Biomedical subjects

Karyn A Esser

Publications and source records attributed to Karyn A Esser.

16 recordsLinked to original sources

PubMed2025

Integrated Multiomics Analyses of the Molecular Landscape of Sarcopenia in Alcohol-Related Liver Disease.

BACKGROUND: Skeletal muscle is a major target for ethanol-induced perturbations, leading to sarcopenia in alcohol-related liver disease (ALD). The complex interactions and pathways involved in adaptive and maladaptive responses to ethanol in skeletal muscle are not well understood. Unlike hypothesis-driven experiments, an integrated multiomics-experimental validation approach provides a comprehensive view of these interactions. METHODS: We performed multiomics analyses with experimental validation to identify novel regulatory mechanisms of sarcopenia in ALD. Studies were done in a comprehensive array of models including ethanol-treated (ET) murine and human-induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD) and human patients with alcohol-related cirrhosis and controls. We generated 13 untargeted datasets, including chromatin accessibility (assay for transposase accessible chromatin), RNA sequencing, proteomics, phosphoproteomics, acetylomics and metabolomics, and conducted integrated multiomics analyses using UpSet plots and feature extraction. Key findings were validated using immunoblots, redox measurements (NAD+/NADH ratio), imaging and senescence-associated molecular phenotype (SAMP) assays. Mechanistic studies included mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) to increase redox ratio and MitoTempo as a mitochondrial free radical scavenger. RESULTS: Multiomics analyses revealed enrichment in mitochondrial oxidative function, protein synthesis and senescence pathways consistent with the known effects of hypoxia-inducible factor 1α (HIF1α) during normoxia. Across preclinical and clinical models, HIF1α targets (n = 32 genes) and signalling genes (n > 100 genes) (n = 3 ATACseq, n = 65 phosphoproteomics, n = 10 acetylomics, n = 6 C2C12 proteomics, n = 106 C2C12 RNAseq, n = 64 hiPSC RNAseq, n = 30 hiPSC proteomics, n = 3 mouse proteomics, n = 25 mouse RNAseq, n = 8 human RNAseq, n = 3 human proteomics) were increased. Stabilization of HIF1α (C2C12, 6hEtOH 0.24 ± 0.09; p = 0.043; mALD 0.32 ± 0.074; p = 0.005; data shown as mean difference ± standard error mean) was accompanied by enrichment in the early transient and late change clusters, -log(p-value) = 1.5-3.8, of the HIF1α signalling pathway. Redox ratio was reduced in ET myotubes (C2C12: 15512 ± 872.1, p < 0.001) and mALD muscle, with decreased expression of electron transport chain components (CI-V, p < 0.05) and Sirt3 (C2C12: 0.067 ± 0.023, p = 0.025; mALD: 0.41 ± 0.12, p = 0.013). Acetylation of mitochondrial proteins was increased in both models (C2C12: 107364 ± 4558, p = 0.03; mALD: 40036 ± 18 987, p = 0.049). Ethanol-induced SAMP was observed across models (P16: C2C12: 0.2845 ± 0.1145, p < 0.05; hiPSCm: 0.2591, p = 0.041). MitoLbNOX treatment reversed redox imbalance, HIF1α stabilization, global acetylation and myostatin expression (p < 0.05). CONCLUSIONS: An integrated multiomics approach, combined with experimental validation, identifies HIF1α stabilization and accelerated post-mitotic senescence as novel mechanisms of sarcopenia in ALD. These findings show the complex molecular interactions leading to mitochondrial dysfunction and progressive sarcopenia in ALD.

Sarcopenia↗

PubMed2024

Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures.

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.

Animals↗

PubMed2006

MicroRNA-1 and microRNA-133a expression are decreased during skeletal muscle hypertrophy.

