A5058540076- Nutrition and Health in Aging
- Muscle Physiology and Disorders
- GDF15 and Related Biomarkers
- Folate and B Vitamins Research
- Adipose Tissue and Metabolism
- Diet and metabolism studies
- Ubiquitin and proteasome pathways
- Cancer, Hypoxia, and Metabolism
- Muscle metabolism and nutrition
- Mesenchymal stem cell research
- Hippo pathway signaling and YAP/TAZ
- Virus-based gene therapy research
- Genetic Neurodegenerative Diseases
- Tissue Engineering and Regenerative Medicine
- Heat shock proteins research
- Renal and related cancers
- Cardiomyopathy and Myosin Studies
- Pharmacological Effects and Assays
- TGF-β signaling in diseases
- Metabolism, Diabetes, and Cancer
- Lipid metabolism and biosynthesis
- MicroRNA in disease regulation
- Kruppel-like factors research
- Pancreatic function and diabetes
- Histone Deacetylase Inhibitors Research
The University of Queensland
2023-2025
Baker Heart and Diabetes Institute
2013-2021
Australian Regenerative Medicine Institute
2018-2021
The University of Melbourne
2013-2021
Monash University
2017-2021
Myostatin is a paracrine myokine that regulates muscle mass in variety of species, including humans. In this work, we report functional role for myostatin as an endocrine hormone directly promotes pituitary follicle-stimulating (FSH) synthesis and thereby ovarian function mice. Previously, FSH-stimulating was attributed to other members the transforming growth factor–β family, activins. Our results both challenge activin’s eponymous FSH establish unexpected axis between skeletal gland. data...
The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development. YAP function has been extensively characterized epithelial cells tissues, but its adult skeletal muscle remains poorly defined. Here we show that positively basal mass synthesis. Mechanistically, via interaction with TEAD transcription factors. Furthermore, abundance activity muscles increased following injury or degeneration motor nerves, as process to...
Neuromuscular junction remodeling and deterioration due to impaired BMP signaling are associated with cancer-induced muscle wasting.
Significance Myostatin, via activation of the Smad2/3 pathway, has long been recognized as body’s major negative regulator skeletal muscle mass. In this study, however, we demonstrate that other TGF-β proteins, particularly activin A and B, act in concert with myostatin to repress growth. Preventing signaling tibialis anterior muscles mice resulted massive hypertrophy (>150%), which was dependent upon both complete inhibition pathway parallel bone morphogenetic protein (BMP)/Smad1/5 axis....
microRNAs regulate the development of myogenic progenitors, and formation skeletal muscle fibers. However, role miRNAs play in controlling growth adaptation post-mitotic musculature is less clear. Here, we show that inhibition established pro-myogenic regulator miR-206 can promote hypertrophy increased protein synthesis cells lineage. We have previously demonstrated histone deacetylase 4 (HDAC4) a target regulation differentiation. confirmed de-repressed HDAC4 accumulation cultured myotubes....
Muscle-directed Smad7 gene delivery prevents the loss of skeletal muscle mass and strength in mouse models cachexia, an important contributor to poor prognosis patients with advanced cancer.
Abstract Cachexia is a life-threatening wasting syndrome lacking effective treatment, which arises in many cancer patients. Although ostensibly induced by multiple tumor-produced cytokines (tumorkines), their functional contribution to initiation and progression of this has proven difficult determine. In study, we used adeno-associated viral vectors elevate circulating levels the tumorkines IL6 and/or activin A animals absence tumors as tactic evaluate hypothesized roles cachexia...
Growth/differentiation factor 8 (GDF8), or myostatin, negatively regulates muscle mass. GDF8 is held in a latent state through interactions with its N-terminal prodomain, much like TGF-β. Using combination of small-angle X-ray scattering and mutagenesis, we characterized the prodomain. Our results show that prodomain:GDF8 complex can exist fully an activated "triggered" where prodomain remains mature domain. However, these states are not reversible, indicating "spring-loaded." Structural...
Abstract Obesity is a major risk factor underlying the development of metabolic disease and growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective limit progression disease. Here, we demonstrate that levels Hippo pathway transcriptional co-activator YAP are decreased in biopsies from obese, insulin-resistant humans mice. Targeted disruption Yap adult resulted incomplete oxidation fatty acids lipotoxicity. Integrated ‘omics analysis isolated...
