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[
BMC Biol,
2017]
BACKGROUND: Exercise exerts remarkably powerful effects on metabolism and health, with anti-disease and anti-aging outcomes. Pharmacological manipulation of exercise benefit circuits might improve the health of the sedentary and the aging populations. Still, how exercised muscle signals to induce system-wide health improvement remains poorly understood. With a long-term interest in interventions that promote animal-wide health improvement, we sought to define exercise options for Caenorhabditis elegans. RESULTS: Here, we report on the impact of single swim sessions on C. elegans physiology. We used microcalorimetry to show that C. elegans swimming has a greater energy cost than crawling. Animals that swam continuously for 90min specifically consumed muscle fat supplies and exhibited post-swim locomotory fatigue, with both muscle fat depletion and fatigue indicators recovering within 1hour of exercise cessation. Quantitative polymerase chain reaction (qPCR) transcript analyses also suggested an increase in fat metabolism during the swim, followed by the downregulation of specific carbohydrate metabolism transcripts in the hours post-exercise. During a 90min swim, muscle mitochondria matrix environments became more oxidized, as visualized by a localized mitochondrial reduction-oxidation-sensitive green fluorescent protein reporter. qPCR data supported specific transcriptional changes in oxidative stress defense genes during and immediately after a swim. Consistent with potential antioxidant defense induction, we found that a single swim session sufficed to confer protection against juglone-induced oxidative stress inflicted 4hours post-exercise. CONCLUSIONS: In addition to showing that even a single swim exercise bout confers physiological changes that increase robustness, our data reveal that acute swimming-induced changes share common features with some acute exercise responses reported in humans. Overall, our data validate an easily implemented swim experience as C. elegans exercise, setting the foundation for exploiting the experimental advantages of this model to genetically or pharmacologically identify the exercise-associated molecules and signaling pathways that confer system-wide health benefits.
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[
International Worm Meeting,
2019]
Human exercise provides widespread health benefits, including protection against cardiovascular diseases, stroke, diabetes, cancer, and age-associated decline in muscle and immune function. However, the molecular mechanisms by which exercise protects multiple tissues in the body, in particular those not directly affected by physical activity, are largely unknown. This gap in knowledge is partially due to the lack of short-lived genetic models in which fundamental questions on exercise trans-tissue signaling can be evaluated during the entire aging process. To address this issue, we established a long-term exercise protocol for C. elegans based on multiple daily swim sessions during the first four days of adulthood. Swim exercise both increased mid-life survival in C. elegans and improved the age-dependent decline in pharyngeal and intestinal functions. Moreover, long-term swim exercise improved the cognitive ability of wild type C. elegans in a positive associative learning assay. Specifically, exercised animals increased their ability to associate food with a particular chemical odor (butanone) by an average of 35% when compared to control counterparts. We also sought to determine whether swim exercise in C. elegans could counter challenges of pathological conditions, namely in neurodegenerative disease models. Pan-neuronal expression of a human pro-aggregant Tau fragment leads to impaired motility and morphological defects in GABAergic motor neurons. Both phenotypes in this tauopathy model were significantly improved by swim exercise. Furthermore, we found that chemotactic ability toward benzaldehyde is increased after exercise in a C. elegans model of Alzheimer's disease in which human amyloid-? peptide is pan-neuronally expressed. Finally, using a C. elegans Huntington's disease model in which the human Huntingtin protein with expanded polyglutamine is expressed in the six touch receptor neurons, we determined that exercised animals retained better touch sensitivity during lifespan. These results demonstrate that long-term swim exercise improves neuronal healthspan, at both morphological and functional levels, for different neuronal cell types in multiple C. elegans neurodegenerative models.
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Hewitt, J. E., Meyer, J. N., Laranjeiro, R., Royal, M. A., Hartman, J. H., Vanapalli, S., Rahman, M., Harinath, G., Driscoll, M., Braeckman, B. P.
