Age-dependent skeletal muscle transcriptome response to bed rest-induced atrophy

Abstract

Short-term muscle disuse induces significant muscle loss in older adults and in some reports may be more accelerated with aging. Identifying muscle transcriptional events in response to bed rest may help identify therapeutic targets to offset muscle loss. Therefore, we compared the muscle transcriptome between young and older adults after bed rest and identified candidate targets related to changes in muscle loss. RNA was sequenced (HiSeq, Illumina; DESeq, R) from muscle biopsies obtained from young [ n = 9; 23 yr (SD 3)] and older [ n = 18; 68 yr (SD 6)] adults before and after 5-day bed rest. Significantly altered pathways in both young and old subjects relating to mechanosensing and cell adhesion (Actin Cytoskeleton Signaling, ILK Signaling, RhoA Signaling, and Integrin Signaling) were altered (activation z score) to a greater extent in old subjects. Hepatic Fibrosis/Hepatic Stellate Cell Activation was the top regulated pathway significantly altered only in the old. Fifty-one differentially regulated genes were only altered in the young after bed rest and resembled a gene expression profile like that in the old at baseline. Inflammation and muscle wasting genes (CXCL2, GADD45A) were uniquely increased in the old after bed rest, and the macrophage gene MAFB decreased in the old and correlated with the change in leg lean mass. In summary, skeletal muscle dysregulation during bed rest in the old may be driven by alterations in molecules related to fibrosis, inflammation, and cell adhesion. This information may aid in the development of mechanistic-based therapies to combat muscle atrophy during short-term disuse. NEW & NOTEWORTHY Using RNA sequencing and bioinformatics approaches, we identified that older adult skeletal muscle was characterized by dysregulated pathways associated with fibrosis, inflammation (upregulated), and cell adhesion and mechanosensing (downregulated) pathways, with a subset of genes differentially regulated in old and young muscle after bed rest that may describe predisposition to muscle loss. Unique upregulated genes only expressed in old muscle after bed rest indicated increased inflammation and muscle wasting (CXCL2, GADD45A) and decreased MAFB correlated with the change in leg lean mass.