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 4

VDR targets genes associated with muscle structure and energy generation genes after ACL reconstruction (ACLR).

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VDR targets genes associated with muscle structure and energy generation...
(A) Distribution of ChIP-seq peaks’ relative gene sequences, including untranslated regions (UTRs), proximal (PROX) and distal (DIST) promoters (PROM), and regions downstream of the 3′-UTR (DOWNSTR). (B) Overlap between genes with significant VDR binding that were also differentially expressed 1 week after ACLR, along with enriched VDR binding sequence motifs. (C) Gene ontology analysis of common 505 genes and their significantly enriched biological processes. (D) ChIP-seq reads for input (blue, top) and VDR (red) showing peaks for ATP transporter, SLC25A4, and skeletal α-actin, ACTA1. Coding sequence for each gene is shown in blue below the VDR red peaks. Rectangles are exons and the arrows along the introns indicate direction of mRNA transcription. (E) ChIP-seq reads for input (blue, top) and VDR (red) showing peaks at the promoters of eukaryotic initiation factor, EIF4E2, and heat shock protein, HSP90AB1. Coding sequences (blue) are shown for multiple splice isoforms.