Mef2 as upstream regulator of the transcriptome signature in human skeletal muscle during unloading

• Our understanding of skeletal muscle structural and functional alterations during unloading has increased in recent decades, yet the molecular mechanisms underpinning these changes have only started to be unraveled. The purpose of the current investigation was to assess changes in skeletal muscle gene expression after 21 days of bed rest, with a particular focus on predicting upstream regulators of muscle disuse. Additionally, the association between differential microRNA expression and the transcriptome signature of bed rest were investigated. mRNAs from m. vastus lateralis biopsies obtained from 12 men before and after the bed rest were analyzed using a microarray. There were 54 significantly up-regulated probesets after bed rest, whereas 103 probesets were down-regulated (FDR 10%; fold-change cut-off ≥1.5). Amongst the up-regulated genes, transcripts related to denervation-induced alterations in skeletal muscle were identified, e.g. CHRND and perinatal myosin. The most down-regulated transcripts were functionally enriched for mitochondrial genes and genes involved in mitochondrial biogenesis, followed by a large number of contractile fiber components. Upstream regulator-analysis identified a robust inhibition of the MEF2 family, in particular MEF2C, which was suggested to act upstream of several key down-regulated genes, most notably PGC-1α/PPARs and CRSP3. Only a few microRNAs were identified as playing a role in the overall transcriptome picture induced by sustained bed rest. Our results suggest that the MEF2 family is a key regulator underlying the transcriptional signature of bed rest, and hence ultimately also skeletal muscle alterations induced by systemic unloading in humans.

Keyword

bed rest

microRNA

microarray

unloading

Publication and Content Type

ref (subject category)

art (subject category)