scholarly journals Age-dependent diastolic heart failure in an in vivo Drosophila model

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Matthew P Klassen ◽  
Christian J Peters ◽  
Shiwei Zhou ◽  
Hannah H Williams ◽  
Lily Yeh Jan ◽  
...  
Keyword(s):  
Diastolic Heart Failure ◽  
Normal Aging ◽  
Signaling Networks ◽  
Drosophila Model ◽  
Age Dependent ◽  
Resolution Imaging ◽  
Open Question ◽  
Pumping Function ◽  
Contractile Performance

While the signals and complexes that coordinate the heartbeat are well established, how the heart maintains its electromechanical rhythm over a lifetime remains an open question with significant implications to human health. Reasoning that this homeostatic challenge confronts all pulsatile organs, we developed a high resolution imaging and analysis toolset for measuring cardiac function in intact, unanesthetized Drosophila melanogaster. We demonstrate that, as in humans, normal aging primarily manifests as defects in relaxation (diastole) while preserving contractile performance. Using this approach, we discovered that a pair of two-pore potassium channel (K2P) subunits, largely dispensable early in life, are necessary for terminating contraction (systole) in aged animals, where their loss culminates in fibrillatory cardiac arrest. As the pumping function of its heart is acutely dispensable for survival, Drosophila represents a uniquely accessible model for understanding the signaling networks maintaining cardiac performance during normal aging.

scholarly journals Author response: Age-dependent diastolic heart failure in an in vivo Drosophila model

2017 ◽  
Author(s):  
Matthew P Klassen ◽  
Christian J Peters ◽  
Shiwei Zhou ◽  
Hannah H Williams ◽  
Lily Yeh Jan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Heart Failure ◽  
Author Response ◽  
Drosophila Model ◽  
Age Dependent

scholarly journals A Protein-trap allele reveals roles for Drosophila ATF4 in photoreceptor degeneration, oogenesis and wing development

2021 ◽  
Author(s):  
Deepika Vasudevan ◽  
Hidetaka Katow ◽  
Huai-Wei Huang ◽  
Grace Tang ◽  
Hyung Don Ryoo
Keyword(s):  
Control Mechanisms ◽  
Loss Of Function ◽  
Pupal Development ◽  
Gfp Fusion Protein ◽  
Drosophila Model ◽  
Evolutionarily Conserved ◽  
Age Dependent ◽  
Cellular Stressors ◽  
Trap Line

Metazoans have evolved various quality control mechanisms to cope with cellular stress inflicted by external and physiological conditions. ATF4 is a major effector of the Integrated Stress Response (ISR), an evolutionarily conserved pathway that mediates adaptation to various cellular stressors. Loss of function of Drosophila ATF4, encoded by the gene cryptocephal (crc), results in lethality during pupal development. The roles of crc in Drosophila disease models and in adult tissue homeostasis thus remain poorly understood. Here, we report that a protein-trap MiMIC insertion in the crc locus generates a crc-GFP fusion protein that allows visualization of crc activity in vivo. This allele also acts as a hypomorphic mutant that uncovers previously unknown roles for crc. Specifically, the crc protein-trap line shows crc-GFP induction in a Drosophila model for Retinitis Pigmentosa (RP). This crc allele renders flies more vulnerable to amino acid deprivation and age-dependent retinal degeneration. These mutants also show defects in wing veins and oocyte maturation. Together, our data reveal previously unknown roles for crc in development, cellular homeostasis and photoreceptor survival.

Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1233-1242
Author(s):  
Joshua M Shulman ◽  
Mel B Feany
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Genetic Modifiers ◽  
Protein Tau ◽  
Major Class ◽  
Drosophila Model ◽  
Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

scholarly journals Robust polarity establishment occurs via an endocytosis-based cortical corralling mechanism

2013 ◽  
Vol 200 (4) ◽  
pp. 407-418 ◽  
Author(s):  
Mini Jose ◽  
Sylvain Tollis ◽  
Deepak Nair ◽  
Jean-Baptiste Sibarita ◽  
Derek McCusker
Keyword(s):  
High Resolution ◽  
Membrane Trafficking ◽  
In Vivo Studies ◽  
Biological Processes ◽  
Constant Frequency ◽  
In Silico Modeling ◽  
Resolution Imaging ◽  
Polarity Establishment ◽  
Endocytic Vesicles

Formation of a stable polarity axis underlies numerous biological processes. Here, using high-resolution imaging and complementary mathematical modeling we find that cell polarity can be established via the spatial coordination of opposing membrane trafficking activities: endocytosis and exocytosis. During polarity establishment in budding yeast, these antagonistic processes become apposed. Endocytic vesicles corral a central exocytic zone, tightening it to a vertex that establishes the polarity axis for the ensuing cell cycle. Concomitantly, the endocytic system reaches an equilibrium where internalization events occur at a constant frequency. Endocytic mutants that failed to initiate periodic internalization events within the corral displayed wide, unstable polarity axes. These results, predicted by in silico modeling and verified by high resolution in vivo studies, identify a requirement for endocytic corralling during robust polarity establishment.

Treatment of type 2 diabetic db/db mice with a novel PPARγ agonist improves cardiac metabolism but not contractile function

2004 ◽  
Vol 286 (3) ◽  
pp. E449-E455 ◽  
Author(s):  
Andrew N. Carley ◽  
Lisa M. Semeniuk ◽  
Yakhin Shimoni ◽  
Ellen Aasum ◽  
Terje S. Larsen ◽  
...  
Keyword(s):  
Contractile Function ◽  
Ex Vivo ◽  
Metabolic Changes ◽  
Pparγ Agonist ◽  
Perfused Hearts ◽  
Type 2 Diabetic ◽  
Contractile Performance ◽  
Exogenous Substrates

Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor-γ that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K+ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.

scholarly journals Transgenic Overexpression of the Ca2+-binding Protein S100A1 in the Heart Leads to Increased in Vivo Myocardial Contractile Performance

2003 ◽  
Vol 278 (36) ◽  
pp. 33809-33817 ◽  
Author(s):  
Patrick Most ◽  
Andrew Remppis ◽  
Sven T. Pleger ◽  
Eva Löffler ◽  
Philipp Ehlermann ◽  
...  
Keyword(s):  
Binding Protein ◽  
Myocardial Contractile ◽  
Contractile Performance

scholarly journals OCT imaging of rod mitochondrial respiration in vivo

2021 ◽  
pp. 153537022110137
Author(s):  
Bruce A Berkowitz ◽  
Haohua Qian
Keyword(s):  
Signaling Pathway ◽  
Mitochondrial Respiration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Body ◽  
Subretinal Space ◽  
Outer Retina ◽  
Water Efflux ◽  
Resolution Imaging

There remains a need for high spatial resolution imaging indices of mitochondrial respiration in the outer retina that probe normal physiology and measure pathogenic and reversible conditions underlying loss of vision. Mitochondria are involved in a critical, but somewhat underappreciated, support system that maintains the health of the outer retina involving stimulus-evoked changes in subretinal space hydration. The subretinal space hydration light–dark response is important because it controls the distribution of vision-critical interphotoreceptor matrix components, including anti-oxidants, pro-survival factors, ions, and metabolites. The underlying signaling pathway controlling subretinal space water management has been worked out over the past 30 years and involves cGMP/mitochondria respiration/pH/RPE water efflux. This signaling pathway has also been shown to be modified by disease-generating conditions, such as hypoxia or oxidative stress. Here, we review recent advances in MRI and commercially available OCT technologies that can measure stimulus-evoked changes in subretinal space water content based on changes in the external limiting membrane-retinal pigment epithelium region. Each step within the above signaling pathway can also be interrogated with FDA-approved pharmaceuticals. A highlight of these studies is the demonstration of first-in-kind in vivo imaging of mitochondria respiration of any cell in the body. Future examinations of subretinal space hydration are expected to be useful for diagnosing threats to sight in aging and disease, and improving the success rate when translating treatments from bench-to-bedside.

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