Immune exhaustion in ME/CFS and long COVID.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating multisystemic conditions sharing similarities in immune dysregulation and cellular signaling pathways contributing to the pathophysiology. In this study, immune exhaustion gene expression was investigated in participants with ME/CFS or long COVID concurrently. RNA was extracted from peripheral blood mononuclear cells isolated from participants with ME/CFS (n = 14), participants with long COVID (n = 15), and healthy controls (n = 18).

Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia.

Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) patients are advised to avoid strenuous exercise due to increased risk of arrhythmias. Mice expressing the human FHC-causing mutation R403Q in the myosin heavy chain gene (MYH6) recapitulate the human phenotype, including cytoskeletal disarray and increased arrhythmia susceptibility. Following in vivo administration of isoproterenol, mutant mice exhibited tachyarrhythmias, poor recovery and fatigue.

A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology.

Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young's Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium.

Volume adaptation of neonatal cardiomyocyte spheroids in 3D stiffness gradient GelMA.

Present understandings of cardiomyocyte mechanobiology have primarily been developed using 2-dimensional, monocellular cell cultures, however the emergence of 3-dimensional (3D) multicellular cardiac constructs has enabled us to develop more sophisticated recapitulations of the cardiac microenvironment. Several of these strategies have illustrated that incorporating elements of the extracellular matrix (ECM) can promote greater maturation and enhance desirable cardiac functions, such as contractility, but the responses of these cardiac constructs to biophysically aberrant conditions, such as in the post-infarct heart, has remained relatively unexplored. In our study, we employ a stiffness gradient gelatin methacryloyl (GelMA) hydrogel platform to unpack the mechanobiology of cardiac spheroids.

How cytoskeletal proteins regulate mitochondrial energetics in cell physiology and diseases.

Mitochondria are ubiquitous organelles that play a pivotal role in the supply of energy through the production of adenosine triphosphate in all eukaryotic cells. The importance of mitochondria in cells is demonstrated in the poor survival outcomes observed in patients with defects in mitochondrial gene or RNA expression. Studies have identified that mitochondria are influenced by the cell's cytoskeletal environment.

Mechanosensation mediates volume adaptation of cardiac cells and spheroids in 3D.

With the adoption of 3-dimensional (3D) cell culture for modelling of cardiac function and regenerative medicine applications, there is an increased need to understand cardiomyocyte mechanosensation in 3D. With existing studies of cardiomyocyte mechanosensation primarily focussed on the behaviour of individual cells in a 2-Dimensional context, it is unclear whether mechanosensation is the same in a 3D, multicellular context. In this study, H9C2 cardiac-derived myoblasts were encapsulated as individual cells and as cell spheroids within stiffness gradient gelatin methacryloyl (GelMA) hydrogels to investigate individual and collective cardiac cell mechanosensation in 3D.

Elucidating the role of the L-type calcium channel in excitability and energetics in the heart: The ISHR 2020 Research Achievement Award Lecture.

Cardiovascular disease continues to be the leading health burden worldwide and with the rising rates in obesity and type II diabetes and ongoing effects of long COVID, it is anticipated that the burden of cardiovascular morbidity and mortality will increase. Calcium is essential to cardiac excitation and contraction. The main route for Ca influx is the L-type Ca channel (Ca1.

A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance.

Mitochondrial energy metabolism plays an important role in the pathophysiology of insulin resistance. Recently, a missense N437S variant was identified in the gene, which encodes a mitochondrial RNA processing enzyme within the RNase P complex, with predicted impact on metabolism. We used CRISPR-Cas9 genome editing to introduce this variant into the mouse gene and show that the variant causes insulin resistance on a high-fat diet.

Interrogating cardiac muscle cell mechanobiology on stiffness gradient hydrogels.

Extracellular matrix (ECM) remodeling is a major facet of cardiac development and disease, yet our understanding of cardiomyocyte mechanotransduction remains limited. To enhance our understanding of cardiomyocyte mechanosensation, we studied stiffness-driven changes to cell morphology and mechanomarker expression in H9C2 cells and neonatal rat cardiomyocytes (NRCMs). Linear stiffness gradient polyacrylamide hydrogels (2-33 kPa) coated with ECM proteins including Collagen I (Col), Fibronectin (Fn) or Laminin (Ln) were used to represent necrotic, healthy, and infarcted cardiac tissue on a continuous stiffness gradient.

Lack of Strategic Funding and Long-Term Job Security Threaten to Have Profound Effects on Cardiovascular Researcher Retention in Australia.

Background: Cardiovascular disease is the leading cause of death in Australia. Investment in research solutions has been demonstrated to yield health and a 9.8-fold return economic benefit.

Preventative therapeutic approaches for hypertrophic cardiomyopathy.

Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in the clinical manifestations of the disease, patients experience variable outcomes in response to therapeutics.

Fidelity and coordination of mitochondrial protein synthesis in health and disease.

The evolutionary acquisition of mitochondria has given rise to the diversity of eukaryotic life. Mitochondria have retained their ancestral α-proteobacterial traits through the maintenance of double membranes and their own circular genome. Their genome varies in size from very large in plants to the smallest in animals and their parasites.

A dendronized polymer variant that facilitates safe delivery of a calcium channel antagonist to the heart.

Therapeutic approaches for myocardial ischemia-reperfusion injury (MI) have been ineffective due to limited bioavailability and poor specificity. We have previously shown that a peptide that targets the α-interaction domain of the cardiac L-type calcium channel (AID-peptide) attenuates MI when tethered to transactivator of transcription sequence (TAT) or spherical nanoparticles. However some reservations remain regarding use of these delivery platforms due to the relationship with human immunodeficiency virus, off-target effects and toxicity.

L-type Ca channel-mediated Ca influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions.

L-type voltage-gated Ca channels (LTCCs) are implicated in neurodegenerative processes and cell death. Accordingly, LTCC antagonists have been proposed to be neuroprotective, although this view is disputed, because intentional LTCC activation can also have beneficial effects. LTCC-mediated Ca influx influences mitochondrial function, which plays a crucial role in the regulation of cell viability.

Fidelity of translation initiation is required for coordinated respiratory complex assembly.

Mammalian mitochondrial ribosomes are unique molecular machines that translate 11 leaderless mRNAs; however, it is not clear how mitoribosomes initiate translation, since mitochondrial mRNAs lack untranslated regions. Mitochondrial translation initiation shares similarities with prokaryotes, such as the formation of a ternary complex of fMet-tRNA, mRNA and the 28 subunit, but differs in the requirements for initiation factors. Mitochondria have two initiation factors: MTIF2, which closes the decoding center and stabilizes the binding of the fMet-tRNA to the leaderless mRNAs, and MTIF3, whose role is not clear.