, stimulates the development of immune cells and affects myogenesis and muscle mass. However, little is known about possible regulators of this myokine. To test whether vitamin D could be a regulator of muscle IL-15 and IL-15Rα expression, C2C12 myotubes were treated with vitamin D3 metabolites and analysis were performed in gastrocnemius muscles of rats treated with a single intraperitoneal dose of 1,25(OH)2D3. The role of VDR was investigated by siRNA technique in C2C12 myotubes and in gastrocnemius muscles of vitamin D receptor knockout (Vdr-KO) mice. Treatment of C2C12 myotubes with 1,25(OH)2D3 or 25(OH)D3 increased Il-15 gene expression in a dose-dependent manner and 1,25(OH)2D3 also moderately increased the relative Il-15 protein amount. Rats treated with a single dose of 1,25(OH)2D3 demonstrated a higher mRNA abundance of muscle Il-15 than controls. The 1,25(OH)2D3 effect on Il-15 was considerably weaker in C2C12 myotubes treated with Vdr-specific siRNA. Vdr-KO mice showed significantly lower muscle Il-15 mRNA than WT mice. Il-15Ra mRNA and Il-15/Il-15Rα protein abundance were unaffected by 1,25(OH)2D3-treatment or VDR functionality, and Cyp27b1 activity is not required for 25(OH)D3-mediated Il-15 gene expression. The results provide evidence for a regulatory role of hydroxyvitamin D3 metabolites on the Il-15 synthesis in skeletal muscle cells, which is largely mediated by the VDR.
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Affiliation(s)
- Franz Ewendt
- Martin Luther University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, 06120, Halle (Saale), Germany
| | - Fabienne Drewitz
- Martin Luther University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, 06120, Halle (Saale), Germany
| | - Michael Althammer
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Cosima Eichler
- Martin Luther University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, 06120, Halle (Saale), Germany
| | - Corinna Brandsch
- Martin Luther University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, 06120, Halle (Saale), Germany
| | - Stefanie Brey
- Division of Genetics, Department Biology, Friedrich-Alexander University Erlangen-Nürnberg, 91058, Erlangen, Germany
| | - Thomas H. Winkler
- Division of Genetics, Department Biology, Friedrich-Alexander University Erlangen-Nürnberg, 91058, Erlangen, Germany
| | - Mirja R. Wilkens
- Institute of Animal Nutrition, Nutrition Diseases and Dietetics, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany
| | - René St-Arnaud
- Shriners Hospitals for Children - Canada and McGill University, Montréal, Quebec, Canada
| | - Marina Kreutz
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Gabriele I. Stangl
- Martin Luther University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, 06120, Halle (Saale), Germany
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Mayakrishnan V, Kannappan P, Balakarthikeyan J, Kim CY. Rodent model intervention for prevention and optimal management of sarcopenia: A systematic review on the beneficial effects of nutrients & non-nutrients and exercise to improve skeletal muscle health. Ageing Res Rev 2024; 102:102543. [PMID: 39427886 DOI: 10.1016/j.arr.2024.102543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 09/25/2024] [Accepted: 10/07/2024] [Indexed: 10/22/2024]
Abstract
Sarcopenia is a common musculoskeletal disorder characterized by degenerative processes and is strongly linked to an increased susceptibility to falls, fractures, physical limitations, and mortality. Several models have been used to explore therapeutic and preventative measures as well as to gain insight into the molecular mechanisms behind sarcopenia. With novel experimental methodologies emerging to design foods or novel versions of conventional foods, understanding the impact of nutrition on the prevention and management of sarcopenia has become important. This review provides a thorough assessment of the use of rodent models of sarcopenia for understanding the aging process, focusing the effects of nutrients, plant extracts, exercise, and combined interventions on skeletal muscle health. According to empirical research, nutraceuticals and functional foods have demonstrated potential benefits in enhancing physical performance. In preclinical investigations, the administration of herbal extracts and naturally occurring bioactive compounds yielded advantageous outcomes such as augmented muscle mass and strength generation. Furthermore, herbal treatments exhibited inhibitory effects on muscle atrophy and sarcopenia. A substantial body of information establishes a connection between diet and the muscle mass, strength, and functionality of older individuals. This suggests that nutrition has a major impact in both the prevention and treatment of sarcopenia.
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Affiliation(s)
- Vijayakumar Mayakrishnan
- Research Institute of Human Ecology, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Priya Kannappan
- PSG College of Arts & Science, Civil Aerodrome, Coimbatore, Tamil Nadu 641014, India
| | | | - Choon Young Kim
- Research Institute of Human Ecology, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea; Department of Food and Nutrition, Yeungnam University Gyeongsan, Gyeongbuk 38541, Republic of Korea.
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Ong MTY, Tsang KCK, Lu VYZ, Yam SLS, Shen W, Man GCW, Yung PSH. Effect of serum 25-hydroxyvitamin D level on quadriceps strength: a systematic review and meta-analysis. BMC Sports Sci Med Rehabil 2024; 16:215. [PMID: 39402687 PMCID: PMC11476103 DOI: 10.1186/s13102-024-01007-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Vitamin D deficiency has been linked to poor muscle function, cartilage degeneration, and the development of knee osteoarthritis. However, the impact of serum 25-hydroxyvitamin D [25(OH)D] level on quadriceps muscle strength remains inconclusive, largely due to variations in study designs, differences in study populations, and the influence of confounding factors such as co-supplementation with other vitamins. The existing literature presents mixed findings, highlighting the need for a comprehensive evaluation of the available evidence. PURPOSE This systematic review and meta-analysis aim to summarise. STUDY DESIGN Systematic review; Level of evidence, 4. METHODS Searches were conducted using Medline (Ovid), Embase (Ovid), CINAHL (EBSCOhost), and SPORTDiscus (EBSCOhost), which aimed to summarise recent (published after 2000 and before March 1st, 2024) studies reporting the effects of serum 25(OH)D levels on quadriceps strength. Appraisal tool for Cross-Sectional Studies (AXIS) for cross-sectional studies and Quality in Prognosis Studies (QUIPS) for longitudinal studies. Results from the AXIS and QUIPS tools were used for GRADE quality assessment. The review was carried out using PRIMSA guidelines and registered in PROSPERO (ID: CRD42022313240). RESULTS Four hundred studies were screened and 28 studies with 5752 participants were included. 28 published studies (24 cross-sectional and 4 longitudinal) were identified. Key results supported the significant positive correlation between serum 25(OH)D levels and isokinetic quadriceps strength at 180°/s in elderly and athletic populations with a correlation coefficient of 0.245 (95%CI: 0.078-0.398, p = 0.004). However, no significant correlation was found with isometric quadriceps strength or isokinetic strength at 60°/s (r = 0.190, p = 0.085). There was only a weak negative correlation with MVC. CONCLUSION This review found a statistically significant positive correlation between serum 25(OH)D levels and isokinetic quadriceps strength. This has important clinical implications, especially in the elderly cohort, with higher 25(OH)D levels being associated with a reduced incidence of falls and fragility fractures.
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Affiliation(s)
- Michael Tim-Yun Ong
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Kitson Chun-Kit Tsang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Victor Yan Zhe Lu
- School of Clinical Medicine, University of Cambridge, Hills Rd, Cambridge, CB2 0SP, UK
| | - Stacy Lok Sze Yam
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wei Shen
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Gene Chi-Wai Man
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Patrick Shu-Hang Yung
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
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Olszewska AM, Zmijewski MA. Genomic and non-genomic action of vitamin D on ion channels - Targeting mitochondria. Mitochondrion 2024; 77:101891. [PMID: 38692383 DOI: 10.1016/j.mito.2024.101891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/26/2024] [Accepted: 04/28/2024] [Indexed: 05/03/2024]
Abstract
Recent studies revealed that mitochondria are not only a place of vitamin D3 metabolism but also direct or indirect targets of its activities. This review summarizes current knowledge on the regulation of ion channels from plasma and mitochondrial membranes by the active form of vitamin D3 (1,25(OH)2D3). 1,25(OH)2D3, is a naturally occurring hormone with pleiotropic activities; implicated in the modulation of cell differentiation, and proliferation and in the prevention of various diseases, including cancer. Many experimental data indicate that 1,25(OH)2D3 deficiency induces ionic remodeling and 1,25(OH)2D3 regulates the activity of multiple ion channels. There are two main theories on how 1,25(OH)2D3 can modify the function of ion channels. First, describes the involvement of genomic pathways of response to 1,25(OH)2D3 in the regulation of the expression of the genes encoding channels, their auxiliary subunits, or additional regulators. Interestingly, intracellular ion channels, like mitochondrial, are encoded by the same genes as plasma membrane channels. Therefore, the comprehensive genomic regulation of the channels from these two different cellular compartments we analyzed using a bioinformatic approach. The second theory explores non-genomic pathways of vitamin D3 activities. It was shown, that 1,25(OH)2D3 indirectly regulates enzymes that impact ion channels, change membrane physical properties, or directly bind to channel proteins. In this article, the involvement of genomic and non-genomic pathways regulated by 1,25(OH)2D3 in the modulation of the levels and activity of plasma membrane and mitochondrial ion channels was investigated by an extensive review of the literature and analysis of the transcriptomic data using bioinformatics.
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Affiliation(s)
- A M Olszewska
- Department of Histology, Medical University of Gdansk, 1a Debinki, 80-211 Gdansk, Poland
| | - M A Zmijewski
- Department of Histology, Medical University of Gdansk, 1a Debinki, 80-211 Gdansk, Poland.
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Shoemaker ME, Dicks ND, Northrup MJ, Daughters SW, Krings TN, Barry AM. Evaluation of Nutrition and Performance Parameters in Division 1 Collegiate Athletes. Nutrients 2024; 16:1896. [PMID: 38931251 PMCID: PMC11206669 DOI: 10.3390/nu16121896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/10/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Testing and evaluating athletes is necessary and should include performance, body composition, and nutrition. The purpose of this study was to report assessments of dietary intake, V˙O2max, and body composition in D1 collegiate athletes and examine relationships between these assessments. METHODS Dietary intake was assessed with 3-day recalls and compared to recommendations, and body composition was assessed via bioelectrical impedance analysis (BIA) (n = 48). V˙O2max was evaluated using a graded exercise test (GXT) with a verification bout (n = 35). Reliability between "true" V˙O2max and verification was determined. Correlations and regressions were performed. RESULTS Energy, carbohydrate, and micronutrient intake was lower than recommendations. Mean V˙O2max was 47.3 and 47.4 mL·kg-1·min-1 for GXT and verification, respectively. While correlations were apparent among dietary intake, V˙O2max, and body composition, percent fat-free mass (%FFM) predicted 36% of V˙O2max. CONCLUSIONS Collegiate athletes are not meeting energy and carbohydrate recommendations and exceed fat recommendations. Vitamin D and magnesium were low in all sports, and iron and calcium were low in females. V˙O2max ranged from 35.6 to 63.0 mL·kg-1·min-1, with females below average and males meeting typical values for their designated sport. Assessing D1 athletes can provide guidance for sports dietitians, coaches, and strength and conditioning specialists to track and monitor nutrition in athletes.
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Affiliation(s)
- Marni E. Shoemaker
- School of Health and Consumer Sciences, South Dakota State University, Brookings, SD 57007, USA; (M.J.N.); (S.W.D.); (T.N.K.); (A.M.B.)
| | - Nathan D. Dicks
- Department of Health, Nutrition, and Exercise Sciences, North Dakota State University, Fargo, ND 58102, USA;
| | - Megan J. Northrup
- School of Health and Consumer Sciences, South Dakota State University, Brookings, SD 57007, USA; (M.J.N.); (S.W.D.); (T.N.K.); (A.M.B.)
| | - Seth W. Daughters
- School of Health and Consumer Sciences, South Dakota State University, Brookings, SD 57007, USA; (M.J.N.); (S.W.D.); (T.N.K.); (A.M.B.)
| | - Taylor N. Krings
- School of Health and Consumer Sciences, South Dakota State University, Brookings, SD 57007, USA; (M.J.N.); (S.W.D.); (T.N.K.); (A.M.B.)
| | - Allison M. Barry
- School of Health and Consumer Sciences, South Dakota State University, Brookings, SD 57007, USA; (M.J.N.); (S.W.D.); (T.N.K.); (A.M.B.)
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Hori M, Takahashi H, Kondo C, Hayashi F, Tokoroyama S, Mori Y, Tsujita M, Shirasawa Y, Takeda A, Morozumi K, Maruyama S. Association between Serum 25-Hydroxyvitamin D Levels and Sarcopenia in Patients Undergoing Chronic Haemodialysis. Am J Nephrol 2024; 55:399-405. [PMID: 38310857 DOI: 10.1159/000536582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/31/2024] [Indexed: 02/06/2024]
Abstract
INTRODUCTION Sarcopenia and vitamin D deficiency are highly prevalent among patients undergoing haemodialysis. Although vitamin D deficiency, assessed using serum 25-hydroxyvitamin D (25(OH)D) levels, is known to be associated with sarcopenia in the general population, whether serum 25(OH)D levels are associated with sarcopenia in patients undergoing haemodialysis with suppressed renal activation of 25(OH)D remains unclear. This study aimed to examine the association between serum 25(OH)D levels and sarcopenia in patients undergoing haemodialysis. METHODS Serum 25(OH)D level measurements and assessment of sarcopenia using the Asian Working Group for Sarcopenia criteria were conducted in 95 stable outpatients undergoing maintenance haemodialysis therapy. RESULTS Sarcopenia was observed in 22 (23.1%) patients. In multiple logistic regression analysis, serum 25(OH)D levels were associated with sarcopenia (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.77-0.99, p = 0.039) independent of traditional risk factors for sarcopenia. In multiple linear regression analyses, serum 25(OH)D levels were associated with parameters of skeletal muscle mass and strength (β = 0.145, p = 0.046, and β = 0.194, p = 0.020, respectively). The adjusted OR for sarcopenia was 5.60 (95% CI 1.52-20.57, p = 0.009) in the vitamin D deficiency group categorized based on the cut-off serum 25(OH)D level of 10 ng/mL. Regarding model discrimination, adding vitamin D deficiency to the traditional risk factors significantly improved the integrated discrimination improvement score (0.093, p = 0.007). CONCLUSION Lower serum 25(OH)D levels were associated with sarcopenia independent of traditional risk factors in patients undergoing haemodialysis with suppressed vitamin D activation in the kidney. This finding implies that circulating 25(OH)D may have an important relationship with the skeletal muscle function of patients undergoing haemodialysis, and its measurement may be recommended to identify patients at high risk for sarcopenia among those undergoing haemodialysis.
