Transcriptomic Profiling of Skeletal Muscle Adaptations to Exercise and Inactivity

Abstract

The molecular mechanisms underlying the response to exercise and inactivity are not fully understood. We propose an innovative approach to profile the skeletal muscle transcriptome to exercise and inactivity using 66 published datasets. Data collected from human studies of aerobic and resistance exercise, including acute and chronic exercise training, were integrated using meta-analysis methods (www.metamex.eu). Gene ontology and pathway analyses reveal selective pathways activated by inactivity, aerobic versus resistance and acute versus chronic exercise training. We identified NR4A3 as one of the most exercise-and inactivity-responsive genes, and established a role for this nuclear receptor in mediating the metabolic responses to exercise-like stimuli in vitro. The meta-analysis (MetaMEx) also highlights the differential response to exercise in individuals with metabolic impairments. MetaMEx provides the most extensive dataset of skeletal muscle transcriptional responses to different modes of exercise and an online interface to readily interrogate the database.

Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers

“…3c), indicating that this may be a progressive feature of aging muscle. Smad3 has been implicated during the muscle aging process 38,39 , while Nr4a3 has a role for metabolic adaptations to exercise but has not been studied during aging 40,41 . smFISH for Nr4a3 in the gastrocnemius muscle confirmed elevated expression in myonuclei in aged muscle, following a heterogeneous pattern (Fig.…”

Time-dependent Effects of Moderate- and High-intensity Exercises on Myocardial Transcriptomics

“…Nr4a3 functioned as an exercise-responsive gene 59 to improve aerobic endurance 60 61 , while we showed it is upregulated by HIE. There are no previous studies on exercise regulation of myocardial Nr4a3 expression, although exercise has been shown to increase skeletal muscle expression of Nr4a3 59 . Tnfrsf12a, is a cell surface-associated type II transmembrane protein with multiple biological activities, including stimulation of cell growth and angiogenesis, induction of inflammatory cytokines, and stimulation of apoptosis under some experimental conditions.…”

Exercise Training and Circulating Small Extracellular Vesicles: Appraisal of Methodological Approaches and Current Knowledge

“…Distinct from assessing small EV abundance, there is greater consistency across studies indicating that exercise training influences the miRNA profile of preparations of small EVs from resting samples. As exercise training can alter the transcriptomes (Pillon et al, 2019) and proteomes (Holloway et al, 2009;Ferreira et al, 2014;Padrão et al, 2016) of contractile tissues, a change in cargo profile is plausible independent of change in small EV abundance, because local changes to the biomolecular environment of a cell could alter the cargo that is released, even in the absence of an altered rate of EV release. However, it is important to reiterate that without adequate characterization of small EVs, the extent to which these differential miRNA profiles associate specifically to small EVs (even when small EV separations have been undertaken) is unknown.…”

“…A pertinent question to our understanding of the biological importance and mechanistic consequence of exercise factors is whether these factors function as transient, beneficial responses exclusively related to the enrichment of factors induced by acute exercise, or whether exercise training induces more persistent changes to circulating exercise factors that are measurable distally from acute exercise. Clearly, exercise training alters the resting proteome (Holloway et al, 2009;Ferreira et al, 2014;Padrão et al, 2016), transcriptome (Pillon et al, 2019), and metabolome (Castro et al, 2019;Klein et al, 2020) of tissues such as skeletal (Holloway et al, 2009;Padrão et al, 2016;Pillon et al, 2019;Klein et al, 2020) and cardiac (Ferreira et al, 2014) muscle. Assuming that the internal biomolecular composition of a cell influences the host of factors it releases into circulation (Uhlén et al, 2019), exercise training-induced changes in the resting profile of exercise factors is a physiologically-plausible outcome.…”