Utilizing Next Generation Sequencing to Describe Age-Related Skeletal Muscle Changes with Bed Rest

Abstract

Short-term bed rest is used to simulate periods of disuse experienced during hospital visitation. In our previous reports, we found that 5d of bed rest induced a ~4% loss of skeletal muscle mass in OLD (60-79 y) but not YOUNG (18-28 y) subjects (Interaction: P < 0.001). Identifying muscle transcriptional events that underlie this consequence of bed rest will help identify therapeutic targets to offset muscle loss in vulnerable older adult populations. PURPOSE: To compare the gene transcriptome response between YOUNG and OLD skeletal muscle after bed rest and identify a transcriptional program that underlies rapid loss of muscle mass. METHODS: RNA was isolated and sequenced (HiSeq, Illumina; DESeq, R) from muscle biopsies obtained from the vastus lateralis of YOUNG (N=9; 22.9 ± 1.1 y, 171.6 ± 2.0 cm, 65.6 ± 4.6 kg) and OLD (N=18; 67.6 ± 1.3 y, 173.7 ± 1.8 cm, 75.7 ± 2.2 kg) men and women before and after five days of bed rest (Tanner et al 2015; Reidy et al 2017). RESULTS: After bed rest, 551 genes responded similarly and 61 genes were differentially regulated between YOUNG and OLD (P < 0.05). Ingenuity Pathway Analysis identified the top commonly regulated pathways to be related to Actin Cytoskeleton Signaling, ILK Signaling, Calcium Signaling, and Mitochondrial Dysfunction. Out of the differentially regulated genes, 51 were altered in YOUNG (42 increased, 9 decreased) but were unresponsive in OLD after bed rest (P < 0.05). On the other hand, 9 genes were altered only in OLD as a result of bed rest (P < 0.05) of which 5 are protein coding (MRPL49, HIST1H2BC: increased; PXDNL, NEXN, MAGI2: decreased). These genes code for proteins related to mitochondrial function, DNA structure, oxidative stress, Z-disc stabilization, and activin signaling, respectively. CONCLUSION: Our preliminary results indicate that altered gene expression in YOUNG in response to bed rest may be indicative of a compensatory expression profile to combat muscle loss. Additional investigation of the differentially regulated gene responses in young and old adults are ongoing in efforts to further describe underlying molecular events that occur in response to bed rest. Supported by NIH Grant R01 AG050781.