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Affiliation(s)
- Mayuko Hori
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Hiroshi Takahashi
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Chika Kondo
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Fumihito Hayashi
- Department of Rehabilitation, Masuko Memorial Hospital, Nagoya, Japan
| | | | - Yoshiko Mori
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Makoto Tsujita
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Yuichi Shirasawa
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Asami Takeda
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Kunio Morozumi
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Wyatt PB, Reiter CR, Satalich JR, O’Neill CN, Edge C, Cyrus JW, O’Connell RS, Vap AR. Effects of Vitamin D Supplementation in Elite Athletes: A Systematic Review. Orthop J Sports Med 2024; 12:23259671231220371. [PMID: 38188620 PMCID: PMC10768611 DOI: 10.1177/23259671231220371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 07/31/2023] [Indexed: 01/09/2024] Open
Abstract
Background Deficiency in vitamin D has been shown to increase the risk of injury. Purpose To synthesize current placebo-controlled randomized trials investigating the effect of vitamin D supplementation in elite athletes on (1) aerobic capacity; (2) anaerobic measures, such as strength, speed, and anaerobic power; (3) serum biomarkers of inflammation; and (4) bone health. Study Design Systematic review; Level of evidence, 1. Methods A literature search was conducted on November 30, 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Included were randomized, placebo-controlled studies of longer than 2 weeks on subjects with active participation in organized sport. Excluded were nonrandomized controlled trial study designs, vitamin D administration routes other than oral, studies that did not use vitamin D supplementation as the sole intervention, and studies with nonathletic or military populations. Results Out of 2331 initial studies, 14 studies (482 athletes) were included. Of the 3 studies that assessed aerobic capacity, 2 demonstrated significantly greater improvements in maximal oxygen uptake and physical working capacity-170 (P < .05) in supplemented versus nonsupplemented athletes. Measurements of anaerobic power and strength were consistently increased in supplemented groups compared with nonsupplemented groups in 5 out of the 7 studies that assessed this. Of the 6 studies that assessed sprint speed, 4 found no significant difference between supplemented and nonsupplemented groups. Aside from 1 study that found significantly lower interleukin-6 levels in supplemented athletes, measures of other inflammatory cytokines were not affected consistently by supplementation. The 4 studies that assessed markers of bone health were conflicting regarding benefits of supplementation. One study found demonstrated improvements in bone mineral density in response to supplementation (P = .02) compared with control whereas another found no significant difference between supplemented and nonsupplemented groups. However, in 3 other studies, serum biomarkers of bone turnover such as bone-specific alkaline phosphatase, parathyroid hormone, and N-terminal telopeptide appeared to be higher in subjects with lower serum vitamin D levels (P < .05). Conclusion Results of this systematic review indicated that the greatest benefit of vitamin D supplementation in elite athletes may be improving aerobic endurance, anaerobic power, and strength. More research is needed to determine the effect of vitamin D supplementation on bone health and injury risk in this population.
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Affiliation(s)
- Phillip B. Wyatt
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Charles R. Reiter
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - James R. Satalich
- Department of Orthopedic Surgery, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Conor N. O’Neill
- Department of Orthopedic Surgery, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Carl Edge
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - John W. Cyrus
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Robert S. O’Connell
- Department of Orthopedic Surgery, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Alexander R. Vap
- Department of Orthopedic Surgery, Virginia Commonwealth University Health System, Richmond, Virginia, USA
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Wen Y, Latham CM, Moore AN, Thomas NT, Lancaster BD, Reeves KA, Keeble AR, Fry CS, Johnson DL, Thompson KL, Noehren B, Fry JL. Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction. JCI Insight 2023; 8:e170518. [PMID: 37856482 PMCID: PMC10795826 DOI: 10.1172/jci.insight.170518] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 10/17/2023] [Indexed: 10/21/2023] Open
Abstract
BACKGROUNDAlthough 25-hydroxyvitamin D [25(OH)D] concentrations of 30 ng/mL or higher are known to reduce injury risk and boost strength, the influence on anterior cruciate ligament reconstruction (ACLR) outcomes remains unexamined. This study aimed to define the vitamin D signaling response to ACLR, assess the relationship between vitamin D status and muscle fiber cross-sectional area (CSA) and bone density outcomes, and discover vitamin D receptor (VDR) targets after ACLR.METHODSTwenty-one young, healthy, physically active participants with recent ACL tears were enrolled (17.8 ± 3.2 years, BMI 26.0 ± 3.5 kg/m2). Data were collected through blood samples, vastus lateralis biopsies, dual energy x-ray bone density measurements, and isokinetic dynamometer measures at baseline, 1 week, 4 months, and 6 months after ACLR. The biopsies facilitated CSA, Western blotting, RNA-seq, and VDR ChIP-seq analyses.RESULTSACLR surgery led to decreased circulating bioactive vitamin D and increased VDR and activating enzyme expression in skeletal muscle 1 week after ACLR. Participants with less than 30 ng/mL 25(OH)D levels (n = 13) displayed more significant quadriceps fiber CSA loss 1 week and 4 months after ACLR than those with 30 ng/mL or higher (n = 8; P < 0.01 for post hoc comparisons; P = 0.041 for time × vitamin D status interaction). RNA-seq and ChIP-seq data integration revealed genes associated with energy metabolism and skeletal muscle recovery, potentially mediating the impact of vitamin D status on ACLR recovery. No difference in bone mineral density losses between groups was observed.CONCLUSIONCorrecting vitamin D status prior to ACLR may aid in preserving skeletal muscle during recovery.FUNDINGNIH grants R01AR072061, R01AR071398-04S1, and K99AR081367.
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Affiliation(s)
- Yuan Wen
- Center for Muscle Biology, College of Health Sciences
- Department of Physiology, College of Medicine
- Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine
| | | | | | | | | | | | - Alexander R. Keeble
- Center for Muscle Biology, College of Health Sciences
- Department of Physiology, College of Medicine
| | | | | | - Katherine L. Thompson
- Dr. Bing Zhang Department of Statistics, University of Kentucky, Lexington, Kentucky, USA
| | - Brian Noehren
- Center for Muscle Biology, College of Health Sciences
- Department of Orthopaedic Surgery & Sports Medicine, and
| | - Jean L. Fry
- Center for Muscle Biology, College of Health Sciences
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11
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Talib NF, Zhu Z, Kim KS. Vitamin D3 Exerts Beneficial Effects on C2C12 Myotubes through Activation of the Vitamin D Receptor (VDR)/Sirtuins (SIRT)1/3 Axis. Nutrients 2023; 15:4714. [PMID: 38004107 PMCID: PMC10674540 DOI: 10.3390/nu15224714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/01/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
The onset of sarcopenia is associated with a decline in vitamin D receptor (VDR) expression, wherein reduced VDR levels contribute to muscle atrophy, while heightened expression promotes muscle hypertrophy. Like VDR, the age-related decline in protein deacetylase sirtuin (SIRT) expression is linked to the development of sarcopenia and age-related muscle dysfunction. This study aimed to investigate whether the VDR agonist 1,25-dihydroxyvitamin D3 (1,25VD3) exerts beneficial effects on muscles through interactions with sirtuins and, if so, the underlying molecular mechanisms. Treatment of 1,25VD3 in differentiating C2C12 myotubes substantially elevated VDR, SIRT1, and SIRT3 expression, enhancing their differentiation. Furthermore, 1,25VD3 significantly enhanced the expression of key myogenic markers, including myosin heavy chain (MyHC) proteins, MyoD, and MyoG, and increased the phosphorylation of AMPK and AKT. Conversely, VDR knockdown resulted in myotube atrophy and reduced SIRT1 and SIRT3 levels. In a muscle-wasting model triggered by IFN-γ/TNF-α in C2C12 myotubes, diminished VDR, SIRT1, and SIRT3 levels led to skeletal muscle atrophy and apoptosis. 1,25VD3 downregulated the increased expression of muscle atrophy-associated proteins, including FoxO3a, MAFbx, and MuRF1 in an IFN-γ/TNF-α induced atrophy model. Importantly, IFN-γ/TNF-α significantly reduced the mtDNA copy number in the C2C12 myotube, whereas the presence of 1,25VD3 effectively prevented this decrease. These results support that 1,25VD3 could serve as a potential preventive or therapeutic agent against age-related muscle atrophy by enhancing the VDR/SIRT1/SIRT3 axis.
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Affiliation(s)
- Nurul Fatihah Talib
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (N.F.T.); (Z.Z.)
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea
| | - Zunshu Zhu
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (N.F.T.); (Z.Z.)
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea
| | - Kyoung-Soo Kim
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (N.F.T.); (Z.Z.)
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea
- East-West Bone & Joint Disease Research Institute, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea
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12
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Książek A, Zagrodna A, Lombardi G, Słowińska-Lisowska M. Seasonal changes in free 25-(OH)D and vitamin D metabolite ratios and their relationship with psychophysical stress markers in male professional football players. Front Physiol 2023; 14:1258678. [PMID: 37908338 PMCID: PMC10613696 DOI: 10.3389/fphys.2023.1258678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 10/03/2023] [Indexed: 11/02/2023] Open
Abstract
Introduction: Novel markers of vitamin D status are currently being investigated, including free 25-(OH)D (25-(OH)DF) and the vitamin D metabolite ratio (24,25-(OH)2D3:25-(OH)D3; VMR). The VMR may provide additional functional information on vitamin D metabolism in athletes. Therefore, the main objective of the current study was to evaluate 25-(OH)DF, bioavailable 25-(OH)D (25-(OH)DB), VMR, and psychophysical stress markers during different training periods over a half-season. The second aim was to assess the association between vitamin D binding protein (VDBP), total and free 25-(OH)D, VMRs, and psychophysical stress markers in professional football players. Moreover, we examined the relationship between 25-(OH)D3 and vitamin D metabolites (24,25-(OH)2D3, 3-epi-25-(OH)D3) to determine if training loads in different training periods influenced the vitamin D metabolome. Methods: Twenty professional football players were tested at six different time points across half a year (V1-June; V2-July; V3-August; V4-October; V5-December; V6-January). Results: Analyses indicated a significant seasonal rhythm for VDBP, and total 25-(OH)D (25-(OH)DT), 25-(OH)DB, 24,25-(OH)2D3, 3-epi-25-(OH)D3, 25-(OH)D3:24,25-(OH)2D3, and 24,25-(OH)2D3:25-(OH)D3 VMRs throughout the training period. No correlation was detected between 25-(OH)DT, 25-(OH)DB, 25-(OH)DF, vitamin D metabolites, VMRs, VDBP, and ferritin, liver enzymes (aspartate transaminase [AST] and alanine transaminase [ALT]), creatine kinase (CK), cortisol, testosterone, and testosterone-to-cortisol ratio (T/C) in each period (V1-V6). However, there was a strong statistically significant correlation between 25-(OH)D3 and 24,25-(OH)D3 in each training period. Conclusion: In conclusion, a seasonal rhythm was present for VDBP, 25-(OH)DT, 25-(OH)DB, vitamin D metabolites (24,25-(OH)2D3, 3-epi-25-(OH)D3), and VMRs (25-(OH)D3:24,25-(OH)2D3, 25-(OH)D3:3-epi-25-(OH)D3). However, no rhythm was detected for 25-(OH)DF and markers of psychophysical stress (ferritin, liver enzymes, CK, testosterone, cortisol, and T/C ratio). Moreover, the relationships between free and total 25-(OH)D with psychophysical stress markers did not demonstrate the superiority of free over total measurements. Furthermore, training loads in different training periods did not affect resting vitamin D metabolite concentrations in football players.
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Affiliation(s)
- Anna Książek
- Department of Biological and Medical Basis of Sport, Faculty of Physical Education and Sports, Wroclaw University of Health and Sport Sciences, Wroclaw, Poland
| | - Aleksandra Zagrodna
- Department of Biological and Medical Basis of Sport, Faculty of Physical Education and Sports, Wroclaw University of Health and Sport Sciences, Wroclaw, Poland
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
| | - Małgorzata Słowińska-Lisowska
- Department of Biological and Medical Basis of Sport, Faculty of Physical Education and Sports, Wroclaw University of Health and Sport Sciences, Wroclaw, Poland
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13
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Agoncillo M, Yu J, Gunton JE. The Role of Vitamin D in Skeletal Muscle Repair and Regeneration in Animal Models and Humans: A Systematic Review. Nutrients 2023; 15:4377. [PMID: 37892452 PMCID: PMC10609905 DOI: 10.3390/nu15204377] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/04/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
Vitamin D deficiency, prevalent worldwide, is linked to muscle weakness, sarcopenia, and falls. Muscle regeneration is a vital process that allows for skeletal muscle tissue maintenance and repair after injury. PubMed and Web of Science were used to search for studies published prior to May 2023. We assessed eligible studies that discussed the relationship between vitamin D, muscle regeneration in this review. Overall, the literature reports strong associations between vitamin D and skeletal myocyte size, and muscle regeneration. In vitro studies in skeletal muscle cells derived from mice and humans showed vitamin D played a role in regulating myoblast growth, size, and gene expression. Animal studies, primarily in mice, demonstrate vitamin D's positive effects on skeletal muscle function, such as improved grip strength and endurance. These studies encompass vitamin D diet research, genetically modified models, and disease-related mouse models. Relatively few studies looked at muscle function after injury, but these also support a role for vitamin D in muscle recovery. The human studies have also reported that vitamin D deficiency decreases muscle grip strength and gait speed, especially in the elderly population. Finally, human studies reported the benefits of vitamin D supplementation and achieving optimal serum vitamin D levels in muscle recovery after eccentric exercise and surgery. However, there were no benefits in rotator cuff injury studies, suggesting that repair mechanisms for muscle/ligament tears may be less reliant on vitamin D. In summary, vitamin D plays a crucial role in skeletal muscle function, structural integrity, and regeneration, potentially offering therapeutic benefits to patients with musculoskeletal diseases and in post-operative recovery.