MicroRNAs (miRNAs) are a class of highly conserved, noncoding RNAs involved in posttranscriptional gene regulation. A small number of muscle-specific miRNAs have been identified and shown to have a role in myoblast proliferation and differentiation as well as embryonic muscle growth. The primary objective of the present study was to determine the expression level of the muscle-specific miRNAs in the soleus and plantaris muscles and whether their expression in the plantaris was altered in response to functional overload. Of the miRNAs examined, only miRNA-206 was differentially expressed between soleus and plantaris muscles, as reflected by the sevenfold higher expression in the soleus for both the primary miRNA (pri-miRNA) and mature miRNA (miR). Following 7 days of functional overload, transcript levels for both pri-miRNA-1-2 and pri-miRNA-133a-2 increased by approximately 2-fold, whereas pri-miRNA-206 levels were elevated 18.3-fold. In contrast, expression of miR-1 and miR-133a were downregulated by approximately 50% following overload. The discrepancy between pri-miRNA and miR expression following overload was not explained by a change in the expression of components of the miRNA biogenesis pathway, since Drosha and Exportin-5 transcript levels were significantly increased by 50% in response to functional overload, whereas Dicer expression remained unchanged. These results are the first to report alterations in expression of muscle-specific miRNAs in adult skeletal muscle and suggest miRNAs may have a role in the adaptation to functional overload.

Animals↗

PubMed2006

Mitochondrial buffering of calcium in the heart: potential mechanism for linking cyclic energetic cost with energy supply?

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Adenosine Triphosphate↗

PubMed2006

Expression of beta-catenin is necessary for physiological growth of adult skeletal muscle.

Expression of beta-catenin is known to be important for developmental processes such as embryonic pattern formation and determination of cell fate. Inappropriate expression, however, has been linked to pathological states such as cancer. Here we report that expression of beta-catenin is necessary for physiological growth of skeletal muscle in response to mechanical overload. Conditional inactivation of beta-catenin was induced in control and overloaded muscle through intramuscular injection of adenovirus expressing Cre recombinase in beta-catenin floxed mice. Individual muscle fiber analysis was performed to identify positively transfected/inactivated cells and determine fiber cross-sectional area. The results demonstrate that fiber growth is completely inhibited when the beta-catenin expression is lost. This effect was cell autonomous, as fibers that did not exhibit recombination in the floxed mice grew to the same magnitude as infected/noninfected fibers from wild-type mice. These findings suggest that beta-catenin may be a primary molecular site through which multiple signaling pathways converge in regulating physiological growth.

Animals↗

PubMed2005

mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators.

The purpose of this study was to identify the potential downstream functions associated with mammalian target of rapamycin (mTOR) signaling during myotube hypertrophy. Terminally differentiated myotubes were serum stimulated for 3, 6, 12, 24, and 48 h. This treatment resulted in significant myotube hypertrophy (protein/DNA) and increased RNA content (RNA/DNA) with no changes in DNA content or indices of cell proliferation. During myotube hypertrophy, the increase in RNA content was accompanied by an increase in tumor suppressor protein retinoblastoma (Rb) phosphorylation and a corresponding increase in the availability of the ribosomal DNA transcription factor upstream binding factor (UBF). Serum stimulation also induced an increase in cyclin D1 protein expression in the differentiated myotubes with a concomitant increase in cyclin D1-dependent cyclin-dependent kinase (CDK)-4 activity toward Rb. The increases in myotube hypertrophy and RNA content were blocked by rapamycin treatment, which also prevented the increase in cyclin D1 protein expression, CDK-4 activity, Rb phosphorylation, and the increase in UBF availability. Our findings demonstrate that activation of mTOR is necessary for myotube hypertrophy and suggest that the role of mTOR is in part to modulate cyclin D1-dependent CDK-4 activity in the regulation of Rb and ribosomal RNA synthesis. On the basis of these results, we propose that common molecular mechanisms contribute to the regulation of myotube hypertrophy and growth during the G1 phase of the cell cycle.

Animals↗

PubMed2005

Wnt/beta-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy.

