Aerobic exercise-mediated changes in the expression of glucocorticoid responsive genes in skeletal muscle differ across the day

Dunlap, Kirsten R.; Laskin, Grant R.; Waddell, David; Black, Adam J.; Steiner, Jennifer L.; Vied, Cynthia; Gordon, Bradley S.

doi:10.1016/j.mce.2022.111652

Cited by 4 publications

(5 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EPN1 which is involved in endocytosis, and loss of function of this gene is associated with reduced tumour growth and progression of cancer [58], and, AMPD3 which has a critical role in balancing energy charge and nucleotide metabolism [59; 60]. While most of these proteins have been previously reported to be associated with either exercise [26; 61-67] and/or skeletal muscle [26; 63-65; 68], SOD3 and RHOT1 have not been previously studied in skeletal muscle. TRIM28 is novel in the exercise context, whilst EPN1 and LYRM7 have not been previously associated with either skeletal muscle or exercise response.…”

Section: Resultsmentioning

confidence: 99%

DNA methylation and proteomics integration uncover dose-dependent group and individual responses to exercise in human skeletal muscle

Michaux

Landen

Alvarez-Romero

et al. 2022

Preprint

View full text Add to dashboard Cite

Objective: Exercise is a major regulator of muscle metabolism, and health benefits acquired by exercise are a result of molecular shifts occurring across multiple OMIC levels (i.e. epigenome, transcriptome, proteome). Identifying robust targets associated with exercise response, at both group and individual levels, is therefore important to develop health guidelines and targeted health interventions. Methods: Twenty, apparently healthy, moderately trained (VO2 max= 51.0 sd= 10.6 mL/min/kg) males (age range= 18-45yrs) from the Gene SMART (Skeletal Muscle Adaptive Responses to Training) study completed a 12-week High-Intensity Interval Training (HIIT) intervention. Muscle biopsies were collected at baseline and after 4, 8, and 12 weeks of HIIT. High throughput DNA methylation (~850 CpG sites), and proteomic (~3000 proteins) analyses were conducted at all-time points. Mixed-models were applied to estimate group and individual changes, and methylome and proteome integration was conducted using a holistic multilevel approach with the mixOmics package. Results: Significant shifts in the methylome (residual analysis) and proteome profiles were observed after 12 weeks of HIIT. 461 proteins significantly changed over time (at 4, 8, and 12 weeks), whilst only one differentially methylated position (DMP) was changed (adj.p-value <0.05). K-means analysis revealed clear protein clustering exhibiting similar changes over time. Individual responses to training were observed in 101 proteins. Seven proteins had a large effect-sizes >0.5, among them are two novel exercise- related proteins, LYRM7 and EPN1. Integration analysis uncovered bidirectional relationships between the methylome and proteome. Conclusions: We showed a significant influence of HIIT on the epigenome and proteome in human muscle, and uncovered groups of proteins clustering according to similar patterns across the exercise intervention. Individual responses to exercise were observed in the proteome with novel mitochondrial and metabolic proteins consistently changed across individuals. Future work is required to elucidate the role of such proteins in response to exercise as well as to investigate the mechanisms associating genes and proteins in response to exercise.

show abstract

Section: Resultsmentioning

confidence: 99%

DNA methylation and proteomics integration uncover dose-dependent group and individual responses to exercise in human skeletal muscle

Michaux

Landen

Alvarez-Romero

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…REDD1 deletion could decrease iron stores through other mechanisms. REDD1 is known to contribute to regulation of circadian clock genes ( 23 ) , so it is possible that REDD1 deletion resulted in greater diurnal increases in hepcidin to decrease dietary iron absorption and basal iron status ( 40 ) .…”

Section: Discussionmentioning

confidence: 99%

“…REDD1 is implicated in a number of metabolic roles, namely as an inhibitor of Aktmammalian target of rapamycin complex-1 signalling and as an enhancer of autophagy, through which REDD1 is thought to decrease protein anabolism and increase substrate availability during periods of energetic stress (18,19) . REDD1 also has glucoregulatory roles, possibly as a mediator of glucocorticoid signalling (20)(21)(22)(23) . Accordingly, REDD1 deletion results in greater energetic distress in mice in response to prolonged exercise.…”

Section: Introductionmentioning

confidence: 99%

REDD1 deletion and treadmill running increase liver hepcidin and gluconeogenic enzymes in male mice

2023

Self Cite

View full text Add to dashboard Cite

The iron-regulatory hormone hepcidin is transcriptionally up-regulated by gluconeogenic signals. Recent evidence suggeststhat increases in circulating hepcidin may decrease dietary iron absorption following prolonged exercise, however evidence is limited on whether gluconeogenic signals contribute to post-exercise increases in hepcidin. Mice with genetic knockout of regulated in development and DNA response-1 (REDD1) display greater glycogen depletion following exercise, possibly indicating greater gluconeogenesis. The objective of the present study was to determine liver hepcidin, markers of gluconeogenesis and iron metabolism in REDD1 knockout and wild-type mice following prolonged exercise. Twelve-week-old male REDD1 knockout and wild-type mice were randomised to rest or 60 min treadmill running with 1, 3 or 6 h recovery (n = 5–8/genotype/group). Liver gene expression of hepcidin (Hamp) and gluconeogenic enzymes (Ppargc1a, Creb3l3, Pck1, Pygl) were determined by qRT-PCR. Effects of genotype, exercise and their interaction were assessed by two-way ANOVAs with Tukey's post-hoc tests, and Pearson correlations were used to assess the relationships between Hamp and study outcomes. Liver Hamp increased 1- and 4-fold at 3 and 6 h post-exercise, compared to rest (P-adjusted < 0⋅009 for all), and was 50% greater in REDD1 knockout compared to wild-type mice (P = 0⋅0015). Liver Ppargc1a, Creb3l3 and Pck1 increased with treadmill running (P < 0⋅0001 for all), and liver Ppargc1a, Pck1 and Pygl were greater with REDD1 deletion (P < 0⋅02 for all). Liver Hamp was positively correlated with liver Creb3l3 (R = 0⋅62, P < 0⋅0001) and Pck1 (R = 0⋅44, P = 0⋅0014). In conclusion, REDD1 deletion and prolonged treadmill running increased liver Hamp and gluconeogenic regulators of Hamp, suggesting gluconeogenic signalling of hepcidin with prolonged exercise.

