Biology subjects

Jarvis, J. C.

Publications and source records attributed to Jarvis, J. C..

7 recordsLinked to original sources

bioRxiv2025

Repeated Disuse Atrophy Imprints a Molecular Memory in Skeletal Muscle: Transcriptional Resilience in Young Adults and Susceptibility in Aged Muscle

Disuse-induced muscle atrophy is common after illness, injury, or falls and becomes increasingly frequent with ageing. Whether skeletal muscle retains a "memory" of repeated disuse remains unknown. We investigated repeated lower-limb immobilization in young adults and a refined aged rat model, integrating physiological, multi-omic, immunohistochemical, biochemical, and primary human muscle stem cell (MuSC) analyses. To enable robust age comparisons, we integrated published young rat data with newly generated aged rat data. In young human muscle, repeated disuse elicited attenuated transcriptional perturbations in oxidative and mitochondrial pathways, suggestive of a protective molecular memory, despite similar atrophy to initial disuse. In contrast, aged muscle exhibited a detrimental memory, characterised by greater atrophy, exaggerated suppression of aerobic metabolism genes despite recovery after initial disuse, NAD and mitochondrial DNA depletion, and activation of proteasomal, extracellular-matrix, and DNA-damage pathways. Whereas young rats recovered muscle mass after initial disuse, aged rats did not. Repeated disuse induced DNA hypermethylation and downregulation of aerobic metabolism and mitochondrial genes across species. NR4A1 remained suppressed into recovery, while AChR subunit genes (CHRNA1, CHRND) were epigenetically primed. NMRK2, an NAD biosynthesis gene, was among the most downregulated after both atrophy periods, and nicotinamide riboside improved myotube size in MuSCs post-atrophy. Repeated disuse atrophy imprints a molecular memory in skeletal muscle shaping transcriptional resilience in young adults and exaggerated susceptibility in aged muscle.

physiology↗

bioRxiv2025

Adaptive time course of the skeletal muscle proteome during programmed resistance training in rats

Resistance training (RT) promotes muscle protein accretion and myofiber hypertrophy, driven by dynamic processes of protein synthesis and degradation. While molecular studies have focused on acute signalling or long-term hypertrophy and strength gains, a critical gap remains in understanding the intermediate processes of muscle adaptation. Acute signalling does not always correlate directly with long-term outcomes, highlighting the need for a time-course analysis of protein abundance and turnover rates. To address this, we utilised deuterium oxide labelling and peptide mass spectrometry to quantify absolute protein content and synthesis rates in skeletal muscle. A daily programmed resistance training regimen was applied to the rat tibialis anterior (TA) via electrical stimulation of the left hind limb for 10, 20, and 30 days (5 sets of 10 repetitions daily). Muscle samples from stimulated (Stim) and contralateral control (Ctrl) limbs were analysed, quantifying 658 protein abundances and 215 protein synthesis rates. Unsupervised temporal clustering of protein responses revealed distinct phases of muscle adaptation, with early (0-10 days) and mid (10-20 days) responses driven by differential protein accretion rates in ribosomal and mitochondrial networks, respectively. These findings suggest that subsets of proteins exhibit distinct adaptation timelines due to variations in translation and/or degradation rates. A deeper understanding of these temporal shifts could improve strategies for optimising muscle growth and functional adaptation to resistance training.

physiology↗

bioRxiv2023

Bile is a route of excretion for homogentisic acid in alkaptonuria

Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of the metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type-1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in the bile in AKU (mean [{+/-}SD] = 1003[{+/-}410] mol/L; nitisinone-treated AKU mean [{+/-}SD] = 45[{+/-}23] mol/L). Biliary tyrosine, HPPA and HPLA are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion and possible metabolism of HGA by the gut microbiome. These data provide new insights into the pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. Take-home messageThis paper presents the first observation of elevated hepatobiliary circulation of metabolites associated with disease in alkaptonuria, including homogentisic acid in addition to tyrosine and the tyrosine metabolites 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid on nitisinone treatment.

biochemistry↗

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↗

bioRxiv2020

UBR5 knockdown in human myotubes in-vitro and mouse skeletal muscle tissue in-vivo determines its pertinent role in anabolism and hypertrophy

UBR5 is an E3-ubiquitin-ligase positively associated with anabolism, hypertrophy and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5s role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in-vitro and in-vivo. The siRNA-induced reduction (-77%) in UBR5 gene expression in human myotubes was prevented by mechanical loading, suggesting that UBR5 gene expression may be regulated via mechano-transduction signalling. Therefore, we electroporated a UBR5-RNAi plasmid into mouse tibialis anterior muscle in-vivo to investigate the impact of reduced UBR5 on mechano-transduction signalling MEK/ERK/p90RSK and Akt/p70S6K/4E-BP1/rpS6 pathways. Seven days post UBR5 RNAi electroporation, while reductions in overall muscle mass were not detected, mean CSA of GFP-positive fibers was reduced (-9.5%) and the number of large fibers was lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2 and Akt phosphorylation. Whilst p90RSK phosphorylation significantly increased, total p90RSK protein levels demonstrated a 45% reduction with UBR5-RNAi. Finally, these early signalling events after 7 days of UBR5 knockdown culminated in significant reductions in muscle mass (-4.6%) and larger reductions in fiber CSA (-18.5%) after 30 days. This was associated with increased levels of the phosphatase, PP2Ac, and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, and corresponding reductions in eIF4e. This study demonstrates UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminates in skeletal muscle atrophy.