Beta-catenin is a transcriptional activator shown to regulate the embryonic, postnatal, and oncogenic growth of many tissues. In most research to date, beta-catenin activation has been the unique downstream function of the Wnt signaling pathway. However, in the heart, a Wnt-independent mechanism involving Akt-mediated phosphorylation of glycogen synthase kinase (GSK)-3beta was recently shown to activate beta-catenin and regulate cardiomyocyte growth. In this study, results have identified the activation of the Wnt/beta-catenin pathway during hypertrophy of mechanically overloaded skeletal muscle. Significant increases in beta-catenin were determined during skeletal muscle hypertrophy. In addition, the Wnt receptor, mFrizzled (mFzd)-1, the signaling mediator disheveled-1, and the transcriptional co-activator, lymphocyte enhancement factor (Lef)-1, are all increased during hypertrophy of the overloaded mouse plantaris muscle. Experiments also determined an increased association between GSK-3beta and the inhibitory frequently rearranged in advanced T cell-1 protein with no increase in GSK-3beta phosphorylation (Ser9). Finally, skeletal muscle overload resulted in increased nuclear beta-catenin/Lef-1 expression and induction of the transcriptional targets c-Myc, cyclin D1, and paired-like homeodomain transcription factor 2. Thus this study provides the first evidence that the Wnt signaling pathway induces beta-catenin/Lef-1 activation of growth-control genes during overload induced skeletal muscle hypertrophy.

Animals↗

PubMed2005

Redox mechanisms of muscle dysfunction in inflammatory disease.

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Angiotensin II↗

PubMed2004

Intracellular signaling specificity in response to uniaxial vs. multiaxial stretch: implications for mechanotransduction.

Several lines of evidence suggest that muscle cells can distinguish between specific mechanical stimuli. To test this concept, we subjected C(2)C(12) myotubes to cyclic uniaxial or multiaxial stretch. Both types of stretch induced an increase in extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt) phosphorylation, but only multiaxial stretch induced ribosomal S6 kinase (p70(S6k)) phosphorylation. Further results demonstrated that the signaling events specific to multiaxial stretch (p70(S6k) phosphorylation) were elicited by forces delivered through the elastic culture membrane and were not due to greater surface area deformations or localized regions of large tensile strain. Experiments performed using medium that was conditioned by multiaxial stretched myotubes indicated that a release of paracrine factors was not sufficient for the induction of signaling to p70(S6k). Furthermore, incubation with gadolinium(III) chloride (500 microM), genistein (250 microM), PD-98059 (250 microM), bisindolylmaleimide I (20 microM), or LY-294002 (100 microM ) did not block the multiaxial stretch-induced signaling to p70(S6k). However, disrupting the actin cytoskeleton with cytochalasin D did block the multiaxial signaling to p70(S6k), with no effect on signaling to PKB/Akt. These results demonstrate that specific types of mechanical stretch activate distinct signaling pathways, and we propose that this occurs through direct mechanosensory-mechanotransduction mechanisms and not through previously defined growth factor/receptor binding pathways.

Animals↗

PubMed2004

Mechanical stimuli regulate rapamycin-sensitive signalling by a phosphoinositide 3-kinase-, protein kinase B- and growth factor-independent mechanism.

In response to growth factors, mTOR (mammalian target of rapamycin) has been identified as a central component of the signalling pathways that control the translational machinery and cell growth. Signalling through mTOR has also been shown to be necessary for the mechanical load-induced growth of cardiac and skeletal muscles. Although the mechanisms involved for mechanically induced activation of mTOR are not known, it has been suggested that activation of PI3K (phosphoinositide 3-kinase) and protein kinase B (Akt), via the release of locally acting growth factors, underlies this process. In the present study, we show that mechanically stimulating (passive stretch) the skeletal muscle ex vivo results in the activation of mTOR-dependent signalling events. The activation of mTOR-dependent signalling events was necessary for an increase in translational efficiency, demonstrating the physiological significance of this pathway. Using pharmacological inhibitors, we show that activation of mTOR-dependent signalling occurs through a PI3K-independent pathway. Consistent with these results, mechanically induced signalling through mTOR was not disrupted in muscles from Akt1-/- mice. In addition, ex vivo co-incubation experiments, along with in vitro conditioned-media experiments, demonstrate that a mechanically induced release of locally acting autocrine/paracrine growth factors was not sufficient for the activation of the mTOR pathway. Taken together, our results demonstrate that mechanical stimuli can activate the mTOR pathway independent of PI3K/Akt1 and locally acting growth factors. Thus mechanical stimuli and growth factors provide distinct inputs through which mTOR co-ordinates an increase in the translational efficiency.