[
International Worm Meeting,
2017]
Physical exercise is the most efficient and accessible intervention that can promote healthy aging in humans. In fact, exercise has been reported to prevent, or mitigate consequences of, a wide range of conditions such as diabetes, cancer, sarcopenia, cardiovascular disease, and neurodegenerative diseases. However, the molecular mechanisms by which exercise can confer systemic health benefits remain poorly understood. We used microcalorimetry to show that C. elegans swimming has a greater energy cost than crawling. Animals that swim continuously for 90 min specifically consume muscle fat supplies and exhibit post-swim locomotory fatigue, with both muscle fat depletion and fatigue indicators recovering within one hour of exercise cessation. qPCR transcript analyses also suggest an increase in fat metabolism during the swim followed by downregulation of specific carbohydrate metabolism transcripts in the hours post-exercise. During a 90 min swim, muscle mitochondria matrix environments become more oxidized as visualized by a localized mito-roGFP reporter. qPCR data support specific transcriptional changes in oxidative stress defense genes during and immediately after a swim. Consistent with potential antioxidant defense induction, we find that a single swim session suffices to confer protection against juglone-induced oxidative stress inflicted 4 hours post-exercise. Exercise adaptation occurs after long-term training. Therefore, we tested different swimming regimens in C. elegans and found that multiple swims per day over several days lead to upregulation of muscle structural genes. Once again, these results are consistent with exercise adaptation described in mammals. Importantly, and taking advantage of the unique characteristics of C. elegans, we show that our training regimen not only leads to changes in body wall muscles but also in neurons. Specifically, mitochondria in touch neurons of exercised worms exhibit a lower oxidation level and an increased turnover rate, both indicators of mitochondrial health. Moreover, long-term swim training in C. elegans delays the functional decline of touch neurons in a polyglutamine (polyQ) aggregation model. These results suggest that physical exercise can promote physiological changes in multiple tissues of C. elegans and open the door to the genetic dissection of exercise systemic health benefits.
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[
iScience,
2021]
Extended space travel is a goal of government space agencies and private companies. However, spaceflight poses risks to human health, and the effects on the nervous system have to be better characterized. Here, we exploited the unique experimental advantages of the nematode <i>Caenorhabditis elegans</i> to explore how spaceflight affects adult neurons <i>invivo</i>. We found that animals that lived 5days of adulthood on the International Space Station exhibited hyperbranching in PVD and touch receptor neurons. We also found that, in the presence of a neuronal proteotoxic stress, spaceflight promotes a remarkable accumulation of neuronal-derived waste in the surrounding tissues, suggesting an impaired transcellular degradation of debris released from neurons. Our data reveal that spaceflight can significantly affect adult neuronal morphology and clearance of neuronal trash, highlighting the need to carefully assess the risks of long-duration spaceflight on the nervous system and to develop adequate countermeasures for safe space exploration.
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[
Proc Natl Acad Sci U S A,
2019]
Regular physical exercise is the most efficient and accessible intervention known to promote healthy aging in humans. The molecular and cellular mechanisms that mediate system-wide exercise benefits, however, remain poorly understood, especially as applies to tissues that do not participate directly in training activity. The establishment of exercise protocols for short-lived genetic models will be critical for deciphering fundamental mechanisms of transtissue exercise benefits to healthy aging. Here we document optimization of a long-term swim exercise protocol for <i>Caenorhabditis elegans</i> and we demonstrate its benefits to diverse aging tissues, even if exercise occurs only during a restricted phase of adulthood. We found that multiple daily swim sessions are essential for exercise adaptation, leading to body wall muscle improvements in structural gene expression, locomotory performance, and mitochondrial morphology. Swim exercise training enhances whole-animal health parameters, such as mitochondrial respiration and midlife survival, increases functional healthspan of the pharynx and intestine, and enhances nervous system health by increasing learning ability and protecting against neurodegeneration in models of tauopathy, Alzheimer's disease, and Huntington's disease. Remarkably, swim training only during early adulthood induces long-lasting systemic benefits that in several cases are still detectable well into midlife. Our data reveal the broad impact of swim exercise in promoting extended healthspan of multiple <i>C. elegans</i> tissues, underscore the potency of early exercise experience to influence long-term health, and establish the foundation for exploiting the powerful advantages of this genetic model for the dissection of the exercise-dependent molecular circuitry that confers system-wide health benefits to aging adults.