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Affiliation(s)
- Miguel Agoncillo
- Centre for Diabetes, Obesity and Endocrinology (CDOE), The Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, Australia
| | - Josephine Yu
- Centre for Diabetes, Obesity and Endocrinology (CDOE), The Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, Australia
| | - Jenny E. Gunton
- Centre for Diabetes, Obesity and Endocrinology (CDOE), The Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney 2145, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney 2145, Australia
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14
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Stratos I, Schleese S, Rinas I, Vollmar B, Mittlmeier T. Effect of Calcitriol and Vitamin D Receptor Modulator 2 on Recovery of Injured Skeletal Muscle in Wistar Rats. Biomedicines 2023; 11:2477. [PMID: 37760917 PMCID: PMC10525631 DOI: 10.3390/biomedicines11092477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/15/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Muscle injuries often result in functional limitations due to insufficient healing. This study assessed the influence of calcitriol and vitamin D Receptor Modulator 2 (VDRM2) on muscle regeneration in male Wistar rats following open blunt muscle injury. The injured left soleus muscle of the rats was treated for the first four days after trauma with local injections of either calcitriol, VDRM2, or a 10% ethanol solution (control). Although muscle strength significantly decreased post-injury, all groups showed gradual improvement but did not achieve full recovery. By the 14th day, calcitriol-treated rats significantly outperformed the control group in the incomplete tetanic force, with VDRM2-treated rats showing muscle strength values that fell between the control and calcitriol groups. Similar trends were observed in complete tetanic contractions and were confirmed histologically via muscle cell width quantification. Additionally, histological analysis showed increased cellular turnover on the fourth postoperative day in the calcitriol group, as indicated by elevated cell proliferation rates and fewer apoptotic cells. VDRM2-treated animals showed only an increased proliferative activity on day 4 after injury. No noticeable differences between the groups for CAE-positive cells or visible muscle tissue area were found. In conclusion, predominantly calcitriol positively influenced post-trauma muscle recovery, where VDRM2 had substantially lower biological activity.
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Affiliation(s)
- Ioannis Stratos
- Department of Orthopaedic Surgery, University of Wuerzburg, 97074 Wuerzburg, Germany
- Department of Trauma, Hand and Reconstructive Surgery, University of Rostock, 18057 Rostock, Germany
| | - Svenja Schleese
- Department of Trauma, Hand and Reconstructive Surgery, University of Rostock, 18057 Rostock, Germany
| | - Ingmar Rinas
- Department of Trauma, Hand and Reconstructive Surgery, University of Rostock, 18057 Rostock, Germany
| | - Brigitte Vollmar
- Institute for Experimental Surgery, University of Rostock, 18057 Rostock, Germany;
| | - Thomas Mittlmeier
- Department of Trauma, Hand and Reconstructive Surgery, University of Rostock, 18057 Rostock, Germany
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15
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Srikuea R, Hirunsai M. TGF-β1 stimulation and VDR-dependent activation modulate calcitriol action on skeletal muscle fibroblasts and Smad signalling-associated fibrogenesis. Sci Rep 2023; 13:13811. [PMID: 37612333 PMCID: PMC10447566 DOI: 10.1038/s41598-023-40978-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023] Open
Abstract
Fibroblasts play a pivotal role in fibrogenesis after skeletal muscle injury. Excess fibrous formation can disrupt contractile functions and delay functional recovery. Although vitamin D receptor (VDR) is expressed explicitly in regenerating muscle compared with uninjured muscle, how calcitriol [1α,25(OH)2D3] directly regulates skeletal muscle primary fibroblast proliferation, the transition to myofibroblasts, and Smad signalling-associated fibrogenesis is currently unknown. Herein, the effects of calcitriol on cultured skeletal muscle primary fibroblasts of male C57BL/6 mice (aged 1 month old) were investigated. The percentage of BrdU+ nuclei in primary fibroblasts was significantly decreased after calcitriol treatment; however, the antiproliferative effect of calcitriol was diminished after TGF-β1 stimulation to induce fibroblast to myofibroblast transition. This suppressive effect was associated with significantly decreased VDR expression in TGF-β1-treated cells. In addition, Vdr siRNA transfection abolished the effects of calcitriol on the suppression of α-SMA expression and Smad2/3 signalling in myofibroblasts, supporting that its antifibrogenic effect requires VDR activation. Compared with calcitriol, the antifibrotic agent suramin could inhibit fibroblast/myofibroblast proliferation and suppress the expression of TCF-4, which regulates fibrogenic determination. Collectively, these findings suggest that profibrotic stimulation and VDR-dependent activation could modulate the effects of calcitriol on skeletal muscle fibroblast proliferation and fibrogenesis processes. Therefore, TGF-β1 and VDR expression levels are crucial determinants for the antifibrogenic effect of calcitriol on skeletal muscle after injury.
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Affiliation(s)
- Ratchakrit Srikuea
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
| | - Muthita Hirunsai
- Department of Biopharmacy, Faculty of Pharmacy, Srinakharinwirot University, Ongkharak, Nakhon Nayok, 26120, Thailand
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16
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Calvani R, Picca A, Coelho-Júnior HJ, Tosato M, Marzetti E, Landi F. "Diet for the prevention and management of sarcopenia". Metabolism 2023:155637. [PMID: 37352971 DOI: 10.1016/j.metabol.2023.155637] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/05/2023] [Accepted: 06/15/2023] [Indexed: 06/25/2023]
Abstract
Sarcopenia is a geriatric condition characterized by a progressive loss of skeletal muscle mass and strength, with an increased risk of adverse health outcomes (e.g., falls, disability, institutionalization, reduced quality of life, mortality). Pharmacological remedies are currently unavailable for preventing the development of sarcopenia, halting its progression, or impeding its negative health outcomes. The most effective strategies to contrast sarcopenia rely on the adoption of healthier lifestyle behaviors, including adherence to high-quality diets and regular physical activity. In this review, the role of nutrition in the prevention and management of sarcopenia is summarized. Special attention is given to current "blockbuster" dietary regimes and agents used to counteract age-related muscle wasting, together with their putative mechanisms of action. Issues related to the design and implementation of effective nutritional strategies are discussed, with a focus on unanswered questions on the most appropriate timing of nutritional interventions to preserve muscle health and function into old age. A brief description is also provided on new technologies that can facilitate the development and implementation of personalized nutrition plans to contrast sarcopenia.
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Affiliation(s)
- Riccardo Calvani
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, 00168 Rome, Italy.
| | - Anna Picca
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, 00168 Rome, Italy; Department of Medicine and Surgery, LUM University, 70100 Casamassima, Italy.
| | - Hélio José Coelho-Júnior
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Matteo Tosato
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, 00168 Rome, Italy.
| | - Emanuele Marzetti
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, 00168 Rome, Italy.
| | - Francesco Landi
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, 00168 Rome, Italy.
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17
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Ceglia L, Rivas DA, Schlögl M, Fielding GB, Egli A, Bischoff-Ferrari HA, Dawson-Hughes B. Effect of vitamin D 3 vs. calcifediol on VDR concentration and fiber size in skeletal muscle. J Bone Miner Metab 2023; 41:41-51. [PMID: 36385193 DOI: 10.1007/s00774-022-01374-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/06/2022] [Indexed: 11/17/2022]
Abstract
INTRODUCTION This study sought to examine the effect of vitamin D3 (VD3) 3200 IU/d, calcifediol (HyD) 20mcg/d, or placebo on intramyonuclear vitamin D receptor (VDR) concentration, muscle fiber cross-sectional area (FCSA), and muscle satellite cell activation. MATERIALS AND METHODS It was conducted on a subset of the VD3 (n = 12), HyD (n = 11), and placebo (n = 13) groups who participated in the 6-month randomized controlled HyD Osteopenia Study in postmenopausal women. Baseline and 6-month vastus lateralis muscle cross sections were probed for VDR, fiber type I and II, and PAX7 (satellite cell marker) using immunofluorescence. RESULTS Baseline mean ± SD age was 61 ± 4 years and serum 25-hydroxyvitamin D (25OHD) level was 55.1 ± 22.8 nmol/L. Baseline characteristics did not differ significantly by group. Six-month mean ± SD 25OHD levels were 138.7 ± 22.2 nmol/L (VD3), 206.8 ± 68.8 nmol/L (HyD), and 82.7 ± 36.1 nmol/L (placebo), ANOVA P < 0.001. There were no significant group differences in 6-month change in VDR concentration (ANOVA P = 0.227). Mean ± SD percent 6-month changes in type I FCSA were 20.5 ± 32.7% (VD3), - 6.6 ± 20.4% (HyD), and - 0.3 ± 14.0% (placebo, ANOVA P = 0.022). Type II FCSA or PAX7 concentration did not change significantly by group (all P > 0.358). CONCLUSION This study demonstrated no significant change in intramyonuclear VDR in response to either form of vitamin D vs. placebo. Type I FCSA significantly increased with VD3, but not with HyD at 6 months. As type I fibers are more fatigue resistant than type II, enlargement in type I suggests potential for improved muscle endurance. Although HyD resulted in the highest 25OHD levels, no skeletal muscle benefits were noted at these high levels. CLINICAL TRIAL NCT02527668.
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Affiliation(s)
- Lisa Ceglia
- Division of EndocrinologyDiabetes and Metabolism, Tufts Medical Center, Boston, MA, 02111, USA.
- Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, USA.
| | - Donato A Rivas
- Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, USA
| | - Mathias Schlögl
- Centre on Aging and Mobility, University of Zurich, Zurich, Switzerland
| | - Grace B Fielding
- Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, USA
| | - Andreas Egli
- Centre on Aging and Mobility, University of Zurich, Zurich, Switzerland
| | - Heike A Bischoff-Ferrari
- Centre on Aging and Mobility, University of Zurich, Zurich, Switzerland
- Department of Aging Medicine, University Hospital Zurich and City Hospital Zurich, Zurich, Switzerland
| | - Bess Dawson-Hughes
- Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, USA
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18
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Ra SG, Nakagawa H, Tomiga Y, Iizawa H, Nakashima S, Higaki Y, Kawanaka K. Effects of Dietary Vitamin D Deficiency on Markers of Skeletal Muscle Mitochondrial Biogenesis and Dynamics. J Nutr Sci Vitaminol (Tokyo) 2022; 68:243-249. [PMID: 36047095 DOI: 10.3177/jnsv.68.243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
We examined the effects of dietary vitamin D deficiency on markers of mitochondrial biogenesis and dynamics in rat soleus muscle. Male Wistar rats were fed a chow with no vitamin D (No-D; 0 IU/kg) or a moderate dose (Mod-D; 2,000 IU/kg) of vitamin D chow for 8 wk. Compared to the Mod-D group, at 8 wk the No-D group showed significantly lower serum 25(OH)D levels. Although vitamin D deficiency had no effect on body composition, the No-D rats showed significantly decreased levels of PGC-1α, a marker of skeletal muscle mitochondrial biogenesis, and DRP1, a marker of skeletal muscle mitochondrial fission. The change in the PGC-1α protein expression and the serum 25(OH)D concentrations were significantly correlated. The change in DRP1 protein expression and the serum 25(OH)D concentrations tended to be correlated. There was no significant between-group difference in markers of mitochondrial fusion (MFN2 and OPA1) and mitophagy (PARKIN) in soleus muscle, and no relationship with serum 25(OH)D concentrations. Collectively our findings suggest that dietary vitamin D deficiency decreased PGC-1α and DRP1 protein expression in rat soleus muscle.
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Affiliation(s)
- Song-Gyu Ra
- Laboratory of Exercise Nutrition and Biochemistry, Faculty of Sports and Health Science, Fukuoka University.,Fukuoka Univerity Institute for Physical Activity.,Institute of Liberal Arts and Sciences, Tokushima University
| | - Hironari Nakagawa
- Laboratory of Exercise Nutrition and Biochemistry, Faculty of Sports and Health Science, Fukuoka University
| | - Yuki Tomiga
- Fukuoka Univerity Institute for Physical Activity.,Laboratory of Exercise Physiology, Faculty of Sports and Health Science, Fukuoka University.,Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University.,Japan Society for the Promotion of Science
| | - Hiroki Iizawa
- Laboratory of Exercise Nutrition and Biochemistry, Faculty of Sports and Health Science, Fukuoka University
| | | | - Yasuki Higaki
- Fukuoka Univerity Institute for Physical Activity.,Laboratory of Exercise Physiology, Faculty of Sports and Health Science, Fukuoka University
| | - Kentaro Kawanaka
- Laboratory of Exercise Nutrition and Biochemistry, Faculty of Sports and Health Science, Fukuoka University.,Fukuoka Univerity Institute for Physical Activity
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19
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Irazoqui AP, Gonzalez A, Buitrago C. Effects of calcitriol on the cell cycle of rhabdomyosarcoma cells. J Steroid Biochem Mol Biol 2022; 222:106146. [PMID: 35710090 DOI: 10.1016/j.jsbmb.2022.106146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/20/2022] [Accepted: 06/10/2022] [Indexed: 11/30/2022]
Abstract
Rhabdomyosarcoma (RMS) is a type of cancer of skeletal muscle. Calcitriol is the active form of vitamin D3, also recognised as a steroid hormone called 1α, 25-dihydroxy vitamin D3 (1,25D). We previously reported that 1,25D promoted cell proliferation and differentiation in non-cancerous skeletal muscle cells C2C12. The aim of this work is to evaluate some of the events triggered by 1,25D in RD cells, a human RMS cell line. In this work we reported that RD cells expressed vitamin D receptor (VDR) and treatment with 1,25D reduced VDR expression at 72 h. At the same time an acute decrease in viable cells as well as in cells in S-phase of cell cycle was also observed. Furthermore, up-regulation of p15INK4b was accompanied in a timely manner by down-regulation of cyclin D3, p21Waf1/Cip1 and myogenin protein levels. Simultaneously, 1,25D induced early apoptosis markers such as cyclin D1 and CDK4, and the disruption of the mitochondrial network together with a redistribution of mitochondria around the nucleus. Finally, 1,25D induced changes in the plasma membrane of RD cells associated with early and late apoptosis at 72 h, as determined by flow cytometry. Taken together, these results determine that treatment with 1,25D for 72 h triggers apoptosis in RD cells.
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Affiliation(s)
- Ana P Irazoqui
- Comisión de Investigaciones Científicas de la provincia de Buenos Aires (CIC PBA); Departamento de Biología, Bioquímica y Farmacia, UNS, (8000) Bahía Blanca, Argentina; Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Universidad Nacional del Sur-CONICET, Bahía Blanca, Argentina
| | - Agustina Gonzalez
- Departamento de Biología, Bioquímica y Farmacia, UNS, (8000) Bahía Blanca, Argentina; Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Universidad Nacional del Sur-CONICET, Bahía Blanca, Argentina
| | - Claudia Buitrago
- Departamento de Biología, Bioquímica y Farmacia, UNS, (8000) Bahía Blanca, Argentina; Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Universidad Nacional del Sur-CONICET, Bahía Blanca, Argentina.
