Biology subjects

Viggars, M. R.

Publications and source records attributed to Viggars, M. R..

5 recordsLinked to original sources

bioRxiv2024

Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.

Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes that accompany gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending the transcriptional regulation and other related nuclear functions. We isolated skeletal muscle nuclei from C57BL/6 mice both sedentary control and one-hour post 30-minute treadmill running, to gain insights into the nuclear proteome after exercise. A substantial number of the 2,323 proteins identified, were related to nuclear functions. For instance, we found 59 proteins linked to nucleocytoplasmic transport were higher in sedentary mice compared to exercise, hinting at an exercise-induced modulation to nuclear trafficking. Furthermore, 135 proteins exhibited increased abundance after exercise (FDR < 0.1) while 89 proteins decreased, with the most prominent changes in proteins linked to mRNA processing and splicing. Super resolution microscopy further highlights potential localization change in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Nonetheless, our data provide important considerations for the study of the nuclear proteome and supports a paradigm through which exercise downregulated mRNA processing and splicing, offering valuable insights into the broader landscape of the impact from acute exercise. New & NoteworthyExercise plays a crucial role in promoting muscle health, but our understanding of nuclear proteins orchestrating exercise responses is limited. Isolation of skeletal muscle nuclei coupled with mass spectrometry enhanced the identification of nuclear proteins. This approach was used to investigate the effects of acute exercise, revealing changes in the muscle nuclear proteome 1-hour post-exercise, including proteins linked to post-transcriptional processing and splicing. Our findings offer insights into the exercise-induced changes within muscle nuclear proteins.

physiology↗

bioRxiv2023

Muscle Bmal1 is necessary for normal transcriptomic and metabolomic adaptation to endurance exercise training.

ObjectivesIn this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodelling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice. MethodsCombining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise. ResultsMuscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including Nr4a3 and Ppargc1a. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of exercise-training responsive genes shared for each tissue between genotypes. ConclusionOur investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle plays in the peripheral tissue adaptation to exercise training. We also note that the transcriptome adaptations to steady state training suggest that without BMAL1, skeletal muscle does not achieve the expected homeostatic program. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.

physiology↗

bioRxiv2023

Early morning run-training results in enhanced endurance performance adaptations in mice.

Endurance performance exhibits time-of-day variation in both humans and rodents, peaking in the late active-phase. However, whether the timing of endurance training influences performance adaptations remains unclear. To investigate, female mice were trained 5-d/week for 6-weeks at either ZT13 or ZT22, using treadmill running at 70% of each animals maximal capacity. Endurance performance was assessed at baseline, week-3, and week-6. Secondary outcomes included blood glucose and lactate, cage activity, body composition, liver and skeletal muscle glycogen content, mitochondrial and contractile protein expression. At baseline, late-active phase (ZT22)-tested mice exhibited significantly higher endurance capacity than early-active phase (ZT13)-tested mice (P<0.05). Following 6 weeks of training, ZT13-trained mice demonstrated a greater rate of improvement, with endurance increasing by 132% (P<0.05), compared to 45% in afternoon ZT22-trained mice. By week 6, performance improved but was similar between groups (P>0.05), despite lower absolute training volumes in the ZT13 group. Both training groups reduced fat-mass (ZT13: -31%,ZT22: -32%; P<0.05 vs. control), with no differences in lean mass, food intake or muscle and liver glycogen content (P>0.05). In skeletal muscle, ZT13-trained mice were associated with increased (P<0.05) COXIV protein expression, citrate synthase activity, and shifts in MyHC isoform expression, without changes (P>0.05) in mitochondrial content. ZT13-training elicited superior performance adaptations despite lower absolute workloads, indicating enhanced training efficiency. These findings identify exercise timing as a biologically relevant factor influencing endurance adaptation and variability in exercise responses. NEW & NOTEWORTHYThis study demonstrates that endurance training in the early active phase induces greater performance adaptations than late active phase training in mice, resulting in overcoming diurnal differences in exercise performance, despite lower absolute training volumes. These findings reveal exercise timing influences training efficiency, likely via circadian regulation of skeletal muscle metabolism. This work identifies time-of-day as a biologically relevant and underappreciated variable contributing to the heterogeneity of exercise responses, even in tightly controlled preclinical models.

physiology↗

bioRxiv2023

Conserved and species-specific transcriptional responses to daily programmed resistance exercise in rat and mouse.

Mice are often used in gain or loss of function studies to understand how genes regulate metabolism and adaptation to exercise in skeletal muscle. Once-daily resistance training with electrical nerve stimulation produces hypertrophy of the dorsiflexors in rat, but not in mouse. Using implantable pulse generators, we assessed the acute transcriptional response (1-hour post exercise) after 2, 10 and 20 days of training in free living mice and rats using identical nerve stimulation paradigms. RNA-sequencing revealed strong concordance in the timecourse of many transcriptional responses in the tibialis anterior muscles of both species including responses related to stress responses/immediate-early genes, and collagen homeostasis, ribosomal subunits, autophagy and focal adhesion. However, pathways associated with energy metabolism including carbon metabolism, oxidative phosphorylation, mitochondrial translation, propanoate metabolism and valine, leucine and isoleucine degradation were oppositely regulated between species. These pathways were suppressed in the rat but upregulated in the mouse. Our transcriptional analysis suggests that although many pathways associated with growth show remarkable similarities between species, absence of an actual growth response in the mouse may be because the mouse prioritises energy metabolism, specifically replenishment of fuel stores and intermediate metabolites.

molecular biology↗

bioRxiv2023

Multiomic identification of key transcriptional regulatory programs during endurance exercise training

Transcription factors (TFs) play a key role in regulating gene expression. We conducted an integrated analysis of chromatin accessibility, DNA methylation, mRNA expression, protein abundance and phosphorylation across eight tissues in fifty rats of equally represented sexes following endurance exercise training (EET) to identify coordinated epigenomic and transcriptional changes and determine key TFs involved. We uncovered tissue-specific EET associated changes and TF motif enrichment across differentially expressed genes (DEGs), accessible regions (DARs), and methylated regions (DMRs). We discovered distinct routes of EET-induced regulation through either epigenomic alterations providing better access for TFs to affect target genes, or via changes in TF expression or activity enabling target gene responses. We identified TF motifs enriched among correlated epigenomic and transcriptomic alterations, DEGs correlated with exercise-related phenotypic and cell type composition changes, and EET-induced activity changes of TFs whose target genes are enriched for DEGs. This analysis elucidates the unique gene regulatory mechanisms mediating diverse transcriptional responses to EET across tissues.

genomics↗