Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction
Yuan Wen, Christine M. Latham, Angelique N. Moore, Nicholas T. Thomas, Brooke D. Lancaster, Kelsey A. Reeves, Alexander R. Keeble, Christopher S. Fry, Darren L. Johnson, Katherine L. Thompson, Brian Noehren, Jean L. Fry
Yuan Wen, Christine M. Latham, Angelique N. Moore, Nicholas T. Thomas, Brooke D. Lancaster, Kelsey A. Reeves, Alexander R. Keeble, Christopher S. Fry, Darren L. Johnson, Katherine L. Thompson, Brian Noehren, Jean L. Fry
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Clinical Research and Public Health Muscle biology

Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction

Abstract

BACKGROUND Although 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.METHODS Twenty-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.RESULTS ACLR 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.CONCLUSION Correcting vitamin D status prior to ACLR may aid in preserving skeletal muscle during recovery.FUNDING NIH grants R01AR072061, R01AR071398-04S1, and K99AR081367.

Authors

Yuan Wen, Christine M. Latham, Angelique N. Moore, Nicholas T. Thomas, Brooke D. Lancaster, Kelsey A. Reeves, Alexander R. Keeble, Christopher S. Fry, Darren L. Johnson, Katherine L. Thompson, Brian Noehren, Jean L. Fry

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Figure 5

Multiomic integration of ChIP-seq and RNA-seq data implicates the role of VDR in regulating muscle ribosome biogenesis.

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Multiomic integration of ChIP-seq and RNA-seq data implicates the role o...
(A) ChIP-seq peaks and RNA-seq differentially expressed genes (DEGs) were integrated by calculating an activation and an inhibition score to estimate the effects of transcriptional regulation. Genes are ranked by score and VDR binding is associated with highly significant activation (red solid line) of a subset of DEGs relative to background (black dotted line). The small subset of DEGs showing significant inactivation by VDR binding is represented by the blue solid line. (B) Top 3 enriched biological processes for VDR-activated DEGs. ChIP-seq reads for input (blue, top) and VDR (red) showing VDR binding at the genomic locations for MYC (C), SNORA4B/SNORD10 (D), MYOG (E), and MYOD1 (F). Coding sequence for each gene is shown in blue below the VDR red peaks. Rectangles are exons and arrows along the introns indicate direction of mRNA transcription. Multiple splice isoforms are shown.