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20
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Lütke-Dörhoff M, Schulz J, Westendarp H, Visscher C, Wilkens MR. Dietary supplementation of 25-hydroxycholecalciferol as an alternative to cholecalciferol in swine diets: A review. J Anim Physiol Anim Nutr (Berl) 2022; 106:1288-1305. [PMID: 36045590 DOI: 10.1111/jpn.13768] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/31/2022] [Accepted: 08/11/2022] [Indexed: 12/01/2022]
Abstract
25-hydroxycholecalciferol (25-OHD3 ) formed via hepatic hydroxylation from vitamin D, cholecalciferol, represents the precursor of the biologically active vitamin D hormone, 1,25-dihydroxyvitamin D. Due to a higher absorption rate and the omission of one hydroxylation, dietary supplementation of 25-OHD3 instead of vitamin D3 is considered to be more efficient as plasma concentrations of 25-OHD3 are increased more pronounced. The present review summarises studies investigating potential beneficial effects on mineral homeostasis, bone metabolism, health status and performance in sows, piglets and fattening pigs. Results are inconsistent. While most studies could not demonstrate any or only a slight impact of partial or total replacement of vitamin D3 by 25-OHD3 , some experiments indicated that 25-OHD3 might alter physiological processes when animals are challenged, for example, by a restricted mineral supply.
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Affiliation(s)
- Michael Lütke-Dörhoff
- Institute for Animal Hygiene, Animal Welfare and Farm Animal Behaviour, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany.,Department of Animal Nutrition, Faculty of Agricultural Sciences and Landscape Architecture, Hochschule Osnabrück, Osnabrück, Germany
| | - Jochen Schulz
- Institute for Animal Hygiene, Animal Welfare and Farm Animal Behaviour, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Heiner Westendarp
- Department of Animal Nutrition, Faculty of Agricultural Sciences and Landscape Architecture, Hochschule Osnabrück, Osnabrück, Germany
| | - Christian Visscher
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Mirja R Wilkens
- Institute of Animal Nutrition, Nutrition Diseases and Dietetics, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany
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21
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Avila LP, Leiva SF, Abascal-Ponciano GA, Flees JJ, Sweeney KM, Wilson JL, Meloche KJ, Turner BJ, Litta G, Waguespack-Levy AM, Pokoo-Aikins A, Starkey CW, Starkey JD. Effect of combined maternal and post-hatch dietary 25-hydroxycholecalciferol supplementation on broiler chicken Pectoralis major muscle growth characteristics and satellite cell mitotic activity. J Anim Sci 2022; 100:6652323. [PMID: 35908786 PMCID: PMC9339277 DOI: 10.1093/jas/skac192] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/24/2022] [Indexed: 11/14/2022] Open
Abstract
Skeletal muscle growth is largely dependent on the proliferation and differentiation of muscle-specific stem cells known as satellite cells (SC). Previous work has shown that dietary inclusion of the vitamin D3 metabolite, 25-hydroxycholecalciferol (25OHD3), also called calcidiol, can promote skeletal muscle growth in post-hatch broiler chickens. Improving vitamin D status of broiler breeder hens by feeding 25OHD3 in addition to vitamin D3 has also been shown to positively impact progeny. Yet, whether combined pre- and post-hatch supplementation with 25OHD3 produces an additive or synergistic SC-mediated, skeletal muscle growth response remains unanswered. To evaluate the effect of combined maternal and post-hatch dietary 25OHD3 supplementation on the growth and SC mitotic activity of the Pectoralis major (PM) muscles in broiler chickens, a randomized complete block design experiment with the main effects of maternal diet (MDIET) and post-hatch diet (PDIET) arranged in a 2 × 2 factorial treatment structure was conducted. From 25 to 36 wk of age, broiler breeder hens were fed 1 of 2 MDIET formulated to provide 5,000 IU D3 (MCTL) or 2,240 IU of D3 + 2,760 IU of 25OHD3 per kg of feed (M25OHD3). Their male broiler chick offspring (n = 400) hatched from eggs collected from 35 to 36 wk of age were reared in raised floor pens. Broilers were fed 1 of 2 PDIET formulated to provide 5,000 IU of D3 per kg of feed (PCTL) or 2,240 IU of D3 + 2,760 IU of 25OHD3 per kg of feed (P25OHD3). Muscle was collected at days 4, 8, 15, 22, and 29 and stored until immunofluorescence analysis. Data were analyzed as a 2-way ANOVA with SAS GLIMMIX. Dietary 25OHD3 was effectively transferred from hen plasma to egg yolks (P = 0.002) and to broiler progeny plasma (days 4 to 22; P ≤ 0.044). Including 25OHD3 in either MDIET or PDIET altered PM hypertrophic growth prior to day 29 (P ≥ 0.001) and tended to reduce Wooden Breast severity (P ≤ 0.089). Mitotic SC populations were increased in PM of MCTL:P25OHD3 and M25OHD:PCTL-fed broilers at d 4 (P = 0.037). At d 8, the PM mitotic SC populations were increased 33% by P25OHD3 (P = 0.054). The results of this study reveal that combined maternal and post-hatch 25OHD3 supplementation does not produce additive or synergistic effects on SC-mediated broiler muscle growth. However, vitamin D status improvement through dietary 25OHD3 inclusion in either the maternal or post-hatch diet stimulated broiler breast muscle growth by increasing proliferating SC populations.
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Affiliation(s)
- Luis P Avila
- Department of Poultry Science, Auburn University, Auburn, AL, USA
| | - Samuel F Leiva
- Department of Poultry Science, Auburn University, Auburn, AL, USA
| | | | - Joshua J Flees
- Department of Poultry Science, Auburn University, Auburn, AL, USA
| | - Kelly M Sweeney
- Department of Poultry Science, The University of Georgia, Athens, GA, USA
| | - Jeanna L Wilson
- Department of Poultry Science, The University of Georgia, Athens, GA, USA
| | | | - Bradley J Turner
- Animal Nutrition and Health, DSM Nutritional Products, Kaiseraugst, Switzerland
| | - Gilberto Litta
- Animal Nutrition and Health, DSM Nutritional Products, Kaiseraugst, Switzerland
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22
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Reis NG, Assis AP, Lautherbach N, Gonçalves DA, Silveira WA, Morgan HJN, Valentim RR, Almeida LF, Heck LC, Zanon NM, Koike TE, Santos AR, Miyabara EH, Kettelhut IC, Navegantes LC. Maternal vitamin D deficiency affects the morphology and function of glycolytic muscle in adult offspring rats. J Cachexia Sarcopenia Muscle 2022; 13:2175-2187. [PMID: 35582969 PMCID: PMC9398225 DOI: 10.1002/jcsm.12986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 02/14/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Fetal stage is a critical developmental window for the skeletal muscle, but little information is available about the impact of maternal vitamin D (Vit. D) deficiency (VDD) on offspring lean mass development in the adult life of male and female animals. METHODS Female rats (Wistar Hannover) were fed either a control (1000 IU Vit. D3/kg) or a VDD diet (0 IU Vit. D3/kg) for 6 weeks and during gestation and lactation. At weaning, male and female offspring were randomly separated and received a standard diet up to 180 days old. RESULTS Vitamin D deficiency induced muscle atrophy in the male (M-VDD) offspring at the end of weaning, an effect that was reverted along the time. Following 180 days, fast-twitch skeletal muscles [extensor digitorum longus (EDL)] from the M-VDD showed a decrease (20%; P < 0.05) in the number of total fibres but an increase in the cross-sectional area of IIB (17%; P < 0.05), IIA (19%; P < 0.05) and IIAX (21%; P < 0.05) fibres. The fibre hypertrophy was associated with the higher protein levels of MyoD (73%; P < 0.05) and myogenin (55% %; P < 0.05) and in the number of satellite cells (128.8 ± 14 vs. 91 ± 7.6 nuclei Pax7 + in the M-CTRL; P < 0.05). M-VDD increased time to fatigue during ex vivo contractions of EDL muscles and showed an increase in the phosphorylation levels of IGF-1/insulin receptor and their downstream targets related to anabolic processes and myogenic activation, including Ser 473 Akt and Ser 21/9 GSK-3β. In such muscles, maternal VDD induced a compensatory increase in the content of calcitriol (two-fold; P < 0.05) and CYP27B1 (58%; P < 0.05), a metabolizing enzyme that converts calcidiol to calcitriol. Interestingly, most morphological and biochemical changes found in EDL were not observed in slow-twitch skeletal muscles (soleus) from the M-VDD group as well as in both EDL and soleus muscles from the female offspring. CONCLUSIONS These data show that maternal VDD selectively affects the development of type-II muscle fibres in male offspring rats but not in female offspring rats and suggest that the enhancement of their size and fatigue resistance in fast-twitch skeletal muscle (EDL) is probably due to a compensatory increase in the muscle content of Vit. D in the adult age.
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Affiliation(s)
- Natany G Reis
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Ana P Assis
- Department of Biochemistry & Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Natália Lautherbach
- Department of Biochemistry & Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Dawit A Gonçalves
- Exercise Physiology Laboratory, School of Physical Education, Physiotherapy and Occupational Therapy, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Wilian A Silveira
- Institute of Biological and Natural Science, Federal University of Triângulo Mineiro, Uberaba, MG, Brazil
| | - Henrique J N Morgan
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Rafael R Valentim
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Lucas F Almeida
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Lilian C Heck
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Neusa M Zanon
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Tatiana E Koike
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil
| | - Audrei R Santos
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil
| | - Elen H Miyabara
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil
| | - Isis C Kettelhut
- Department of Biochemistry & Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Luiz C Navegantes
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
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23
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Influences of Vitamin D and Iron Status on Skeletal Muscle Health: A Narrative Review. Nutrients 2022; 14:nu14132717. [PMID: 35807896 PMCID: PMC9268405 DOI: 10.3390/nu14132717] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 12/02/2022] Open
Abstract
There is conflicting evidence of the roles vitamin D and iron have in isolation and combined in relation to muscle health. The purpose of this narrative review was to examine the current literature on the roles that vitamin D and iron have on skeletal muscle mass, strength, and function and how these nutrients are associated with skeletal muscle health in specific populations. Secondary purposes include exploring if low vitamin D and iron status are interrelated with skeletal muscle health and chronic inflammation and reviewing the influence of animal-source foods rich in these nutrients on health and performance. PubMed, Scopus, SPORT Discus, EMBAE, MEDLINE, and Google Scholar databases were searched to determine eligible studies. There was a positive effect of vitamin D on muscle mass, particularly in older adults. There was a positive effect of iron on aerobic and anaerobic performance. Studies reported mixed results for both vitamin D and iron on muscle strength and function. While vitamin D and iron deficiency commonly occur in combination, few studies examined effects on skeletal muscle health and inflammation. Isolated nutrients such as iron and vitamin D may have positive outcomes; however, nutrients within food sources may be most effective in improving skeletal muscle health.
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24
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Jiang Z, Zhang L, Yao Z, Cao W, Ma S, Chen Y, Guang L, Zheng Z, Li C, Yu K, Shyh-Chang N. Machine learning-based phenotypic screening for postmitotic growth inducers uncover vitamin D3 metabolites as small molecule ribosome agonists. Cell Prolif 2022; 55:e13214. [PMID: 35411556 PMCID: PMC9136510 DOI: 10.1111/cpr.13214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 11/30/2022] Open
Abstract
Objectives To restore tissue growth without increasing the risk for cancer during aging, there is a need to identify small molecule drugs that can increase cell growth without increasing cell proliferation. While there have been numerous high‐throughput drug screens for cell proliferation, there have been few screens for post‐mitotic anabolic growth. Materials and Methods A machine learning (ML)‐based phenotypic screening strategy was used to discover metabolites that boost muscle growth. Western blot, qRT‐PCR and immunofluorescence staining were used to evaluate myotube hypertrophy/maturation or protein synthesis. Mass spectrometry (MS)‐based thermal proteome profiling‐temperature range (TPP‐TR) technology was used to identify the protein targets that bind the metabolites. Ribo‐MEGA size exclusion chromatography (SEC) analysis was used to verify whether the ribosome proteins bound to calcitriol. Results We discovered both the inactive cholecalciferol and the bioactive calcitriol are amongst the top hits that boost post‐mitotic growth. A large number of ribosomal proteins' melting curves were affected by calcitriol treatment, suggesting that calcitriol binds to the ribosome complex directly. Purified ribosomes directly bound to pure calcitriol. Moreover, we found that calcitriol could increase myosin heavy chain (MHC) protein translation and overall nascent protein synthesis in a cycloheximide‐sensitive manner, indicating that calcitriol can directly bind and enhance ribosomal activity to boost muscle growth. Conclusion Through the combined strategy of ML‐based phenotypic screening and MS‐based omics, we have fortuitously discovered a new class of metabolite small molecules that can directly activate ribosomes to promote post‐mitotic growth.
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Affiliation(s)
- Zongmin Jiang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Liping Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ziyue Yao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Wenhua Cao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Shilin Ma
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yu Chen
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Lu Guang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Zipeng Zheng
- Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing, China
| | - Chunwei Li
- Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing, China
| | - Kang Yu
- Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS), Peking Union Medical College (PUMC), Beijing, China
| | - Ng Shyh-Chang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
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25
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The relationship between dynapenia and vitamin D level in geriatric women with type 2 diabetes mellitus. North Clin Istanb 2022; 9:64-73. [PMID: 35340314 PMCID: PMC8889215 DOI: 10.14744/nci.2021.28009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/06/2021] [Indexed: 11/20/2022] Open
Abstract
Objective In this study, we examined the possible relationship between dynapenia and vitamin D (VD) levels in geriatric women with type 2 diabetes mellitus (T2DM). Methods One hundred and twenty-two geriatric female patients aged 65-80 years with a diagnosis of T2DM were included in this prospective study. Physical examinations of the patients were performed, and biochemical tests were analyzed. The muscle strength of the patients was measured with a hand dynamometer. Dynapenia was defined as low grip strength with normal skeletal muscle mass index. In muscle strength measurements, for female patients, over 20 kg was accepted as normal and below 20 kg as decreased muscle strength. Patients were separated into three groups as <10 ng/ml, 10-30 ng/ml, and >30 ng/ml according to VD levels; according to the status of dynapenia, they were divided into two groups as dynapenic and non-dynapenic. By comparing all these parameters between these groups, the relationship between VD level and dynapenia was evaluated. In statistical analysis, significance was accepted as p<0.05. Results While 54 of the patients (44.3%) met the dynapenia criterion, 68 patients (55.7%) were non-dynapenic. Patients were first compared according to their dynapenia status. VD level was significantly lower in the dynapenic group (p<0.05). In the correlation analysis, a moderate positive correlation was found between muscle strength and VD (p=0.033, r: 0.23). The patients were then compared according to the VD groups. In the VD insufficient group, muscle strength (p=0.015), body mass index (p=0.025), systolic blood pressure (p<0.01), and glucose (p<0.01) were statistically significantly higher. Conclusion In the present study, we found a considerable relationship between VD levels and dynapenia in geriatric women with T2DM.
