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.

Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures

“…The current data show that the biological perturbations in skeletal muscle after 84 days of bed rest are at least as large, if not greater, than what has been described after 21 15 or 60 days of bed rest 18,19 . For example, pathways related to mitochondria, energy metabolism, and structural components were downregulated, and those involved in the ubiquitin system upregulated, which is consistent with findings in skeletal muscle after short‐ 10‐15,17 and moderately long periods of unloading 18,19 . Similarly, we found a transcriptomic profile indicating slow‐to‐fast fiber transition, a common event in unloading studies 6,43‐46 .…”

“…Hitherto attempts to provide mechanistic information on the molecular programs governing unloading‐induced muscle deconditioning have included the exploration of transcriptome changes in muscle after short‐term bed rest or unilateral lower limb suspension/cast immobilization, ranging from 24 hours to 21 days, 10‐17 or longer periods of bed rest (60 days) 18,19 . A common disuse signature, regardless of the differences in methods and/or study duration, is a marked downregulation of gene networks related to both energy metabolism and structural components, together with an upregulation of the ubiquitin‐proteasome pathway 10‐12,14,15,17‐19 .…”

Loss of melusin is a novel, neuronal NO synthase/FoxO3‐independent master switch of unloading‐induced muscle atrophy

“…Costameres assembly is jeopardized by unloading, because of either decreased FAK activation or reduced expression of the kinase and its inhibitor FRNK, which characterized human muscle already after 8 day bed rest . Five days of bed rest are sufficient to downregulate transcriptome of integrin signalling pathway in both young and old subjects . Our finding that melusin, a FAK‐interacting protein, decreased early after unloading also in human muscle is in line with these reports and may represent a major determinant of costamere deregulation.…”

Skeletal Muscle Energetics and Mitochondrial Function Are Impaired Following 10 Days of Bed Rest in Older Adults

“…Lastly, we found the extracellular matrix and collagen pathways to be significantly up-regulated in the CON group with BR, which was attenuated in the HMB group. A recent investigation also found fibrotic pathways to be significantly up-regulated in older adults after 5 days of BR ( 31 ). Up-regulation of the extracellular matrix and collagen proteins may have important implications for skeletal muscle function.…”

“…These findings are supported by our recent findings in a preclinical animal model of disuse atrophy in which several upstream regulators, for example, PGC-1α and ERRα, of mitochondrial biogenesis and energetics were significantly affected ( 30 ). Mahmassani et al also found mitochondrial dysfunction and oxidative phosphorylation pathways were significantly regulated in both young and old individuals following 5 days of BR ( 31 ). Collectively, these studies highlight the potent effect of short-term disuse on skeletal muscle oxidative metabolism and mitochondrial transcriptome.…”