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[
International Worm Meeting,
2021]
Axonal regeneration is a promising approach to overcome impaired functionality due to axonal injury. In mammals, central nervous system has poor regenerative capacity due to both extrinsic and intrinsic factors. The regenerative capacity also declines significantly with ageing. Therefore, functional axon regeneration in adulthood is challenging and needs more understanding. The pharmacological manipulations are not very successful for functional restoration whereas rehabilitation and physical activity shows improvement. As physical exercise has complex systemic effects, understanding the downstream effectors of physical exercise that is relevant for axon regeneration might be useful. Studying this using simple model organism has several advantages. Using posterior gentle touch circuit neuron (PLM) of Caenorhabditis elegans, we are studying effect of swimming exercise on functional restoration after laser assisted axotomy. We found that a single swimming exercise session of 90 minutes, which is an established paradigm of exercise in worm (Laranjeiro et al., 2017; Laranjeiro et al., 2019) improves functional recovery irrespective of age. However multiple swimming session is required for older worms (A5 stage). Anatomical correlation showed that swimming session improves regrowth initiation, regrowth length and functional connections. We found that the energy sensor kinase AMPK/AAK-2 plays an essential role mediating swimming benefits. Characterizing tissue specific requirement, we found that it has both cell autonomous (PLM neuron) and non-autonomous (muscle) requirement. Pharmacological activation of AMPK/AAK-2 showed enhanced functional restoration similar to swimming. We are studying the downstream molecules and their specific roles in various tissues for swimming mediated functional enhancement which will be helpful for better implementation of this approach. References Laranjeiro R, Harinath G, Burke D, Braeckman BP, Driscoll M (2017) Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biology 15. Laranjeiro R, Harinath G, Hewitt JE, Hartman JH, Royal MA, Meyer JN, Vanapalli SA, Driscoll M (2019) Swim exercise in Caenorhabditis elegans extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration. Proc Natl Acad Sci U S A 116:23829-23839.
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[
Zootaxa,
2022]
Rhagovelia medinae sp. nov., of the hambletoni group (angustipes complex), and R. utria sp. nov., of the hirtipes group (robusta complex), are described, illustrated, and compared with similar congeners. Based on the examination of type specimens, six new synonymies are proposed: R. elegans Uhler, 1894 = R. pediformis Padilla-Gil, 2010, syn. nov.; R. cauca Polhemus, 1997 = R. azulita Padilla-Gil, 2009, syn. nov., R. huila Padilla-Gil, 2009, syn. nov., R. oporapa Padilla-Gil, 2009, syn. nov, R. quilichaensis Padilla-Gil, 2011, syn. nov.; and R. gaigei, Drake Hussey, 1947 = R. victoria Padilla-Gil, 2012 syn. nov. The first record from Colombia is presented for R. trailii (White, 1879), and the distributions of the following species are extended in the country: R. cali Polhemus, 1997, R. castanea Gould, 1931, R. cauca Polhemus, 1997, R. gaigei Drake Hussey, 1957, R. elegans Uhler, 1894, R. femoralis Champion, 1898, R. malkini Polhemus, 1997, R. perija Polhemus, 1997, R. sinuata Gould, 1931, R. venezuelana Polhemus, 1997, R. williamsi Gould, 1931, and R. zeteki Drake, 1953.