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26
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Kim Y, Chang Y, Ryu S, Cho IY, Kwon MJ, Wild SH, Byrne CD. Serum 25-hydroxy vitamin D and the risk of low muscle mass in young and middle-aged Korean adults. Eur J Endocrinol 2022; 186:477-487. [PMID: 35147511 PMCID: PMC8942330 DOI: 10.1530/eje-21-1229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/11/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Despite the known benefit of vitamin D in reducing sarcopenia risk in older adults, its effect against muscle loss in the young population is unknown. We aimed to examine the association of serum 25-hydroxy vitamin D [25(OH)D] level and its changes over time with the risk of incident low muscle mass (LMM) in young and middle-aged adults. DESIGN This study is a cohort study. METHODS The study included Korean adults (median age: 36.9 years) without LMM at baseline followed up for a median of 3.9 years (maximum: 7.3 years). LMM was defined as the appendicular skeletal muscle (ASM) mass by body weight (ASM/weight) of 1 s.d. below the sex-specific mean for the young reference group. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% CIs. RESULTS Of the 192,908 individuals without LMM at baseline, 19,526 developed LMM. After adjusting for potential confounders, the multivariable-adjusted HRs (95% CIs) for incident LMM comparing 25(OH)D levels of 25-<50, 50-<75, and ≥75 nmol/L to 25(OH)D <25 nmol/L were 0.93 (0.90-0.97), 0.85 (0.81-0.89), and 0.77 (0.71-0.83), respectively. The inverse association of 25(OH)D with incident LMM was consistently observed in young (aged <40 years) and older individuals (aged ≥40 years). Individuals with increased 25(OH)D levels (<50-≥50 nmol/L) or persistently adequate 25(OH)D levels (≥50 nmol/L) between baseline and follow-up visit had a lower risk of incident LMM than those with persistently low 25(OH)D levels. CONCLUSIONS Maintaining sufficient serum 25(OH)D could prevent unfavourable changes in muscle mass in both young and middle-aged Korean adults.
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Affiliation(s)
- Yejin Kim
- Center for Cohort Studies, Total Healthcare Center
| | - Yoosoo Chang
- Center for Cohort Studies, Total Healthcare Center
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
- Correspondence should be addressed to Y Chang or S Ryu or S H Wild; or or
| | - Seungho Ryu
- Center for Cohort Studies, Total Healthcare Center
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
- Correspondence should be addressed to Y Chang or S Ryu or S H Wild; or or
| | - In Young Cho
- Center for Cohort Studies, Total Healthcare Center
- Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Min-Jung Kwon
- Center for Cohort Studies, Total Healthcare Center
- Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sarah H Wild
- Usher Institute, University of Edinburgh, Edinburgh, UK
- Correspondence should be addressed to Y Chang or S Ryu or S H Wild; or or
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK
- National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
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27
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MIZUTANI S, OYABU M, YAMAMOTO A, UCHITOMI R, SUGIMOTO T, KAMEI Y. Vitamin D Activates Various Gene Expressions, Including Lipid Metabolism, in C2C12 Cells. J Nutr Sci Vitaminol (Tokyo) 2022; 68:65-72. [DOI: 10.3177/jnsv.68.65] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Sako MIZUTANI
- Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
| | - Mamoru OYABU
- Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
| | - Arisa YAMAMOTO
- Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
| | - Ran UCHITOMI
- Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
| | - Takumi SUGIMOTO
- Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
| | - Yasutomi KAMEI
- Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University
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28
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Girgis CM, Brennan-Speranza TC. Vitamin D and Skeletal Muscle: Current Concepts From Preclinical Studies. JBMR Plus 2021; 5:e10575. [PMID: 34950830 PMCID: PMC8674777 DOI: 10.1002/jbm4.10575] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/07/2021] [Accepted: 10/24/2021] [Indexed: 12/12/2022] Open
Abstract
Muscle weakness has been recognized as a hallmark feature of vitamin D deficiency for many years. Until recently, the direct biomolecular effects of vitamin D on skeletal muscle have been unclear. Although in the past, some reservations have been raised regarding the expression of the vitamin D receptor in muscle tissue, this special issue review article outlines the clear evidence from preclinical studies for not only the expression of the receptor in muscle but also the roles of vitamin D activity in muscle development, mass, and strength. Additionally, muscle may also serve as a dynamic storage site for vitamin D, and play a central role in the maintenance of circulating 25-hydroxy vitamin D levels during periods of low sun exposure. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Christian M Girgis
- Faculty of Medicine and Health University of Sydney Sydney NSW Australia.,Department of Diabetes and Endocrinology Westmead Hospital Sydney NSW Australia.,Department of Endocrinology Royal North Shore Hospital Sydney NSW Australia
| | - Tara C Brennan-Speranza
- Faculty of Medicine and Health University of Sydney Sydney NSW Australia.,School of Medical Sciences University of Sydney Sydney NSW Australia.,School of Public Health University of Sydney Sydney NSW Australia
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29
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Iolascon G, Moretti A, Paoletta M, Liguori S, Di Munno O. Muscle Regeneration and Function in Sports: A Focus on Vitamin D. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1015. [PMID: 34684052 PMCID: PMC8537590 DOI: 10.3390/medicina57101015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 08/30/2021] [Accepted: 09/24/2021] [Indexed: 02/05/2023]
Abstract
Muscle is one of the main targets for the biological effects of vitamin D. This hormone modulates several functions of skeletal muscles, from development to tissue repair after injury, through genomic and non-genomic mechanisms. Vitamin D deficiency and supplementation seem to significantly affect muscle strength in different populations, including athletes, although optimal serum 25(OH)D3 level for sport performance has not been defined so far. Additionally, vitamin D deficiency results in myopathy characterized by fast-twitch fiber atrophy, fatty infiltration, and fibrosis. However, less is known about regenerative effects of vitamin D supplementation after sport-related muscle injuries. Vitamin D receptor (VDR) is particularly expressed in the embryonic mesoderm during intrauterine life and in satellite cells at all stages of life for recovery of the skeletal muscle after injury. Vitamin D supplementation enhances muscle differentiation, growth, and regeneration by increasing the expression of myogenic factors in satellite cells. The objective of this narrative review is to describe the role of vitamin D in sport-related muscle injury and tissue regeneration.
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Affiliation(s)
- Giovanni Iolascon
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Via de Crecchio, 6, 80138 Naples, Italy; (G.I.); (M.P.); (S.L.)
| | - Antimo Moretti
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Via de Crecchio, 6, 80138 Naples, Italy; (G.I.); (M.P.); (S.L.)
| | - Marco Paoletta
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Via de Crecchio, 6, 80138 Naples, Italy; (G.I.); (M.P.); (S.L.)
| | - Sara Liguori
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Via de Crecchio, 6, 80138 Naples, Italy; (G.I.); (M.P.); (S.L.)
| | - Ombretta Di Munno
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56122 Pisa, Italy;
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30
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Chang Villacreses MM, Karnchanasorn R, Panjawatanan P, Ou HY, Chiu KC. Conundrum of vitamin D on glucose and fuel homeostasis. World J Diabetes 2021; 12:1363-1385. [PMID: 34630895 PMCID: PMC8472505 DOI: 10.4239/wjd.v12.i9.1363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 05/10/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
As an endocrine hormone, vitamin D plays an important role in bone health and calcium homeostasis. Over the past two decades, the non-calcemic effects of vitamin D were extensively examined. Although the effect of vitamin D on beta cell function were known for some time, the effect of vitamin D on glucose and fuel homeostasis has attracted new interest among researchers. Yet, to date, studies remain inconclusive and controversial, in part, due to a lack of understanding of the threshold effects of vitamin D. In this review, a critical examination of interventional trials of vitamin D in prevention of diabetes is provided. Like use of vitamin D for bone loss, the benefits of vitamin D supplementation in diabetes prevention were observed in vitamin D-deficient subjects with serum 25-hydroxyvitamin D < 50 nmol/L (20 ng/mL). The beneficial effect from vitamin D supplementation was not apparent in subjects with serum 25-hydroxyvitamin D > 75 nmol/L (30 ng/mL). Furthermore, no benefit was noted in subjects that achieved serum 25-hydroxyvitamin D > 100 nmol/L (40 ng/mL). Further studies are required to confirm these observations.
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Affiliation(s)
- Maria Mercedes Chang Villacreses
- Department of Clinical Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Duarte, CA 91010, United States
- Division of Endocrinology, Metabolism and Nutrition, Department of Internal Medicine, Harbor-UCLA Medical Center, Torrance, CA 90509, United States
| | - Rudruidee Karnchanasorn
- Division of Endocrinology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Panadeekarn Panjawatanan
- Department of Clinical Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Duarte, CA 91010, United States
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY 13326, United States
| | - Horng-Yih Ou
- Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan 700, Taiwan
| | - Ken C Chiu
- Department of Clinical Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Duarte, CA 91010, United States
- Division of Endocrinology, Metabolism and Nutrition, Department of Internal Medicine, Harbor-UCLA Medical Center, Torrance, CA 90509, United States
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Caballero-García A, Córdova-Martínez A, Vicente-Salar N, Roche E, Pérez-Valdecantos D. Vitamin D, Its Role in Recovery after Muscular Damage Following Exercise. Nutrients 2021; 13:nu13072336. [PMID: 34371846 PMCID: PMC8308579 DOI: 10.3390/nu13072336] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
Aside from its role in bone metabolism, vitamin D is a key immunomodulatory micronutrient. The active form of vitamin D (1,25(OH)D) seems to modulate the innate immune system through different mechanisms. The vitamin is involved in the differentiation of monocytes into macrophages, increasing the phagocytic and chemotactic functions of these cells. At the same time, vitamin D enables efferocytosis and prevents immunopathology. In addition, vitamin D is involved in other processes related to immune function, such as inflammation. Regarding muscle tissue, vitamin D plays an active role in muscle inflammatory response, protein synthesis, and regulation of skeletal muscle function. Two mechanisms have been proposed: A direct role of 1,25(OH)D binding to vitamin D receptors (VDRs) in muscle cells and the modulation of calcium transport in the sarcoplasmic reticulum. This second mechanism needs additional investigation. In conclusion, vitamin D seems to be effective in cases of deficiency and/or if there is a great muscular commitment, such as in high intensity exercises.
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Affiliation(s)
- Alberto Caballero-García
- Department of Anatomy and Radiology, Health Sciences Faculty, GIR: “Physical Exercise and Aging”, Campus Universitario “Los Pajaritos”, University of Valladolid, 42004 Soria, Spain
- Correspondence: ; Tel.: +34-649-827-663
| | - Alfredo Córdova-Martínez
- Department of Biochemistry, Molecular Biology and Physiology, Health Sciences Faculty, GIR: “Physical Exercise and Aging”, Campus Universitario “Los Pajaritos”, University of Valladolid, 42004 Soria, Spain; (A.C.-M.); (D.P.-V.)
| | - Néstor Vicente-Salar
- Department of Applied Biology-Nutrition, Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain; (N.V.-S.); (E.R.)
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain
| | - Enrique Roche
- Department of Applied Biology-Nutrition, Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain; (N.V.-S.); (E.R.)
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Daniel Pérez-Valdecantos
- Department of Biochemistry, Molecular Biology and Physiology, Health Sciences Faculty, GIR: “Physical Exercise and Aging”, Campus Universitario “Los Pajaritos”, University of Valladolid, 42004 Soria, Spain; (A.C.-M.); (D.P.-V.)
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32
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Fogarty MJ, Losbanos LL, Craig TA, Reynolds CJ, Brown AD, Kumar R, Sieck GC. Muscle-specific deletion of the vitamin D receptor in mice is associated with diaphragm muscle weakness. J Appl Physiol (1985) 2021; 131:95-106. [PMID: 34013750 PMCID: PMC8325609 DOI: 10.1152/japplphysiol.00194.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 11/22/2022] Open
Abstract
Diseases or conditions where diaphragm muscle (DIAm) function is impaired, including chronic obstructive pulmonary disease, cachexia, asthma, and aging, are associated with an increased risk of pulmonary symptoms, longer duration of hospitalizations, and increasing requirements for mechanical ventilation. Vitamin D deficiency is associated with proximal muscle weakness that resolves following therapy with vitamin D3. Skeletal muscle expresses the vitamin D receptor (VDR), which responds to the active form of vitamin D, 1,25-dihydroxyvitamin D3 by altering gene expression in target cells. In knockout mice without skeletal muscle VDRs, there is marked atrophy of muscle fibers and a change in skeletal muscle biochemistry. We used a tamoxifen-inducible skeletal muscle Cre recombinase in Vdrfl/fl mice (Vdrfl/fl actin.iCre+) to assess the role of muscle-specific VDR signaling on DIAm-specific force, fatigability, and fiber type-dependent morphology. Vdrfl/fl actin.iCre+ mice treated with vehicle and Vdrfl/fl mice treated with tamoxifen served as controls. Seven days following the final treatment, mice were euthanized, the DIAm was removed, and isometric force and fatigue were assessed in DIAm strips using direct muscle stimulation. The proportion and cross-sectional areas of DIAm fiber types were evaluated by immunolabeling with myosin heavy chain antibodies differentiating type I, IIa and IIx, and/or IIb fibers. We show that in mice with skeletal muscle-specific VDR deletion, maximum specific force and residual force following fatigue are impaired, along with a selective atrophy of type IIx and/or IIb fibers. These results show that the VDR has a significant biological effect on DIAm function independent of systemic effects on mineral metabolism.NEW & NOTEWORTHY Vitamin D deficiency and vitamin D receptor (VDR) polymorphisms are associated with adverse pulmonary and diaphragm muscle (DIAm)-associated respiratory outcomes. We used a skeletal muscle-specific tamoxifen-inducible VDR knockout to investigate DIAm dysfunction following reduced VDR signaling. Marked DIAm weakness and atrophy of type IIx and/or IIb fibers are present in muscle-specific tamoxifen-induced VDR knockout mice compared with controls. These results show that the VDR has a significant biological effect on DIAm function independent of systemic effects on mineral metabolism.