Animals↗

PubMed2004

Altered activity of signaling pathways in diaphragm and tibialis anterior muscle of dystrophic mice.

Duchenne muscular dystrophy is a musculoskeletal disease caused by mutations in the dystrophin gene. The purpose of this study was to use the mouse model of muscular dystrophy (mdx) to determine if the progression of the dystrophic phenotype in the diaphragm (costal) versus limb skeletal muscle (tibialis anterior) is associated with specific changes in extracellular regulated kinase (ERK1/2), p70 S6 kinase (p70(S6k)), or p38 signaling pathways. The studies detected that consistent with an earlier dystrophic phenotype, phosphorylation of p70(S6k) is elevated by 40% in the diaphragm with no change in limb muscle. In addition, phosphorylation of p38 kinase was decreased by 33% in the mdx diaphragm muscle. Levels of ERK1/2 as well as phosphorylation states were elevated in the diaphragm and limb muscle of mdx mice compared with age-matched control muscles. These results indicate that distinct signaling pathways are differentially activated in skeletal muscle of mdx mice. The specificity of these responses, particularly in the diaphragm, provides insight for potential targets for blunting the progression of the muscular dystrophy phenotype.

Animals↗

PubMed2003

Cardiac structure and function after short-term ethanol consumption in rats.

Using an animal model of alcoholism, we investigated whether 4 months of ethanol consumption was associated with a preclinical stage of alcoholic cardiomyopathy (ACM), as well as activation of the renin-angiotensin system and natriuretic peptides (NPs). In other forms of cardiovascular disease, the latter peptide systems have been used as markers of left ventricular (LV) remodeling and dysfunction. Rats were fed either a liquid ethanol or control diet, and serial blood samples were collected at baseline, as well as at 2 and 4 months, for plasma renin activity (PRA), angiotensin II (ANG II), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) levels. Serial echocardiography (echo) was performed at the same time points, and isolated heart studies were performed to assess ex vivo contractility at 4 months. In both groups at 4 months, there were significant and similar increases in end-diastolic and end-systolic echo dimensions and LV mass. At 4 months, however, a significant decrease was found in the relative wall thickness in the ethanol-fed group compared with findings for the control group. In both groups at 4 months, significant and similar time-dependent decreases were shown in BNP and ANP levels compared with baseline values. No differences were found in NP gene expression or tissue levels. In both groups at 4 months, significant and similar increases were found in ANG II levels compared with baseline values. Over time, in both groups, PRA levels were unchanged. In this study, the only cardiac structural feature characteristic of a preclinical ACM was a decrease in relative wall thickness.

Alcohol Drinking↗

PubMed2003

Selenoprotein-deficient transgenic mice exhibit enhanced exercise-induced muscle growth.

Dietary intake of selenium has been implicated in a wide range of health issues, including aging, heart disease and cancer. Selenium deficiency, which can reduce selenoprotein levels, has been associated with several striated muscle pathologies. To investigate the role of selenoproteins in skeletal muscle biology, we used a transgenic mouse (referred to as i6A-) that has reduced levels of selenoproteins due to the introduction and expression of a dominantly acting mutant form of selenocysteine transfer RNA (tRNA[Ser]Sec). As a consequence, each organ contains reduced levels of most selenoproteins, yet these mice are normal with regard to fertility, overall health, behavior and blood chemistries. In the present study, although skeletal muscles from i6A- mice were phenotypically indistinguishable from those of wild-type mice, plantaris muscles were approximately 50% heavier after synergist ablation, a model of exercise overload. Like muscle in wild-type mice, the enhanced growth in the i6A- mice was completely blocked by inhibition of the mammalian target of rapamycin (mTOR) pathway. Muscles of transgenic mice exhibited increased site-specific phosphorylation on both Akt and p70 ribosomal S6 kinase (p70S6k) (P < 0.05) before ablation, perhaps accounting for the enhanced response to synergist ablation. Thus, a single genetic alteration resulted in enhanced skeletal muscle adaptation after exercise, and this is likely through subtle changes in the resting phosphorylation state of growth-related kinases.

