The RU486-dependent activation of the GeneSwitch system in adult muscles leads to severe adverse effects in Drosophila.

Robust genetic systems to control the expression of transgenes in a spatial and temporal manner are a valuable asset for researchers. The GeneSwitch system induced by the drug RU486 has gained widespread use in the Drosophila community. However, some concerns were raised as negative effects were seen depending on the stock, transgene, stage, and tissue under study.

Octopamine Rescues Endurance and Climbing Speed in Mutants with Circadian Rhythm Disruption.

Circadian rhythm disturbances are associated with various negative health outcomes, including an increasing incidence of chronic diseases with high societal costs. While exercise can protect against the negative effects of rhythm disruption, it is not available to all those impacted by sleep disruptions, in part because sleep disruption itself reduces exercise capacity. Thus, there is a need for therapeutics that bring the benefits of exercise to this population.

, a homolog of the Irisin precursor , is critical for exercise performance and cardiac autophagy.

Mammalian encodes a protein precursor of Irisin, which is important for exercise-dependent regulation of whole-body metabolism. In a genetic screen in , we identified (), which shows substantial protein homology to mouse and human , as a regulator of autophagy acting downstream of Atg1/Atg13. Physiologically, -deficient flies showed reduced exercise performance and defective cold resistance, which were rescued by exogenous expression of .

Endurance exercise ameliorates phenotypes in models of spinocerebellar ataxias.

Endurance exercise is a potent intervention with widespread benefits proven to reduce disease incidence and impact across species. While endurance exercise supports neural plasticity, enhanced memory, and reduced neurodegeneration, less is known about the effect of chronic exercise on the progression of movement disorders such as ataxias. Here, we focused on three different types of ataxias, spinocerebellar ataxias type (SCAs) 2, 3, and 6, belonging to the polyglutamine (polyQ) family of neurodegenerative disorders.

Navigation of a Freely Walking Fruit Fly in Infinite Space Using a Transparent Omnidirectional Locomotion Compensator (TOLC).

Animal behavior is an essential element in behavioral neuroscience study. However, most behavior studies in small animals such as fruit flies () have been performed in a limited spatial chamber or by tethering the fly's body on a fixture, which restricts its natural behavior. In this paper, we developed the Transparent Omnidirectional Locomotion Compensator (TOLC) for a freely walking fruit fly without tethering, which enables its navigation in infinite space.

The glutamic acid-rich-long C-terminal extension of troponin T has a critical role in insect muscle functions.

The troponin complex regulates the Ca activation of myofilaments during striated muscle contraction and relaxation. Troponin genes emerged 500-700 million years ago during early animal evolution. Troponin T (TnT) is the thin-filament-anchoring subunit of troponin.

Sestrins are evolutionarily conserved mediators of exercise benefits.

Exercise is among the most effective interventions for age-associated mobility decline and metabolic dysregulation. Although long-term endurance exercise promotes insulin sensitivity and expands respiratory capacity, genetic components and pathways mediating the metabolic benefits of exercise have remained elusive. Here, we show that Sestrins, a family of evolutionarily conserved exercise-inducible proteins, are critical mediators of exercise benefits.

Atg2, Atg9 and Atg18 in mitochondrial integrity, cardiac function and healthspan in Drosophila.

In yeast, the Atg2-Atg18 complex regulates Atg9 recycling from phagophore assembly site during autophagy; their function in higher eukaryotes remains largely unknown. In a targeted screening in Drosophila melanogaster, we show that Mef2-GAL4-RNAi-mediated knockdown of Atg2, Atg9 or Atg18 in the heart and indirect flight muscles led to shortened healthspan (declined locomotive function) and lifespan. These flies displayed an accelerated age-dependent loss of cardiac function along with cardiac hypertrophy (increased heart tube wall thickness) and structural abnormality (distortion of the lumen surface).

Nanothermometry Measure of Muscle Efficiency.

Despite recent advances in thermometry, determination of temperature at the nanometer scale in single molecules to live cells remains a challenge that holds great promise in disease detection among others. In the present study, we use a new approach to nanometer scale thermometry with a spatial and thermal resolution of 80 nm and 1 mK respectively, by directly associating 2 nm cadmium telluride quantum dots (CdTe QDs) to the subject under study. The 2 nm CdTe QDs physically adhered to bovine cardiac and rabbit skeletal muscle myosin, enabling the determination of heat released when ATP is hydrolyzed by both myosin motors.

Delayed Induction of Human NTE (PNPLA6) Rescues Neurodegeneration and Mobility Defects of Drosophila swiss cheese (sws) Mutants.

Human PNPLA6 gene encodes Neuropathy Target Esterase protein (NTE). PNPLA6 gene mutations cause hereditary spastic paraplegia (SPG39 HSP), Gordon-Holmes syndrome, Boucher-Neuhäuser syndromes, Laurence-Moon syndrome, and Oliver-McFarlane syndrome. Mutations in the Drosophila NTE homolog swiss cheese (sws) cause early-onset, progressive behavioral defects and neurodegeneration characterized by vacuole formation.

My gut feeling says rest: Increased intestinal permeability contributes to chronic diseases in high-intensity exercisers.

Chronic diseases are the leading cause of death and disability worldwide, and many of these conditions are linked to chronic inflammation. One potential cause of chronic inflammation is an increased intestinal epithelial permeability. Recent studies have demonstrated that parasympathetic stimulation via the efferent abdominal vagus nerve increases the expression and proper localization of tight junction proteins and decreases intestinal epithelial permeability.

Endurance exercise and selective breeding for longevity extend Drosophila healthspan by overlapping mechanisms.