Abstract Follistatin is an inhibitor of TGF-β superfamily ligands that repress skeletal muscle growth and promote wasting. Accordingly, follistatin has emerged as a potential therapeutic to ameliorate the deleterious effects atrophy. However, it remains unclear whether anabolic are conserved across different modes non-degenerative In this study, delivery recombinant adeno-associated viral vector expressing (rAAV:Fst) hind-limb musculature mice two weeks prior denervation or tenotomy promoted...
Ubiquitination is a posttranslational protein modification that has been shown to have range of effects, including regulation function, interaction, localization, and degradation. We previously the muscle-specific ubiquitin E3 ligase, ASB2β, downregulated in models muscle growth overexpression ASB2β sufficient induce atrophy. To gain insight into effects increased expression on skeletal mass we used liquid chromatography coupled tandem spectrometry investigate ASB2β-mediated changes proteome...
Abstract Anabolic β 2 -adrenoceptor (β -AR) agonists have been proposed as therapeutics for treating muscle wasting but concerns regarding possible off-target effects hampered their use. We investigated whether -AR-mediated signalling could be modulated in skeletal via gene delivery to the target tissue, thereby avoiding risks of -AR agonists. In mice, intramuscular administration a recombinant adeno-associated virus-based vector (rAAV vector) expressing increased mass by >20% within 4...
Abstract In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective tumor progression. excess, activins A and B use the myostatin signaling pathway in triggering a decrease protein synthesis an increase degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery engineered propeptides (natural inhibitors these growth factors) could induce profound muscle hypertrophy healthy mice. Additionally, expression effectively attenuated...
Type 2 diabetes (T2D) manifests from inadequate glucose control due to insulin resistance, hypoinsulinemia, and deteriorating pancreatic β-cell function.The proinflammatory factor Activin has been implicated as a positive correlate of severity in T2D patients, negative regulator uptake by skeletal muscle, phenotype mice.Accordingly, we sought determine whether intervention with the antagonist Follistatin can ameliorate diabetic pathology.Here, report that an intravenous gene delivery tropism...
Inhibition of myostatin- and activin-mediated SMAD2/3 signaling using ligand traps, such as soluble receptors, ligand-targeting propeptides antibodies, or follistatin can increase skeletal muscle mass in healthy mice ameliorate wasting models cancer cachexia muscular dystrophy. However, clinical translation these extracellular approaches targeting myostatin activin has been hindered by the challenges achieving efficacy without potential effects other tissues. Toward goal developing...
Abstract Growth/differentiation factor 8 (GDF8) or myostatin negatively regulates muscle mass. GDF8 is held in a latent state through interactions with its N-terminal prodomain, much like TGF-β. Using combination of small angle X-ray scattering and mutagenesis, we characterized the prodomain. Our results show that prodomain:GDF8 complex can exist fully an activated ‘triggered’ where prodomain remains mature domain. However, these states are not reversible, indicating ‘spring-loaded’....
Although originally characterised as proteins involved in the control of reproductive function, activins, and to a lesser degree inhibins, are also important regulators homeostasis extragonadal tissues. Accordingly, disrupted inhibin/activin expression can have detrimental effects not only on fertility fecundity but regulation muscle, fat bone mass. Indeed, recently, two complementary mouse models inhibin designed lack bioactivity/responsiveness revealed that A/B deficiency during pregnancy...
<div>Abstract<p>Cachexia is a life-threatening wasting syndrome lacking effective treatment, which arises in many cancer patients. Although ostensibly induced by multiple tumor-produced cytokines (tumorkines), their functional contribution to initiation and progression of this has proven difficult determine. In study, we used adeno-associated viral vectors elevate circulating levels the tumorkines IL6 and/or activin A animals absence tumors as tactic evaluate hypothesized roles...
<p>mRNA expression of activin A and Il-6 in the TA muscle, heart, liver spleen mice bearing colon-26 tumors.</p>
<p>Legends</p>
<p>In mice injected with rAAV6:activin A and/or rAAV6:IL-6, the mRNA expression of E3 ubiquitin ligases was determined in quadriceps muscles. In addition, skeletal muscle, epididymal WAT and BAT depots were probed for IL-6 target genes or involved lipolysis browning.</p>
<p>TA muscles of mice injected with rAAV6:TNF-α and rAAV6:Tweak exhibited muscle loss increases in the phosphorylation p65, but did not induce cachexia.</p>
<p>Titrating rAAV6:IL-6 doses in wild type mice to elevate circulating levels of IL-6. High result cachexia.</p>
<p>Comparing the rate of lean and fat mass loss in mice bearing colon-26 tumors injected with rAAV6:activin A and/or rAAV6:IL-6.</p>