Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

AbstractThe 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). Here we use gene ontology and pathway analyses to reveal selective pathways activated by inactivity, aerobic versus resistance and acute versus chronic exercise training. We identify NR4A3 as one of the most exercise- and inactivity-responsive genes, and establish 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.

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Transcriptomic Profiling of Skeletal Muscle Adaptations to Exercise and Inactivity

10.1101/813048 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nicolas J. Pillon ◽

Brendan M. Gabriel ◽

Lucile Dollet ◽

Jonathon A. Smith ◽

Laura Sardón Puig ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Molecular Mechanisms ◽

Meta Analysis ◽

Chronic Exercise ◽

Transcriptional Responses ◽

Pathway Analyses ◽

Response To Exercise ◽

Skeletal Muscle Adaptations

SummaryThe 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.

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Pterostilbene Enhances Endurance Capacity via Promoting Skeletal Muscle Adaptations to Exercise Training in Rats

Molecules ◽

10.3390/molecules25010186 ◽

2020 ◽

Vol 25 (1) ◽

pp. 186 ◽

Cited By ~ 2

Author(s):

Jiawei Zheng ◽

Wujian Liu ◽

Xiaohui Zhu ◽

Li Ran ◽

Hedong Lang ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Mitochondrial Biogenesis ◽

C2c12 Myotubes ◽

Endurance Capacity ◽

Muscle Adaptations ◽

Slow Twitch ◽

Slow Twitch Fibers ◽

Skeletal Muscle Adaptations

It has been demonstrated that skeletal muscle adaptions, including muscle fibers transition, angiogenesis, and mitochondrial biogenesis are involved in the regular exercise-induced improvement of endurance capacity and metabolic status. Herein, we investigated the effects of pterostilbene (PST) supplementation on skeletal muscle adaptations to exercise training in rats. Six-week-old male Sprague Dawley rats were randomly divided into a sedentary control group (Sed), an exercise training group (Ex), and exercise training combined with 50 mg/kg PST (Ex + PST) treatment group. After 4 weeks of intervention, an exhaustive running test was performed, and muscle fiber type transformation, angiogenesis, and mitochondrial content in the soleus muscle were measured. Additionally, the effects of PST on muscle fiber transformation, paracrine regulation of angiogenesis, and mitochondrial function were tested in vitro using C2C12 myotubes. In vivo study showed that exercise training resulted in significant increases in time-to-exhaustion, the proportion of slow-twitch fibers, muscular angiogenesis, and mitochondrial biogenesis in rats, and these effects induced by exercise training could be augmented by PST supplementation. Moreover, the in vitro study showed that PST treatment remarkably promoted slow-twitch fibers formation, angiogenic factor expression, and mitochondrial function in C2C12 myotubes. Collectively, our results suggest that PST promotes skeletal muscle adaptations to exercise training thereby enhancing the endurance capacity.

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Oral quercetin supplementation hampers skeletal muscle adaptations in response to exercise training

Scandinavian Journal of Medicine and Science in Sports ◽

10.1111/sms.12136 ◽

2013 ◽

Vol 24 (6) ◽

pp. 920-927 ◽

Cited By ~ 16

Author(s):

R. A. Casuso ◽

E. J. Martínez-López ◽

N. B. Nordsborg ◽

F. Hita-Contreras ◽

R. Martínez-Romero ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Muscle Adaptations ◽

Response To Exercise ◽

Skeletal Muscle Adaptations

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Time trajectories in the transcriptomic response to exercise - a meta-analysis

Nature Communications ◽

10.1038/s41467-021-23579-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

David Amar ◽

Malene E. Lindholm ◽

Jessica Norrbom ◽

Matthew T. Wheeler ◽

Manuel A. Rivas ◽

...

Keyword(s):

Skeletal Muscle ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Meta Analysis ◽

Older Individuals ◽

Transcriptomic Response ◽

Exercise Adaptation ◽

Exercise Response ◽

Before And After ◽

Response To Exercise

AbstractExercise training prevents multiple diseases, yet the molecular mechanisms that drive exercise adaptation are incompletely understood. To address this, we create a computational framework comprising data from skeletal muscle or blood from 43 studies, including 739 individuals before and after exercise or training. Using linear mixed effects meta-regression, we detect specific time patterns and regulatory modulators of the exercise response. Acute and long-term responses are transcriptionally distinct and we identify SMAD3 as a central regulator of the exercise response. Exercise induces a more pronounced inflammatory response in skeletal muscle of older individuals and our models reveal multiple sex-associated responses. We validate seven of our top genes in a separate human cohort. In this work, we provide a powerful resource (www.extrameta.org) that expands the transcriptional landscape of exercise adaptation by extending previously known responses and their regulatory networks, and identifying novel modality-, time-, age-, and sex-associated changes.

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Cytokine response of primary human myotubes in an in vitro exercise model

AJP Cell Physiology ◽

10.1152/ajpcell.00043.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. C877-C886 ◽

Cited By ~ 73

Author(s):

Mika Scheler ◽

Martin Irmler ◽

Stefan Lehr ◽

Sonja Hartwig ◽

Harald Staiger ◽

...