show abstract

“…67,68 Most of these proteins have been previously reported to be expressed in skeletal muscle [69][70][71][72][73] and for some associated with exercise. [69][70][71][72][74][75][76][77] However, SOD3 had only been studied in rodent muscle, and this is the first time that this gene has been confirmed to be induced by exercise training in vivo human skeletal muscle. TRIM28 is novel in the exercise context in humans but has been previously associated with skeletal muscle size regulation in mice, 73 whilst EPN1 and LYRM7 have not been previously associated with either skeletal muscle or exercise response.…”

Section: Individual Responses In Dna Methylation and Protein Expressi...mentioning

confidence: 99%

“…Seven of the proteins that presented significant individual changes also had large effect sizes >0.5 at the group level (Figure 4B), including: USP2, a protein known to be involved in biological rhythms (i.e., circadian clock) and aging, 64 and differentiation of myoblasts to myotubes 65 ; TRIM28, a chromatin regulator that mediates repression of many transcriptional factors 66 ; SOD3, an antioxidant enzyme that catalyzes the conversion of superoxide radicals, protecting tissues from oxidative stress 66 ; RHOT1, a mitochondrial GTPase involved in mitochondrial trafficking 66 ; LYRM7 which works as a chaperone of the inner mitochondrial complex III (the main enzyme complex in the mitochondrial respiratory chain) stabilizing this matrix prior to its translocation and insertion into the late CIII dimeric intermediate within the mitochondrial inner membrane 66 ; EPN1 which is involved in endocytosis, and loss of function of this gene is associated with reduced tumor growth and progression of cancer 66 ; and AMPD3 which has a critical role in balancing energy charge and nucleotide metabolism. 67,68 Most of these proteins have been previously reported to be expressed in skeletal muscle [69][70][71][72][73] and for some associated with exercise. [69][70][71][72][74][75][76][77] However, SOD3 had only been studied in rodent muscle, and this is the first time that this gene has been confirmed to be induced by exercise training in vivo human skeletal muscle.…”

Section: Individual Responses In Dna Methylation and Protein Expressi...mentioning

confidence: 99%

Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high‐intensity interval training

Jacques,

Landen,

Romero

et al. 2023

The FASEB Journal

View full text Add to dashboard Cite

Exercise is a major beneficial contributor to muscle metabolism, and health benefits acquired by exercise are a result of molecular shifts occurring across multiple molecular layers (i.e., epigenome, transcriptome, and proteome). Identifying robust, across‐molecular level targets associated with exercise response, at both group and individual levels, is paramount to develop health guidelines and targeted health interventions. Sixteen, apparently healthy, moderately trained (VO2 max = 51.0 ± 10.6 mL min−1 kg−1) males (age range = 18–45 years) from the Gene SMART (Skeletal Muscle Adaptive Responses to Training) study completed a longitudinal study composed of 12‐week high‐intensity interval training (HIIT) intervention. Vastus lateralis muscle biopsies were collected at baseline and after 4, 8, and 12 weeks of HIIT. DNA methylation (~850 CpG sites) and proteomic (~3000 proteins) analyses were conducted at all time points. Mixed models were applied to estimate group and individual changes, and methylome and proteome integration was conducted using a holistic multilevel approach with the mixOmics package. A total of 461 proteins significantly changed over time (at 4, 8, and 12 weeks), whilst methylome overall shifted with training only one differentially methylated position (DMP) was significant (adj.p‐value < .05). K‐means analysis revealed cumulative protein changes by clusters of proteins that presented similar changes over time. Individual responses to training were observed in 101 proteins. Seven proteins had large effect‐sizes >0.5, among them are two novel exercise‐related proteins, LYRM7 and EPN1. Integration analysis showed bidirectional relationships between the methylome and proteome. We showed a significant influence of HIIT on the epigenome and more so on the proteome in human muscle, and uncovered groups of proteins clustering according to similar patterns across the exercise intervention. Individual responses to exercise were observed in the proteome with novel mitochondrial and metabolic proteins consistently changed across individuals. Future work is required to elucidate the role of these proteins in response to exercise.

show abstract

Aerobic exercise-mediated changes in the expression of glucocorticoid responsive genes in skeletal muscle differ across the day

Cited by 4 publications

References 68 publications

DNA methylation and proteomics integration uncover dose-dependent group and individual responses to exercise in human skeletal muscle

DNA methylation and proteomics integration uncover dose-dependent group and individual responses to exercise in human skeletal muscle

REDD1 deletion and treadmill running increase liver hepcidin and gluconeogenic enzymes in male mice

Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high‐intensity interval training

Contact Info

Product

Resources

About