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Affiliation(s)
- Matthew J Fogarty
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Louis L Losbanos
- Division of Nephrology & Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Theodore A Craig
- Division of Nephrology & Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Carmen J Reynolds
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Alyssa D Brown
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Rajiv Kumar
- Division of Nephrology & Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Gary C Sieck
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
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Pierce JL, Perrien DS. Do Interactions of Vitamin D 3 and BMP Signaling Hold Implications in the Pathogenesis of Fibrodysplasia Ossificans Progressiva? Curr Osteoporos Rep 2021; 19:358-367. [PMID: 33851285 PMCID: PMC8515998 DOI: 10.1007/s11914-021-00673-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/16/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE OF REVIEW Fibrodysplasia ossificans progressiva (FOP) is a debilitating rare disease known for episodic endochondral heterotopic ossification (HO) caused by gain-of-function mutations in ACVR1/ALK2. However, disease severity varies among patients with identical mutations suggesting disease-modifying factors, including diet, may have therapeutic implications. The roles of vitamin D3 in calcium metabolism and chondrogenesis are known, but its effects on BMP signaling and chondrogenesis are less studied. This review attempts to assess the possibility of vitamin D's effects in FOP by exploring relevant intersections of VD3 with mechanisms of FOP flares. RECENT FINDINGS In vitro and in vivo studies suggest vitamin D suppresses inflammation, while clinical studies suggest that vitamin D3 protects against arteriosclerosis and inversely correlates with non-genetic intramuscular HO. However, the enhancement of chondrogenesis, BMP signaling, and possibly Activin A expression by vitamin D may be more relevant in FOP. There appears to be little potential for vitamin D to reduce HO in FOP, but testing the potential for excess vitamin D to promote HO may be warranted.
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Affiliation(s)
- Jessica L Pierce
- Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, 101 Woodruff Circle, WMRB 1027, Atlanta, GA, 30232, USA
| | - Daniel S Perrien
- Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, 101 Woodruff Circle, WMRB 1027, Atlanta, GA, 30232, USA.
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34
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Tellez-Garcia AA, Álvarez-Martínez R, López-Martínez JM, Arellano-Carbajal F. Transcriptome analysis during early regeneration of Lumbriculus variegatus. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101050] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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35
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Maintenance of Skeletal Muscle to Counteract Sarcopenia in Patients with Advanced Chronic Kidney Disease and Especially Those Undergoing Hemodialysis. Nutrients 2021; 13:nu13051538. [PMID: 34063269 PMCID: PMC8147474 DOI: 10.3390/nu13051538] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/18/2022] Open
Abstract
Life extension in modern society has introduced new concepts regarding such disorders as frailty and sarcopenia, which has been recognized in various studies. At the same time, cutting-edge technology methods, e.g., renal replacement therapy for conditions such as hemodialysis (HD), have made it possible to protect patients from advanced lethal chronic kidney disease (CKD). Loss of muscle and fat mass, termed protein energy wasting (PEW), has been recognized as prognostic factor and, along with the increasing rate of HD introduction in elderly individuals in Japan, appropriate countermeasures are necessary. Although their origins differ, frailty, sarcopenia, and PEW share common components, among which skeletal muscle plays a central role in their etiologies. The nearest concept may be sarcopenia, for which diagnosis techniques have recently been reported. The focus of this review is on maintenance of skeletal muscle against aging and CKD/HD, based on muscle physiology and pathology. Clinically relevant and topical factors related to muscle wasting including sarcopenia, such as vitamin D, myostatin, insulin (related to diabetes), insulin-like growth factor I, mitochondria, and physical inactivity, are discussed. Findings presented thus far indicate that in addition to modulation of the aforementioned factors, exercise combined with nutritional supplementation may be a useful approach to overcome muscle wasting and sarcopenia in elderly patients undergoing HD treatments.
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36
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Dominguez LJ, Farruggia M, Veronese N, Barbagallo M. Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment. Metabolites 2021; 11:255. [PMID: 33924215 PMCID: PMC8074587 DOI: 10.3390/metabo11040255] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Studies on vitamin/hormone D deficiency have received a vast amount of attention in recent years, particularly concerning recommendations, guidelines, and treatments. Moreover, vitamin D's role as a hormone has been confirmed in various enzymatic, metabolic, physiological, and pathophysiological processes related to many organs and systems in the human body. This growing interest is mostly due to the evidence that modest-to-severe vitamin D deficiency is widely prevalent around the world. There is broad agreement that optimal vitamin D status is necessary for bones, muscles, and one's general health, as well as for the efficacy of antiresorptive and anabolic bone-forming treatments. Food supplementation with vitamin D, or the use of vitamin D supplements, are current strategies to improve vitamin D levels and treat deficiency. This article reviews consolidated and emerging concepts about vitamin D/hormone D metabolism, food sources, deficiency, as well as the different vitamin D supplements available, and current recommendations on the proper use of these compounds.
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Affiliation(s)
- Ligia J. Dominguez
- Geriatric Unit, Department of Medicine, University of Palermo, Via del Vespro 141, 90127 Palermo, Italy; (M.F.); (N.V.); (M.B.)
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37
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Latham CM, Brightwell CR, Keeble AR, Munson BD, Thomas NT, Zagzoog AM, Fry CS, Fry JL. Vitamin D Promotes Skeletal Muscle Regeneration and Mitochondrial Health. Front Physiol 2021; 12:660498. [PMID: 33935807 PMCID: PMC8079814 DOI: 10.3389/fphys.2021.660498] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Vitamin D is an essential nutrient for the maintenance of skeletal muscle and bone health. The vitamin D receptor (VDR) is present in muscle, as is CYP27B1, the enzyme that hydroxylates 25(OH)D to its active form, 1,25(OH)D. Furthermore, mounting evidence suggests that vitamin D may play an important role during muscle damage and regeneration. Muscle damage is characterized by compromised muscle fiber architecture, disruption of contractile protein integrity, and mitochondrial dysfunction. Muscle regeneration is a complex process that involves restoration of mitochondrial function and activation of satellite cells (SC), the resident skeletal muscle stem cells. VDR expression is strongly upregulated following injury, particularly in central nuclei and SCs in animal models of muscle injury. Mechanistic studies provide some insight into the possible role of vitamin D activity in injured muscle. In vitro and in vivo rodent studies show that vitamin D mitigates reactive oxygen species (ROS) production, augments antioxidant capacity, and prevents oxidative stress, a common antagonist in muscle damage. Additionally, VDR knockdown results in decreased mitochondrial oxidative capacity and ATP production, suggesting that vitamin D is crucial for mitochondrial oxidative phosphorylation capacity; an important driver of muscle regeneration. Vitamin D regulation of mitochondrial health may also have implications for SC activity and self-renewal capacity, which could further affect muscle regeneration. However, the optimal timing, form and dose of vitamin D, as well as the mechanism by which vitamin D contributes to maintenance and restoration of muscle strength following injury, have not been determined. More research is needed to determine mechanistic action of 1,25(OH)D on mitochondria and SCs, as well as how this action manifests following muscle injury in vivo. Moreover, standardization in vitamin D sufficiency cut-points, time-course study of the efficacy of vitamin D administration, and comparison of multiple analogs of vitamin D are necessary to elucidate the potential of vitamin D as a significant contributor to muscle regeneration following injury. Here we will review the contribution of vitamin D to skeletal muscle regeneration following injury.
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Affiliation(s)
- Christine M Latham
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, United States
| | - Camille R Brightwell
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, United States
| | - Alexander R Keeble
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, United States
| | - Brooke D Munson
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, United States
| | - Nicholas T Thomas
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, United States
| | - Alyaa M Zagzoog
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, United States
| | - Christopher S Fry
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, United States.,Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, United States
| | - Jean L Fry
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, United States.,Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, United States
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38
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Teixeira MA, De Feudis M, Reano S, Raiteri T, Scircoli A, Zaggia I, Ruga S, Salvadori L, Prodam F, Marzullo P, Molinari C, Corà D, Filigheddu N. Cholecalciferol (vitamin D 3) has a direct protective activity against interleukin 6-induced atrophy in C2C12 myotubes. Aging (Albany NY) 2021; 13:4895-4910. [PMID: 33618332 PMCID: PMC7950266 DOI: 10.18632/aging.202669] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 01/13/2021] [Indexed: 11/30/2022]
Abstract
We previously determined that different vitamin D metabolites can have opposite effects on C2C12 myotubes, depending on the sites of hydroxylation or doses. Specifically, 25(OH)D3 (25VD) has an anti-atrophic activity, 1,25(OH)2D3 induces atrophy, and 24,25(OH)2D3 is anti-atrophic at low concentrations and atrophic at high concentrations. This study aimed to clarify whether cholecalciferol (VD3) too, the non-hydroxylated upstream metabolite, has a direct effect on muscle cells. Assessing the effects of VD3 treatment on mouse C2C12 skeletal muscle myotubes undergoing atrophy induced by interleukin 6 (IL6), we demonstrated that VD3 has a protective action, preserving C2C12 myotubes size, likely through promoting the differentiation and fusion of residual myoblasts and by modulating the IL6-induced autophagic flux. The lack, in C2C12 myotubes, of the hydroxylase transforming VD3 in the anti-atrophic 25VD metabolite suggests that VD3 may have a direct biological activity on the skeletal muscle. Furthermore, we found that the protective action of VD3 depended on VDR, implying that VD3 too might bind to and activate VDR. However, despite the formation of VDR-RXR heterodimers, VD3 effects do not depend on RXR activity. In conclusion, VD3, in addition to its best-known metabolites, may directly impact on skeletal muscle homeostasis.
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Affiliation(s)
- Maraiza Alves Teixeira
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Istituto Interuniversitario di Miologia (IIM), Italy
| | - Marilisa De Feudis
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Simone Reano
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Tommaso Raiteri
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Andrea Scircoli
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Ivan Zaggia
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Sara Ruga
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Laura Salvadori
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Istituto Interuniversitario di Miologia (IIM), Italy
| | - Flavia Prodam
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Paolo Marzullo
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,IRCCS Istituto Auxologico Italiano, Laboratory of Metabolic Research, Piancavallo (VB), Italy
| | - Claudio Molinari
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Davide Corà
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Nicoletta Filigheddu
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Istituto Interuniversitario di Miologia (IIM), Italy
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Chen C, White DL, Marshall B, Kim WK. Role of 25-Hydroxyvitamin D 3 and 1,25-Dihydroxyvitamin D 3 in Chicken Embryo Osteogenesis, Adipogenesis, Myogenesis, and Vitamin D 3 Metabolism. Front Physiol 2021; 12:637629. [PMID: 33597896 PMCID: PMC7882680 DOI: 10.3389/fphys.2021.637629] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/05/2021] [Indexed: 12/16/2022] Open
Abstract
A study was conducted to understand the effects of 25-hydroxyvitamin D3 (25OHD) and 1,25-dihydroxyvitamin D3 (1,25OHD) administration on the expression of key genes related to osteogenesis, adipogenesis, myogenesis, and vitamin D3 metabolism in the chicken embryo. A total of 120 fertilized Cobb 500 eggs were used in the current study and were reared under standard incubation conditions. On embryonic day 3 (ED 3), PBS (C), PBS with 40ng 1,25OHD (1,25D-L), 200ng 1,25OHD (1,25D-H), 40ng 25OHD (25D-L), or 200ng 25OHD (25D-H) were injected into the dorsal vein of developing embryos. Whole embryos were harvested at 1, 3, and 6h post-injection for gene expression analyses (n=8). Gene expression for key osteogenesis markers (RUNX2: runt-related transcription factor 2; BMP2: bone morphogenetic protein 2; COL1A2: collagen type I alpha 2 chain; BGLAP: bone gamma-carboxyglutamate protein; SPP1: secreted phosphoprotein 1; and ALP: alkaline phosphatese), adipogenesis markers (PPAR-γ: peroxisome proliferator-activated receptor gamma; FASN: fatty acid synthase; and FABP4: fatty acid binding protein 4), myogenesis markers (MYOG: myogenin; MYOD1: myogenic differentiation 1; and MYF5: myogenic factor 5), and the enzyme responsible for vitamin D3 inactivation (CYP24A1: cytochrome P450 family 24 subfamily A member 1) were measured using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Data were normalized by the ΔΔCT method and analyzed using a one-way ANOVA. Results indicated that at 1h post-injection, no differences were found among treatments. At 3h, the early osteogenesis differentiation marker, ALP, was increased by 1,25D-H and 25D-H, and 25D-H also stimulated the expression of adipogenesis markers (FAPB4 and FASN). In contrast, the expression of myogenesis markers (MYOD1 and MYF5) was suppressed by 25OHD or 1,25OHD treatments, respectively. At 6h, a late osteogenic differentiation marker, SPP1, was increased by 25D-H. MYOD1 and MYF5 were continuously suppressed by 25OHD treatments or 1,25D-H. The evidence of vitamin D3 metabolite retention was assessed by measuring CYP24A1 expression. At 1h, there were no differences in CYP24A1 expression. At 3h, all treatments upregulated CYP24A1 expression relative to control (PBS) embryos. However, at 6h, only the 25D-H group retained higher CYP24A1 expression compared to the other treatments. In conclusion, the results suggested both 1,25OHD and 25OHD induced chicken embryo osteogenesis and adipogenesis, but inhibited myogenesis during early chicken embryo development. The higher dosage of 25OHD showed a possibility of a longer retention time in the embryos.