Keyword(s):

Skeletal Muscle ◽

Molecular Mechanisms ◽

Kinase Inhibitor ◽

Electric Pulse ◽

Transcriptional Response ◽

Individual Response ◽

Molecular Response ◽

Human Myotubes ◽

Response To Exercise

Muscle contraction during exercise is a major stimulus for the release of peptides and proteins (myokines) that are supposed to take part in the beneficial adaptation to exercise. We hypothesize that application of an in vitro exercise stimulus as electric pulse stimulation (EPS) to human myotubes enables the investigation of the molecular response to exercise in a clearly defined model. We applied EPS for 24 h to primary human myotubes and studied the whole genome-wide transcriptional response as well as the release of candidate myokines. We observed 183 differentially regulated transcripts with fold changes >1.3. The transcriptional response resembles several properties of the in vivo situation in the skeletal muscle after endurance exercise, namely significant enrichment of pathways associated with interleukin and chemokine signaling, lipid metabolism, and antioxidant defense. Multiplex immunoassays verified the translation of the transcriptional response of several cytokines into high-secretion levels (IL-6, IL-8, CXCL1, LIF, CSF3, IL-1B, and TNF) and the increased secretion of further myokines such as angiopoietin-like 4. Notably, EPS did not induce the release of creatine kinase. Inhibitor studies and immunoblotting revealed the participation of ERK1/2-, JNK-, and NF-κB-dependent pathways in the upregulation of myokines. To conclude, our data highlight the importance of skeletal muscle cells as endocrine cells. This in vitro exercise model is not only suitable to identify exercise-regulated myokines, but it might be applied to primary human myotubes obtained from different muscle biopsy donors to study the molecular mechanisms of the individual response to exercise.

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Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.4.e806 ◽

2000 ◽

Vol 279 (4) ◽

pp. E806-E814 ◽

Cited By ~ 351

Author(s):

Henriette Pilegaard ◽

George A. Ordway ◽

Bengt Saltin ◽

P. Darrell Neufer

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Molecular Mechanisms ◽

Uncoupling Protein ◽

Pyruvate Dehydrogenase Kinase ◽

Heme Oxygenase 1 ◽

Metabolic Efficiency ◽

Vastus Lateralis Muscle ◽

Mrna Levels

Exercise training elicits a number of adaptive changes in skeletal muscle that result in an improved metabolic efficiency. The molecular mechanisms mediating the cellular adaptations to exercise training in human skeletal muscle are unknown. To test the hypothesis that recovery from exercise is associated with transcriptional activation of specific genes, six untrained male subjects completed 60–90 min of exhaustive one-legged knee extensor exercise for five consecutive days. On day 5, nuclei were isolated from biopsies of the vastus lateralis muscle of the untrained and the trained leg before exercise and from the trained leg immediately after exercise and after 15 min, 1 h, 2 h, and 4 h of recovery. Transcriptional activity of the uncoupling protein 3 (UCP3), pyruvate dehydrogenase kinase 4 (PDK4), and heme oxygenase-1 (HO-1) genes (relative to β-actin) increased by three- to sevenfold in response to exercise, peaking after 1–2 h of recovery. Increases in mRNA levels followed changes in transcription, peaking between 2 and 4 h after exercise. Lipoprotein lipase and carnitine pamitoyltransferase I gene transcription and mRNA levels showed similar but less dramatic induction patterns, with increases ranging from two- to threefold. In a separate study, a single 4-h bout of cycling exercise ( n = 4) elicited from 5 to >20-fold increases in UCP3, PDK4, and HO-1 transcription, suggesting that activation of these genes may be related to the duration or intensity of exercise. These data demonstrate that exercise induces transient increases in transcription of metabolic genes in human skeletal muscle. Moreover, the findings suggest that the cumulative effects of transient increases in transcription during recovery from consecutive bouts of exercise may represent the underlying kinetic basis for the cellular adaptations associated with exercise training.

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Effects of aging and exercise training on spinotrapezius muscle microvascular Po2 dynamics and vasomotor control

Journal of Applied Physiology ◽

10.1152/japplphysiol.01084.2010 ◽

2011 ◽

Vol 110 (3) ◽

pp. 695-704 ◽

Cited By ~ 19

Author(s):

Danielle J. McCullough ◽

Robert T. Davis ◽

James M. Dominguez ◽

John N. Stabley ◽

Christian S. Bruells ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Exercise Training ◽