Endurance exercise has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. In addition, long-term exercise reduces the incidence of age-related diseases in humans and in model organisms. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood.

A novel MitoTimer reporter gene for mitochondrial content, structure, stress, and damage in vivo.

Mitochondrial dysfunction plays important roles in many diseases, but there is no satisfactory method to assess mitochondrial health in vivo. Here, we engineered a MitoTimer reporter gene from the existing Timer reporter gene. MitoTimer encodes a mitochondria-targeted green fluorescent protein when newly synthesized, which shifts irreversibly to red fluorescence when oxidized.

Endurance training protocol and longitudinal performance assays for Drosophila melanogaster.

One of the most pressing problems facing modern medical researchers is the surging levels of obesity, with the consequent increase in associated disorders such as diabetes and cardiovascular disease (1-3). An important topic of research into these associated health problems involves the role of endurance exercise as a beneficial intervention. Exercise training is an inexpensive, non-invasive intervention with several beneficial results, including reduction in excess body fat (4), increased insulin sensitivity in skeletal muscle (5), increased anti-inflammatory and antioxidative responses (6), and improved contractile capacity in cardiomyocytes (7).

The Drosophila PGC-1α homolog spargel modulates the physiological effects of endurance exercise.

Endurance exercise is an inexpensive intervention that is thought to provide substantial protection against several age-related pathologies, as well as inducing acute changes to endurance capacity and metabolism. Recently, it has been established that endurance exercise induces conserved alterations in physiological capacity in the invertebrate Drosophila model. If the genetic factors underlying these exercise-induced physiological alterations are widely conserved, then invertebrate genetic model systems will become a valuable tool for testing of genetic and pharmacological mimetics for endurance training.

Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects.

A significant current challenge in human genetics is the identification of interacting genetic loci mediating complex polygenic disorders. One of the best characterized polygenic diseases is Down syndrome (DS), which results from an extra copy of part or all of chromosome 21. A short interval near the distal tip of chromosome 21 contributes to congenital heart defects (CHD), and a variety of indirect genetic evidence suggests that multiple candidate genes in this region may contribute to this phenotype.

Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila.

The epidemic of obesity and diabetes is causing an increased incidence of dyslipidemia-related heart failure. While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of membrane phospholipid homeostasis and lipid-induced cardiomyopathy. In the present study, we report that the Drosophila easily shocked (eas) mutants that harbor a disturbance in phosphatidylethanolamine (PE) synthesis display tachycardia and defects in cardiac relaxation and are prone to developing cardiac arrest and fibrillation under stress.

KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging.

Population profiles of industrialized countries show dramatic increases in cardiovascular disease with age, but the molecular and genetic basis of disease progression has been difficult to study because of the lack of suitable model systems. Our studies of Drosophila show a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in the expression of the Drosophila homolog of human KCNQ1-encoded K(+) channel alpha subunits. In humans, this channel is involved in myocardial repolarization, and alterations in the function of this channel are associated with an increased risk for Torsades des Pointes arrhythmias and sudden death.

Cardiac aging.

Health care for the elderly in western society has emerged as an increasingly important economic and political issue in recent years. As the elderly proportion of western populations continues to expand, maintaining health and wellness of the aged will continue to be an important research priority in the near future. This review will attempt to briefly highlight what is known about age-related changes in cardiac performance in humans, then focus on recent work on cellular mechanisms of cardiac deterioration in vertebrate models.

Age-related cardiac deterioration: insights from Drosophila.

As the average lifespan in Western countries continues to expand, health care for the aged has become an increasingly important research focus. While clinicians and vertebrate researchers have frequently concentrated on specific age-related diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's Diseases, researchers working with invertebrate genetic model systems have gained important insights into global mechanisms of lifespan determination. Still others have employed biochemical and molecular approaches to elucidate processes contributing to common diseases of the elderly, such as cancer and diabetes.

Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity.

Reducing insulin/IGF signaling allows for organismal survival during periods of inhospitable conditions by regulating the diapause state, whereby the organism stockpiles lipids, reduces fertility, increases stress resistance, and has an increased lifespan. The Target of Rapamycin (TOR) responds to changes in growth factors, amino acids, oxygen tension, and energy status; however, it is unclear how TOR contributes to physiological homeostasis and disease conditions. Here, we show that reducing the function of Drosophila TOR results in decreased lipid stores and glucose levels.

Hedgehog and RAS pathways cooperate in the anterior-posterior specification and positioning of cardiac progenitor cells.

The Drosophila heart is a highly ordered structure with only a limited number of cell types, which are arranged in a stereotyped metameric pattern. Ras signaling has previously been implicated in contributing to heart formation, but how positional information is integrated with this pathway to specify, distinguish and precisely position individual cardiac progenitors within the presumptive heart-forming region are not known. Here, we present evidence that the striped pattern of the secreted factor Hedgehog (Hh), in combination with the RAS pathway, specifies and positions neighboring groups of cardiac progenitors within each segment: the anterior ladybird (lbe)- and the posterior even skipped (eve)-expressing cardiac progenitors.

Embryonic even skipped-dependent muscle and heart cell fates are required for normal adult activity, heart function, and lifespan.

The Drosophila pair-rule gene even skipped (eve) is required for embryonic segmentation and later in specific cell lineages in both the nervous system and the mesoderm. We previously generated eve mesoderm-specific mutants by combining an eve null mutant with a rescuing transgene that includes the entire locus, but with the mesodermal enhancer removed. This allowed us to analyze in detail the defects that result from a precisely targeted elimination of mesodermal eve expression in the context of an otherwise normal embryo.