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Affiliation(s)
- Chongxiao Chen
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC, United States
| | - Dima Lynn White
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | - Brett Marshall
- Department of Poultry Science, University of Georgia, Athens, GA, United States
| | - Woo Kyun Kim
- Department of Poultry Science, University of Georgia, Athens, GA, United States
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40
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Bass JJ, Kazi AA, Deane CS, Nakhuda A, Ashcroft SP, Brook MS, Wilkinson DJ, Phillips BE, Philp A, Tarum J, Kadi F, Andersen D, Garcia AM, Smith K, Gallagher IJ, Szewczyk NJ, Cleasby ME, Atherton PJ. The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo. J Physiol 2021; 599:963-979. [PMID: 33258480 PMCID: PMC7986223 DOI: 10.1113/jp280652] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/25/2020] [Indexed: 12/12/2022] Open
Abstract
KEY POINTS Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy. Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged. In response to VDR-knockdown mitochondrial function and related gene-set expression is impaired. In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation. These results highlight the autonomous role the VDR has within skeletal muscle mass regulation. ABSTRACT Vitamin D deficiency is estimated to affect ∼40% of the world's population and has been associated with impaired muscle maintenance. Vitamin D exerts its actions through the vitamin D receptor (VDR), the expression of which was recently confirmed in skeletal muscle, and its down-regulation is linked to reduced muscle mass and functional decline. To identify potential mechanisms underlying muscle atrophy, we studied the impact of VDR knockdown (KD) on mature skeletal muscle in vivo, and myogenic regulation in vitro in C2C12 cells. Male Wistar rats underwent in vivo electrotransfer (IVE) to knock down the VDR in hind-limb tibialis anterior (TA) muscle for 10 days. Comprehensive metabolic and physiological analysis was undertaken to define the influence loss of the VDR on muscle fibre composition, protein synthesis, anabolic and catabolic signalling, mitochondrial phenotype and gene expression. Finally, in vitro lentiviral transfection was used to induce sustained VDR-KD in C2C12 cells to analyse myogenic regulation. Muscle VDR-KD elicited atrophy through a reduction in total protein content, resulting in lower myofibre area. Activation of autophagic processes was observed, with no effect upon muscle protein synthesis or anabolic signalling. Furthermore, RNA-sequencing analysis identified systematic down-regulation of multiple mitochondrial respiration-related protein and genesets. Finally, in vitro VDR-knockdown impaired myogenesis (cell cycling, differentiation and myotube formation). Together, these data indicate a fundamental regulatory role of the VDR in the regulation of myogenesis and muscle mass, whereby it acts to maintain muscle mitochondrial function and limit autophagy.
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Affiliation(s)
- Joseph J. Bass
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre (BRC)School of MedicineUniversity of NottinghamNottinghamUK
| | - Abid A. Kazi
- Department of Cellular and Molecular PhysiologyPennsylvania State University College of MedicineHersheyPAUSA
| | - Colleen S. Deane
- Department of Sport and Health SciencesUniversity of ExeterExeterUK
- Living Systems InstituteUniversity of ExeterExeterUK
| | - Asif Nakhuda
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre (BRC)School of MedicineUniversity of NottinghamNottinghamUK
| | - Stephen P. Ashcroft
- School of Sport, Exercise and Rehabilitation SciencesUniversity of BirminghamBirminghamUK
| | - Matthew S. Brook
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre (BRC)School of MedicineUniversity of NottinghamNottinghamUK
| | - Daniel J. Wilkinson
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre (BRC)School of MedicineUniversity of NottinghamNottinghamUK
| | - Bethan E. Phillips
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre (BRC)School of MedicineUniversity of NottinghamNottinghamUK
| | - Andrew Philp
- School of Sport, Exercise and Rehabilitation SciencesUniversity of BirminghamBirminghamUK
- Mitochondrial Metabolism & Ageing Laboratory, Diabetes and Metabolism DivisionGarvan Institute of Medical ResearchNew South WalesAustralia
- St Vincent's Medical School, UNSW Medicine, UNSWSydneyAustralia
| | - Janelle Tarum
- School of Health SciencesÖrebro UniversityÖrebroSweden
| | - Fawzi Kadi
- School of Health SciencesÖrebro UniversityÖrebroSweden
| | - Ditte Andersen
- Molecular Physiology of Diabetes LaboratoryDepartment of Comparative Biomedical SciencesRoyal Veterinary CollegeLondonUK
| | - Amadeo Muñoz Garcia
- Institute of Metabolism and Systems ResearchThe University of BirminghamBirminghamUK
- Department of Bioinformatics – BiGCaTNUTRIM School of Nutrition and Metabolism in Translational ResearchMaastricht UniversityMaastrichtThe Netherlands
| | - Ken Smith
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre (BRC)School of MedicineUniversity of NottinghamNottinghamUK
| | - Iain J. Gallagher
- Physiology, Exercise and Nutrition Research GroupFaculty of Health Sciences and SportUniversity of StirlingStirlingUK
| | - Nathaniel J. Szewczyk
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre (BRC)School of MedicineUniversity of NottinghamNottinghamUK
| | - Mark E. Cleasby
- Molecular Physiology of Diabetes LaboratoryDepartment of Comparative Biomedical SciencesRoyal Veterinary CollegeLondonUK
| | - Philip J Atherton
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre (BRC)School of MedicineUniversity of NottinghamNottinghamUK
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Bass JJ, Nakhuda A, Deane CS, Brook MS, Wilkinson DJ, Phillips BE, Philp A, Tarum J, Kadi F, Andersen D, Garcia AM, Smith K, Gallagher IJ, Szewczyk NJ, Cleasby ME, Atherton PJ. Overexpression of the vitamin D receptor (VDR) induces skeletal muscle hypertrophy. Mol Metab 2020; 42:101059. [PMID: 32771696 PMCID: PMC7475200 DOI: 10.1016/j.molmet.2020.101059] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused on the loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofibre size and function and impaired muscle development. To understand the mechanistic role upregulation of the VDR elicits in muscle mass/health, we studied the impact of VDR over-expression (OE) in vivo before exploring the importance of VDR expression upon muscle hypertrophy in humans. METHODS Wistar rats underwent in vivo electrotransfer (IVE) to overexpress the VDR in the Tibialis anterior (TA) muscle for 10 days, before comprehensive physiological and metabolic profiling to characterise the influence of VDR-OE on muscle protein synthesis (MPS), anabolic signalling and satellite cell activity. Stable isotope tracer (D2O) techniques were used to assess sub-fraction protein synthesis, alongside RNA-Seq analysis. Finally, human participants underwent 20 wks of resistance exercise training, with body composition and transcriptomic analysis. RESULTS Muscle VDR-OE yielded total protein and RNA accretion, manifesting in increased myofibre area, i.e., hypertrophy. The observed increases in MPS were associated with enhanced anabolic signalling, reflecting translational efficiency (e.g., mammalian target of rapamycin (mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodelling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were upregulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training. CONCLUSION VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and upregulation of ECM remodelling-related gene-sets. Furthermore, VDR expression is a robust marker of the hypertrophic response to resistance exercise in humans. The VDR is a viable target of muscle maintenance through testable Vitamin D molecules, as active molecules and analogues.
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Affiliation(s)
- Joseph J Bass
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Asif Nakhuda
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Colleen S Deane
- Department of Sport and Health Sciences, University of Exeter, EX1 2LU, UK
| | - Matthew S Brook
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Daniel J Wilkinson
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Bethan E Phillips
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Andrew Philp
- Mitochondrial Metabolism and Ageing Laboratory, Diabetes and Metabolism Division, Garvan Institute of Medical Research, NSW, 2010, Australia; School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, B15 2TT, UK
| | - Janelle Tarum
- School of Health Sciences, Örebro University, 70182, Sweden
| | - Fawzi Kadi
- School of Health Sciences, Örebro University, 70182, Sweden
| | - Ditte Andersen
- Molecular Physiology of Diabetes Laboratory, Dept. of Comparative Biomedical Sciences, Royal Veterinary College, NW1 0TU, UK
| | - Amadeo Muñoz Garcia
- Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, UK; Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Metabolism in Translational Research, Maastricht University, Maastricht, the Netherlands
| | - Ken Smith
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Iain J Gallagher
- Physiology, Exercise and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, FK9 4LA, UK
| | - Nathaniel J Szewczyk
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK
| | - Mark E Cleasby
- Molecular Physiology of Diabetes Laboratory, Dept. of Comparative Biomedical Sciences, Royal Veterinary College, NW1 0TU, UK
| | - Philip J Atherton
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, DE22 3DT, UK.
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Uchitomi R, Oyabu M, Kamei Y. Vitamin D and Sarcopenia: Potential of Vitamin D Supplementation in Sarcopenia Prevention and Treatment. Nutrients 2020; 12:nu12103189. [PMID: 33086536 PMCID: PMC7603112 DOI: 10.3390/nu12103189] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/14/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022] Open
Abstract
Skeletal muscle, the largest organ in the human body, accounting for approximately 40% of body weight, plays important roles in exercise and energy expenditure. In the elderly, there is often a progressive decline in skeletal muscle mass and function, a condition known as sarcopenia, which can lead to bedridden conditions, wheelchair confinement as well as reducing the quality of life (QOL). In developed countries with aging populations, the prevention and management of sarcopenia are important for the improvement of health and life expectancy in these populations. Recently, vitamin D, a fat-soluble vitamin, has been attracting attention due to its importance in sarcopenia. This review will focus on the effects of vitamin D deficiency and supplementation on sarcopenia.
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Bollen SE, Atherton PJ. Myogenic, genomic and non-genomic influences of the vitamin D axis in skeletal muscle. Cell Biochem Funct 2020; 39:48-59. [PMID: 33037688 DOI: 10.1002/cbf.3595] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/21/2020] [Accepted: 09/27/2020] [Indexed: 12/14/2022]
Abstract
Despite vitamin D-deficiency clinically presenting with myopathy, muscle weakness and atrophy, the mechanisms by which vitamin D exerts its homeostatic effects upon skeletal muscle remain to be fully established. Recent studies have shown that the receptor by which 1α,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ) exerts its biological actions (ie, the vitamin D receptor, VDR) elicits both genomic and non-genomic effects upon skeletal muscle. The controversy surrounding skeletal muscle VDR mRNA/protein expression in post-natal muscle has been allayed by myriad recent studies, while dynamic expression of VDR throughout myogenesis, and association of higher VDR levels during muscle regeneration/immature muscle cells, suggests a role in myogenesis and perhaps an enrichment of VDR in satellite cells. Accordingly, in vitro studies have demonstrated 1,25(OH)2 D3 is anti-proliferative in myoblasts, yet pro-differentiation in latter stages of myogenesis. These effects involve modulation of gene expression (VDR as a transcriptional co-activator controls ~3% of the genome) and post-genomic intracellular signalling for example, via c-Src and alterations to intramuscular calcium homeostasis and proteostasis. The aim of this review is to consider the biomolecular role for the vitamin D/VDR axis in myogenesis, while also exploring global evidence for genomic and non-genomic mechanisms of action for 1,25(OH)2 D3 /VDR.
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Affiliation(s)
- Shelby E Bollen
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Derby, UK
| | - Philip J Atherton
- MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Derby, UK
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44
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Puangthong C, Sukhong P, Saengnual P, Srikuea R, Chanda M. A single bout of high-intensity exercise modulates the expression of vitamin D receptor and vitamin D-metabolising enzymes in horse skeletal muscle. Equine Vet J 2020; 53:796-805. [PMID: 32902017 DOI: 10.1111/evj.13346] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 07/23/2020] [Accepted: 08/27/2020] [Indexed: 01/05/2023]
Abstract
BACKGROUND The expressions of vitamin D receptor (VDR) and vitamin D-metabolising enzymes (CYP27B1 and CYP24A1) in skeletal muscle have been reported. However, the regulation of this vitamin D system in horse skeletal muscle after high-intensity exercise has not yet been elucidated. OBJECTIVES To investigate the effect of high-intensity exercise on the expression of vitamin D system-related proteins in horse skeletal muscle and its associations with skeletal muscle stem cell (SMSC) activity and serum 25(OH)D level. STUDY DESIGN Longitudinal study. METHODS Six healthy ponies (5 geldings, 1 mare; age 6.3 ± 2.2 years) were studied. Serum and muscle samples were taken from the jugular vein and gluteus medius respectively. Samples were collected at pre-exercise, post-exercise, 1 and 3 weeks after a single bout of high-intensity exercise. Protein expression levels of VDR, CYP27B1, CYP24A1, OxPhos and Pax7 (SMSC marker) were determined using immunohistochemical analysis. Oxidative capacity and intramuscular glycogen content were evaluated using histochemical analysis. Blood biochemistry was analysed for lactate concentration and creatine kinase (CK), and 25(OH)D activity. RESULTS High-intensity exercise significantly upregulated Pax7 and VDR protein expression, which correlated with significantly increased blood lactate and serum CK levels immediately post-exercise. Serum 25(OH)D2 level correlated with CYP27B1 protein expression in skeletal muscle, and it reduced significantly immediately post-exercise and at 1 and 3 weeks post-exercise. However, CYP24A1 protein expression was unchanged throughout study periods. MAIN LIMITATION The healthy ponies could not represent a fit population of racehorses and eventers. CONCLUSIONS The rapid increase in Pax7 and VDR protein expression along with serum CK level after high-intensity exercise demonstrated an association between SMSC activity and activation of the vitamin D system in response to muscle injury in horses. Moreover, a decrease in CYP27B1 protein expression, correlated with a reduction in serum 25(OH)D2 , may indicate a compromised vitamin D metabolism after high-intensity exercise.