physiology↗

bioRxiv2020

Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

Background and Purposealkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of the enzyme homogentisate 1,2-dioxygenase (HGD). The primary biochemical consequence of HGD-deficiency is increased circulating homogentisic acid (HGA), which is central to AKU disease pathology. The aim of this study was to investigate the wider metabolic consequences of targeted Hgd disruption. Experimental Approachthe first metabolomic analysis of the Hgd-/- AKU mouse model was performed. Urinary metabolites altered in Hgd-/- were further validated by showing that the HGA-lowering drug nitisinone reversed their direction of alteration in AKU Key Resultscomparison of Hgd-/- (AKU) versus Hgd+/- (heterozygous control) urine revealed increases in HGA and a group of 8 previously unreported HGA-derived transformation products from phase I and II metabolism. HGA biotransformation products HGA-sulfate, HGA-glucuronide, HGA-hydrate and hydroxymethyl-HGA were also decreased in urine from both mice and patients with AKU on the HGA-lowering agent nitisinone. Hgd knockout also revealed a host of previously unrecognised associations between tyrosine, purine and TCA cycle metabolic pathways. Conclusion and ImplicationsAKU is rare, but our findings further what is currently understood about tyrosine metabolism more generally, and show for the first time that phase I and II detoxification is recruited to prevent accumulation of endogenously-produced metabolites in inborn errors of metabolism. The data highlight the misconception that phase I and II metabolic biotransformations are reserved solely for drug clearance; these are ancient mechanisms, which represent new potential treatment targets in inherited metabolic diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/044347v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@12b0b2forg.highwire.dtl.DTLVardef@eb4bacorg.highwire.dtl.DTLVardef@1b511e1org.highwire.dtl.DTLVardef@a8ef8e_HPS_FORMAT_FIGEXP M_FIG C_FIG Bullet point summaryWhat is already known O_LIIncreased circulating homogentisic acid is central to disease pathology in the inherited metabolic disease alkaptonuria C_LIO_LIThe Hgd knockout mouse, created in our laboratory, accurately models human alkaptonuria C_LI What this study adds O_LIPhase I and II biotransformations are recruited in alkaptonuria for detoxification of homogentisic acid C_LIO_LIThese data challenge misconceptions that phase I and II metabolism is solely for drug clearance C_LI Clinical significance O_LIPhase I and II metabolic processes represent new treatment targets in inherited metabolic diseases C_LIO_LIThe molecular pathology of AKU extends much further than the known alteration to tyrosine metabolism C_LI

biochemistry↗

bioRxiv2019

UBR5 is a Novel E3 Ubiquitin Ligase involved in Skeletal Muscle Hypertrophy and Recovery from Atrophy

We aimed to investigate a novel and uncharacterised E3 ubiquitin ligase in skeletal muscle atrophy, recovery from atrophy/injury, anabolism and hypertrophy. We demonstrated an alternate gene expression profile for UBR5 versus well characterised E3-ligases, MuRF1/MAFbx, where after atrophy evoked by continuous-low-frequency electrical-stimulation in rats, MuRF1/MAFbx were both elevated yet UBR5 was unchanged. Furthermore, after recovery of muscle mass post tetrodotoxin (TTX) induced-atrophy in rats, UBR5 was hypomethylated and increased at the gene expression level, while a suppression of MuRF1/MAFbx was observed. At the protein level, we also demonstrated a significant increase in UBR5 after recovery of muscle mass from hindlimb unloading in both adult and aged rats, and after recovery from atrophy evoked by nerve crush injury in mice. During anabolism and hypertrophy, UBR5 gene expression increased following acute loading in three-dimensional bioengineered mouse muscle in-vitro, and after chronic electrical-stimulation-induced hypertrophy in rats in-vivo, without increases in MuRF1/MAFbx. Additionally, UBR5 protein abundance increased following functional overload-induced hypertrophy of the plantaris muscle in mice and during differentiation of primary human muscle cells. Finally, in humans, genetic association studies (>700,000 SNPs) demonstrated that the A alleles of rs10505025 and rs4734621 SNPs in the UBR5 gene were strongly associated with larger cross-sectional area of fast-twitch muscle fibres and favoured strength/power versus endurance/untrained phenotypes. Overall, we suggest that UBR5 is a novel E3 ubiquitin ligase that is inversely regulated to MuRF1/MAFbx, is epigenetically regulated, and is elevated at both the gene expression and protein level during recovery from skeletal muscle atrophy and hypertrophy.\n\nKey PointsO_LIWe have recently identified that a HECT domain E3 ubiquitin ligase, named UBR5, is altered epigenetically (via DNA methylation) after human skeletal muscle hypertrophy, where its gene expression is positively correlated with increasing lean leg mass after training and retraining.\nC_LIO_LIIn the present study we extensively investigate this novel and uncharacterised E3 ubiquitin ligase (UBR5) in skeletal muscle atrophy, recovery from atrophy and injury, anabolism and hypertrophy.\nC_LIO_LIWe demonstrated that UBR5 was epigenetically via altered DNA methylation during recovery from atrophy.\nC_LIO_LIWe also determined that UBR5 was alternatively regulated versus well characterised E3 ligases, MuRF1/MAFbx, at the gene expression level during atrophy, recovery from atrophy and hypertrophy.\nC_LIO_LIUBR5 also increased at the protein level during recovery from atrophy and injury, hypertrophy and during human muscle cell differentiation.\nC_LIO_LIFinally, in humans, genetic variations of the UBR5 gene were strongly associated with larger fast-twitch muscle fibres and strength/power performance versus endurance/untrained phenotypes.\nC_LI

physiology↗