Animals↗

PubMed2002

Response of rat muscle to acute resistance exercise defined by transcriptional and translational profiling.

To further understand molecular mechanisms underlying skeletal muscle hypertrophy, expression profiles of translationally and transcriptionally regulated genes were characterized following an acute bout of maximally activated eccentric contractions. Experiments demonstrated that translational mechanisms contribute to acute gene expression changes following high resistance contractions with two candidate mRNAs, basic fibroblast growth factor (bFGF) and elongation factor-1 alpha (EF1alpha), targeted to the heavier polysomal fractions after a bout of contractions. Gene profiling was performed using Affymetrix Rat U34A GeneChips with either total RNA or polysomal RNA at one and six hours following contractions. There were 18 genes that changed expression at one hour and 70 genes that were different (60 genes increased:10 genes decreased)at six hours after contractions. The model from this profiling suggests that following high resistance contractions skeletal muscle shares a common growth profile with proliferating cells exposed to serum. This cluster of genes can be classified as "growth" genes and is commonly associated with progression of the cell cycle. However, a unique aspect was that there was induction of a cluster of tumour suppressor or antigrowth genes. We propose that this cluster of "antigrowth" genes is induced by the stress of contractile activity and may act to maintain skeletal muscle in the differentiated state. From the profiling results, further experiments determined that p53 levels increased in skeletal muscle at 6 h following contractions. This novel finding of p53 induction following exercise also demonstrates the power of expression profiling for identification of novel pathways involved in the response to muscle contraction.

Animals↗

PubMed2002

Inflammatory cells in rat skeletal muscle are elevated after electrically stimulated contractions.

We determined the effect of muscle contractions resulting from high-frequency electrical stimulation (HFES) on inflammatory cells in rat tibialis anterior (TA), plantaris (Pln), and soleus (Sol) muscles at 6, 24, and 72 h post-HFES. A minimum of four and a maximum of seven rats were analyzed at each time point. HFES, applied to the sciatic nerve, caused the Sol and Pln to contract concentrically and the TA to contract eccentrically. Neutrophils were higher (P < 0.05) at 6 and 24 h after HFES in the Sol, Pln, and TA muscles relative to control muscles. ED1(+) macrophages in the Pln were elevated at 6 and 24 h after HFES and were also elevated in the Sol and TA after HFES relative to controls. ED2(+) macrophages in the Sol and TA were elevated at 24 and 72 h after HFES, respectively, and were also elevated in the Pln after HFES relative to controls. In contrast to the TA muscles, the Pln and Sol muscles showed no gross histological abnormalities. Collectively, these data indicate that both eccentric and concentric contractions can increase inflammatory cells in muscle, regardless of whether overt histological signs of injury are apparent.

Animals↗

PubMed2002

Translational control: implications for skeletal muscle hypertrophy.

Skeletal muscle hypertrophy is characterized, in part, by increases in protein mass per fiber. This increased accumulation of protein results from a net increase in protein synthesis relative to breakdown. Increases in rates of protein synthesis (translation) have been reported across different models of resistance exercise and across all species studied. However, although an increase in protein synthesis after exercise is reported commonly, the mechanisms underlying this response are not understood clearly. Therefore, the aim of the current review was to select areas of research within which translational control has been well-studied. The logic is that the mechanisms described in this review have the potential to contribute to the changes seen in protein synthesis after high-resistance exercise. The field of translational control has seen rapid growth in the past 5 to 10 years and although attempts have been made to include all contributing studies, apologies are given from the start because many have undoubtedly been overlooked.

Eukaryotic Initiation Factor-2↗