Sodium Nitroprusside ◽

Vascular Function ◽

Treadmill Running ◽

Aged Rats ◽

Phosphorescence Quenching

With advancing age, there is a reduction in exercise tolerance, resulting, in part, from a perturbed ability to match O2 delivery to uptake within skeletal muscle. In the spinotrapezius muscle (which is not recruited during incline treadmill running) of aged rats, we tested the hypotheses that exercise training will 1) improve the matching of O2 delivery to O2 uptake, evidenced through improved microvascular Po2 (PmO2), at rest and throughout the contractions transient; and 2) enhance endothelium-dependent vasodilation in first-order arterioles. Young (Y, ∼6 mo) and aged (O, >24 mo) Fischer 344 rats were assigned to control sedentary (YSED; n = 16, and OSED; n = 15) or exercise-trained (YET; n = 14, and OET; n = 13) groups. Spinotrapezius blood flow (via radiolabeled microspheres) was measured at rest and during exercise. Phosphorescence quenching was used to quantify PmO2 in vivo at rest and across the rest-to-twitch contraction (1 Hz, 5 min) transition in the spinotrapezius muscle. In a follow-up study, vasomotor responses to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) stimuli were investigated in vitro. Blood flow to the spinotrapezius did not increase above resting values during exercise in either young or aged groups. Exercise training increased the precontraction baseline PmO2 (OET 37.5 ± 3.9 vs. OSED 24.7 ± 3.6 Torr, P < 0.05); the end-contracting PmO2 and the time-delay before PmO2 fell in the aged group but did not affect these values in the young. Exercise training improved maximal vasodilation in aged rats to acetylcholine (OET 62 ± 16 vs. OSED 27 ± 16%) and to sodium nitroprusside in both young and aged rats. Endurance training of aged rats enhances the PmO2 in a nonrecruited skeletal muscle and is associated with improved vascular smooth muscle function. These data support the notion that improvements in vascular function with exercise training are not isolated to the recruited muscle.

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Impact of Physical Activity and Exercise on the Epigenome in Skeletal Muscle and Effects on Systemic Metabolism

Biomedicines ◽

10.3390/biomedicines10010126 ◽

2022 ◽

Vol 10 (1) ◽

pp. 126

Author(s):

Julio Plaza-Diaz ◽

David Izquierdo ◽

Álvaro Torres-Martos ◽

Aiman Tariq Baig ◽

Concepción M. Aguilera ◽

...

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Gene Transcription ◽

Histone Modifications ◽

Epigenetic Modification ◽

Epigenetic Modifications ◽

Late Response ◽

Transcriptional Responses ◽

Response To Exercise ◽

The Impact

Exercise and physical activity induces physiological responses in organisms, and adaptations in skeletal muscle, which is beneficial for maintaining health and preventing and/or treating most chronic diseases. These adaptations are mainly instigated by transcriptional responses that ensue in reaction to each individual exercise, either resistance or endurance. Consequently, changes in key metabolic, regulatory, and myogenic genes in skeletal muscle occur as both an early and late response to exercise, and these epigenetic modifications, which are influenced by environmental and genetic factors, trigger those alterations in the transcriptional responses. DNA methylation and histone modifications are the most significant epigenetic changes described in gene transcription, linked to the skeletal muscle transcriptional response to exercise, and mediating the exercise adaptations. Nevertheless, other alterations in the epigenetics markers, such as epitranscriptomics, modifications mediated by miRNAs, and lactylation as a novel epigenetic modification, are emerging as key events for gene transcription. Here, we provide an overview and update of the impact of exercise on epigenetic modifications, including the well-described DNA methylations and histone modifications, and the emerging modifications in the skeletal muscle. In addition, we describe the effects of exercise on epigenetic markers in other metabolic tissues; also, we provide information about how systemic metabolism or its metabolites influence epigenetic modifications in the skeletal muscle.

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PPADS does not block contraction-induced prostaglandin E2 synthesis in cat skeletal muscle

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00904.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. H2043-H2045 ◽

Cited By ~ 10

Author(s):

Jennifer L. McCord ◽

Shawn G. Hayes ◽

Marc P. Kaufman

Keyword(s):

Skeletal Muscle ◽

Pyridoxal Phosphate ◽

Pressor Response ◽

Triceps Surae ◽

Prostaglandin E ◽

Exercise Pressor Reflex ◽

Before And After ◽

Pressor Reflex ◽

Response To Exercise

Pyridoxal-phosphate-6-azophenyl-2′-4-disulfonate (PPADS), a purinergic 2 (P2) receptor antagonist, has been shown to attenuate the exercise pressor reflex in cats. In vitro, however, PPADS has been shown to block the production of prostaglandins, some of which play a role in evoking the exercise pressor reflex. Thus the possibility exists that PPADS blocks the exercise pressor reflex through a reduction in prostaglandin synthesis rather than through the blockade of P2 receptors. Using microdialysis, we collected interstitial fluid from skeletal muscle to determine prostaglandin E2 (PGE2) concentrations during the intermittent contraction of the triceps surae muscle before and after a popliteal arterial injection of PPADS (10 mg/kg). We found that the PGE2 concentration increased in response to the intermittent contraction before and after the injection of PPADS (both, P < 0.05). PPADS reduced the pressor response to exercise ( P < 0.05) but had no effect on the magnitude of PGE2 production during contraction ( P = 0.48). These experiments demonstrate that PPADS does not block the exercise pressor reflex through a reduction in PGE2 synthesis. We suggest that PGE2 and P2 receptors play independent roles in stimulating the exercise pressor reflex.

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