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Affiliation(s)
- Chanikarn Puangthong
- Veterinary Clinical Studies Program, Faculty of Veterinary Medicine, Kasetsart University Kamphaeng Saen Campus, Nakhon Pathom, Thailand
| | - Patskit Sukhong
- Department of Large Animal and Wildlife Clinical Science, Faculty of Veterinary Medicine, Kasetsart University Kamphaeng Saen Campus, Nakhon Pathom, Thailand
| | - Pattrawut Saengnual
- Pathological unit, Veterinary Diagnostic Laboratory, Faculty of Veterinary Medicine, Kasetsart University Kamphaeng Saen Campus, Nakhon Pathom, Thailand
| | - Ratchakrit Srikuea
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Metha Chanda
- Department of Large Animal and Wildlife Clinical Science, Faculty of Veterinary Medicine, Kasetsart University Kamphaeng Saen Campus, Nakhon Pathom, Thailand.,Center of Veterinary Research and Academic Service, Faculty of Veterinary Medicine, Kasetsart University Bang Khen Campus, Bangkok, Thailand
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45
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Sun X, Ma XK, Zhang L, Cao ZB. Effects of resistance training on serum 25(OH) D concentrations in young men: a randomized controlled trial. Nutr Metab (Lond) 2020; 17:59. [PMID: 32774437 PMCID: PMC7395973 DOI: 10.1186/s12986-020-00480-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 07/22/2020] [Indexed: 11/26/2022] Open
Abstract
Background Previous studies indicated that serum 25-hydroxyvitamin D [25(OH)D] concentrations are positively associated with physical activity levels independent of sun exposure. However, the effect of resistance training on serum 25(OH) D concentrations remains unclear. Thus, this study aimed to examine the effect of chronic resistance training on serum 25(OH) D concentrations and determine whether 25(OH) D concentration variations are influenced by body composition changes. Methods Eighteen young men aged 19–39 years were randomly divided into a 12-week resistance training group (RT, n = 9) and non-exercise control group (CON, n = 9). The trial was undertaken in Shanghai University of Sport in Shanghai, China. Randomization and allocation to trial group were carried out by a central computer system. Serum 25(OH) D and intact parathyroid hormone concentrations were measured using commercially available enzyme-linked immunosorbent assay kits. Body composition was measured by dual-energy X-ray absorptiometry. Results The average serum 25(OH) D concentrations were 26.6 nmol/L at baseline. After the 12-week intervention program, serum 25(OH) D concentrations significantly increased in both groups. Serum 25(OH) D concentrations at midpoint (6-week) increased significantly only in the CON group (P < 0.01). From training midpoint to endpoint, a significantly greater increase in serum 25(OH) D concentrations was noted in the RT group (P-interaction = 0.043); 25(OH) D concentration changes (end-pre) were negatively related to fat-free mass (mid-pre) (r = − 0.565, P = 0.015) and muscle mass (mid-pre) (r = − 0.554, P = 0.017). Conclusions There were no beneficial effects of the 12-week resistance training on serum 25(OH) D concentration in vitamin D deficient young men, and an indication that seasonal increase in serum 25(OH) D concentrations during the early phase of resistance training was transiently inhibited, which may partly be attributed to resistance training-induced muscle mass gain. Trial registration Chinese Clinical Trial Registry, ChiCTR2000030876. Registered 16 March 2020 - Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=50504.
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Affiliation(s)
- Xiaomin Sun
- Global Health Institute, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, 710061 China
| | - Xiao-Kai Ma
- School of Kinesiology, Shanghai University of Sport, 399 Chang Hai Road, Shanghai, 200438 China
| | - Lin Zhang
- School of Kinesiology, Shanghai University of Sport, 399 Chang Hai Road, Shanghai, 200438 China
| | - Zhen-Bo Cao
- School of Kinesiology, Shanghai University of Sport, 399 Chang Hai Road, Shanghai, 200438 China
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Nakamura S, Sato Y, Kobayashi T, Kaneko Y, Ito E, Soma T, Okada H, Miyamoto K, Oya A, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T. Vitamin D protects against immobilization-induced muscle atrophy via neural crest-derived cells in mice. Sci Rep 2020; 10:12242. [PMID: 32699341 PMCID: PMC7376070 DOI: 10.1038/s41598-020-69021-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 07/06/2020] [Indexed: 12/18/2022] Open
Abstract
Vitamin D deficiency is a recognized risk factor for sarcopenia development, but mechanisms underlying this outcome are unclear. Here, we show that low vitamin D status worsens immobilization-induced muscle atrophy in mice. Mice globally lacking vitamin D receptor (VDR) exhibited more severe muscle atrophy following limb immobilization than controls. Moreover, immobilization-induced muscle atrophy was worse in neural crest-specific than in skeletal muscle-specific VDR-deficient mice. Tnfα expression was significantly higher in immobilized muscle of VDR-deficient relative to control mice, and was significantly elevated in neural crest-specific but not muscle-specific VDR-deficient mice. Furthermore, muscle atrophy induced by limb immobilization in low vitamin D mice was significantly inhibited in Tnfα-deficient mice. We conclude that vitamin D antagonizes immobilization-induced muscle atrophy via VDR expressed in neural crest-derived cells.
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Affiliation(s)
- Satoshi Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yuiko Sato
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.,Department of Advanced Therapy for Musculoskeletal Disorders II, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.,Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Tami Kobayashi
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.,Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yosuke Kaneko
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Eri Ito
- Institute for Integrated Sports Medicine, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Tomoya Soma
- Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroyuki Okada
- Department of Orthopedic Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kana Miyamoto
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Akihito Oya
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Morio Matsumoto
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Arihiko Kanaji
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Takeshi Miyamoto
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan. .,Department of Advanced Therapy for Musculoskeletal Disorders II, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan. .,Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan. .,Department of Orthopedic Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
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Mori R, Yokokawa T, Fujita S. Modified expression of vitamin D receptor and CYP27B1 in denervation-induced muscle atrophy. Biochem Biophys Res Commun 2020; 529:733-739. [PMID: 32736700 DOI: 10.1016/j.bbrc.2020.05.205] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 05/27/2020] [Indexed: 11/29/2022]
Abstract
The vitamin D pathway is related to the mass and function of skeletal muscles. Several studies have demonstrated the role of vitamin D receptor (VDR) and CYP27B1 in skeletal muscles, suggesting that these proteins may regulate skeletal muscles and their function. However, it remains unclear whether the expression of VDR and CYP27B1 is modified in skeletal muscle atrophy. We investigated whether denervation-induced muscle atrophy is associated with altered expression of VDR and CYP27B1 in murine skeletal muscles. Skeletal muscles were excised from C57BL/6J mice, 3 and 7 days after the mice underwent denervation surgery. Denervation induced muscle atrophy and enhanced the expression of MuRF1 and Atrogin-1 in the gastrocnemius and soleus. The protein expression of VDR was increased in the denervated gastrocnemius; in contrast, denervation decreased the protein expression of CYP27B1 in the gastrocnemius and soleus. These results suggest that denervation-induced muscle atrophy is associated with changes in the expression of vitamin D-related proteins in murine skeletal muscles.
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Affiliation(s)
- Risako Mori
- Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Takumi Yokokawa
- Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Satoshi Fujita
- Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan.
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48
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Zhang C, Fu S, Zhao M, Liu D, Zhao Y, Yao Y. Associations Between Complement Components and Vitamin D and the Physical Activities of Daily Living Among a Longevous Population in Hainan, China. Front Immunol 2020; 11:1543. [PMID: 32765534 PMCID: PMC7379858 DOI: 10.3389/fimmu.2020.01543] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/11/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Vitamin D and complement components shared some common pathophysiological pathways in the musculoskeletal system, circulation, and metabolism, which were linked to physical function. It is hypothesized that serum complement components may interact with vitamin D in respect of the physical activities of daily living (PADLs). Objective: To investigate if serum complement components 3 (C3), complement components 4 (C4), and 25-hydroxyvitamin D [25(OH)D] associate with PADLs, and to examine whether the association between 25(OH)D levels and PADLs varies at different complement component levels among Chinese centenarians. Methods: This study was conducted in a group of population-based centenarians. PADLs were evaluated using the Barthel Index. Multiple regressions were used to analyze the associations among 25(OH)D, complements C3 and C4, and PADLs. Results: Among 943 participants, 672 (71.3%) had physical dependence (PD). After adjusting for potential confounders, serum 25(OH)D and C3 levels were positively correlated with PADLs, while C4 levels were negatively correlated with PADLs (Ps < 0.05). Serum 25(OH)D levels significantly interacted with both C3 (P for interaction = 0.033) and C4 (P for interaction = 0.006) levels on PADLs. At lower complement component levels, the multivariate odds ratios (ORs) of the upper tertile of vitamin D for PD were 0.32 (95% CI: 0.18-0.55) in the C3 group and 0.29 (95% CI: 0.16-0.50) in the C4 group. At higher complement component levels, the ORs in the C3 and C4 groups were not statistically significant. Conclusions: In a group of population-based Chinese centenarians, we observed that serum complement C3 and 25(OH)D levels were positively associated with PADLs, while C4 was negatively associated with PADLs. The associations between 25(OH)D levels and PADLs were more pronounced in groups with lower serum complement component levels.
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Affiliation(s)
- Chi Zhang
- Department of Education, Beijing Hospital, National Center of Gerontology, Beijing, China.,Institute of Geriatrics Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Shihui Fu
- Department of Cardiology, Hainan Hospital of Chinese PLA General Hospital, Sanya, China
| | - Minghao Zhao
- School of Medicine, Peking University Health Science Center, Beijing, China
| | - Deping Liu
- Department of Education, Beijing Hospital, National Center of Gerontology, Beijing, China.,Institute of Geriatrics Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yali Zhao
- Central Laboratory, Hainan Hospital of Chinese PLA General Hospital, Sanya, China
| | - Yao Yao
- Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, China.,Center for the Study of Aging and Human Development and Geriatrics Division, Medical School of Duke University, Durham, NC, United States
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49
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Si Y, Kazamel M, Kwon Y, Lee I, Anderson T, Zhou S, Bamman M, Wiggins D, Kwan T, King PH. The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis. J Steroid Biochem Mol Biol 2020; 200:105650. [PMID: 32142934 PMCID: PMC7274892 DOI: 10.1016/j.jsbmb.2020.105650] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/29/2020] [Accepted: 03/03/2020] [Indexed: 12/11/2022]
Abstract
Extra-renal expression of Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1) has been well recognized and reflects the importance of intracrine/paracrine vitamin D signaling in different tissues under physiological and pathological conditions. In a prior RNA sequencing project, we identified CYP27B1 mRNA as upregulated in muscle samples from patients with amyotrophic lateral sclerosis (ALS) compared to normal controls. Our aims here were: (1) to validate this finding in a larger sample set including disease controls, (2) to determine which cell type is expressing CYP27B1 protein in muscle tissue, (3) to correlate CYP27B1 mRNA expression with disease progression in the SOD1G93A ALS mouse and in ALS patients. We assessed CYP27B1 expression by qPCR, western blot, and immunohistochemistry in a repository of muscle samples from ALS, disease controls (myopathy and non-ALS neuropathic disease), normal subjects, and muscle samples from the SOD1G93A mouse. Eight ALS patients were studied prospectively over 6-12 months with serial muscle biopsies. We found that CYP27B1 mRNA and protein levels were significantly increased in ALS versus normal and myopathy muscle samples. Neuropathy samples had increased CYP27B1 mRNA and protein expression but at a lower level than the ALS group. Immunohistochemistry showed that CYP27B1 localized to myofibers, especially those with features of denervation. In the SOD1G93A mouse, CYP27B1 mRNA and protein were detected in skeletal muscle in early pre-symptomatic stages and increased through end-stage. In the human study, increases in CYP27B1 mRNA in muscle biopsies correlated with disease progression rates over the same time period. In summary, we show for the first time that CYP27B1 mRNA and protein expression are elevated in muscle fibers in denervating disease, especially ALS, where mRNA levels can potentially serve as a surrogate marker for tracking disease progression. Its upregulation may reflect a local perturbation of vitamin D signaling, and further characterization of this pathway may provide insight into underlying molecular processes linked to muscle denervation.
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Affiliation(s)
- Ying Si
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA; Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, USA
| | - Mohamed Kazamel
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA
| | - Yuri Kwon
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA
| | - Ikjae Lee
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA
| | - Tina Anderson
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA
| | - Siyu Zhou
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA
| | - Marcas Bamman
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA; Department of Cell, Developmental, and Integrative Biology, and Medicine, University of Alabama, Birmingham, AL 35294, USA; Department of Medicine, University of Alabama, Birmingham, AL 35294, USA; Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, USA
| | - Derek Wiggins
- Department of Cell, Developmental, and Integrative Biology, and Medicine, University of Alabama, Birmingham, AL 35294, USA
| | - Thaddaeus Kwan
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA
| | - Peter H King
- Department of Neurology, University of Alabama, Birmingham, AL 35294, USA; Department of Cell, Developmental, and Integrative Biology, and Medicine, University of Alabama, Birmingham, AL 35294, USA; Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, USA.
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Ren L, Xuan L, Han F, Zhang J, Gong L, Lv Y, Zhang W, Yang S, Xu B, Yan Y, Guo L, Liu H, Wan Z, Liu L. Vitamin D supplementation rescues simvastatin induced myopathy in mice via improving mitochondrial cristae shape. Toxicol Appl Pharmacol 2020; 401:115076. [PMID: 32479918 DOI: 10.1016/j.taap.2020.115076] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 05/14/2020] [Accepted: 05/26/2020] [Indexed: 01/06/2023]
Abstract
Statin induced myopathy (SIM) is a main deleterious effect leading to the poor treatment compliance, while the preventive or therapeutic treatments are absent. Mounting evidences demonstrated that vitamin D plays a vital role in muscle as a direct modulator. The deficiency of vitamin D was considered as a cause of muscle dysfunction, whereas the supplementation resulted in a remission. However, there is no causal proof that vitamin D supplementation rescues SIM. Here, using the mice model of simvastatin-induced myopathy, we investigated the role of vitamin D supplementation and the mechanisms associated with mitochondria. Results indicated that simvastatin administration (80 mg/kg) impaired skeletal muscle with the increased serum creatine kinase (CK) level and the declined grip strength, which were alleviated by vitamin D supplementation. Moreover, vitamin D supplementation rescued the energy metabolism dysfunction in simvastatin-treated mice gastrocnemius by reducing the abnormal aggregation of muscular glycogen and lactic acid. Mitochondrial homeostasis plays a key role in the process of energy metabolism. Thus, the mitochondrial dysfunction is a mortal damage for the highly energy-requiring tissue. In our study, the mitochondrial cristae observed under transmission electron microscope (TEM) were lytic in simvastatin-treated gastrocnemius. Interestingly, vitamin D supplementation improved the mitochondrial cristae shape by regulating the expression of mitofusin-1/2 (MFN1/2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (Drp1). As expected, the mitochondrial dysfunction and oxidative stress was mitigated by vitamin D supplementation. In conclusion, these findings suggested that moderate vitamin D supplementation rescued simvastatin induced myopathy via improving the mitochondrial cristae shape and function.
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Affiliation(s)
- Lulu Ren
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Lingling Xuan
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Feifei Han
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Jie Zhang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Lili Gong
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Yali Lv
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Wen Zhang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Song Yang
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Benshan Xu
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Yan Yan
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Lifang Guo
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - He Liu
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Zirui Wan
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
| | - Lihong Liu
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
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