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[
MicroPubl Biol,
2021]
Parkinson's disease (PD) patients have been shown to benefit greatly from intense physical activity (Schenkman et al. 2018). Recent studies have demonstrated that exercise causes changes in the levels of alpha-synuclein aggregate species, a hallmark of PD, in different mammalian animal models (Koo and Cho 2017; Shin et al. 2017; Zhou et al. 2017; Minakaki et al. 2019). However, questions still remain about how exercise affects specifically native alpha-synuclein protein species directly after the cessation of exercise and the longer-term downstream effects which exercise may have on organismal health. It was recently discovered that periods of thrashing in liquid solution, otherwise called swimming exercise, in C. elegans worms, induces many mechanisms invoked during mammalian exercise (Laranjeiro et al. 2017). This has provided an avenue for studying exercise conditions in various C. elegans models of neurodegeneration (Laranjeiro et al. 2019). In order to study the effect of exercise on native human alpha-synuclein protein species, we utilized the NL5901- pkIs2386 worm model of Parkinson's which contains human alpha-synuclein tagged to a yellow fluorescent protein (YFP) in the muscle cells (van Ham et al. 2008). We performed tissue analysis via Blue Native (BN) page westerns and confocal microscopy. In addition, because pharyngeal pumping is decreased while worms are swimming, we controlled for this effect by exposing worms in parallel to a period of food restriction (FR) conditions (Vidal-Gadea et al. 2012). We also performed thrashing assays to assess longer term downstream behavioral effects on the animals after either exercise or food restriction conditions.
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Gordon, K.L., Driscoll, M., Sherwood, D.R., Meyer, J.N., Laranjeiro, R., Hartman, J.H.
[
International Worm Meeting,
2017]
Health, disease, and aging are determined by genetic factors, environment, and lifestyle. In humans, environmental contributions to long-term health arise from ambient factors such as environmental chemical exposures and sun exposure, while lifestyle impacts health through mental health and stress, diet, drug usage, and exercise. In laboratory animals, the impact of environment and lifestyle are minimized through carefully controlled experimental conditions, and can therefore be modulated to study the effects of these factors. The effect of exercise on general health has been reported: positive impacts on cognitive function, maintenance of skeletal muscle, and protection from age-related diseases are increasingly recognized. However, molecular mechanisms underlying those protections are not well understood. Furthermore, it is unknown what impacts regular exercise training may have on other health-modifying factors such as toxic exposures from the environment. In this study, we used C. elegans to study the impact of regular exercise training on mitochondrial health and chemical toxicity. For exercise experiments, beginning at L4 stage, animals were transferred to unseeded agar plates without (control) or with liquid (causing worms to swim/thrash) for 90 minutes twice daily. This regimen was carried out for six days, and mitochondrial and toxicity outcomes were tested following exercise on adult day 6 and adult day 10. Preliminary results show that mitochondrial morphology is not significantly different between control and exercise groups at adult day 6 (p=0.64); however, on day 10, control animals have highly fragmented and disorganized mitochondria, while exercised animals exhibit significantly healthier mitochondrial morphology (p=0.0065). Furthermore, mitochondrial respiration significantly differed in spare capacity (p<0.001) on adult day 6, with exercised animals showing increased spare capacity compared to controls. Respiration experiments with day 10 adults are underway; total ATP, mitochondrial DNA copy number, and mitochondrial DNA lesions are also being investigated. Preliminary toxicity experiments showed that exercise-induced changes in mitochondrial health were accompanied by a 30-50% reduction in lethality induced by the mitochondrial toxicants arsenite and rotenone. Together, these data demonstrate that changes in physical activity result in altered mitochondrial health, which extends to protection against chemical toxicants known to damage mitochondria. Ongoing and future experiments will further explore the biochemical and metabolic changes underlying this phenomenon.
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Raval, K., Driscoll, M., Brook, S., Wang, G., Abbott, M., Laranjeiro, R.
[
International Worm Meeting,
2019]
Superoxide (O2-) is a toxic byproduct in energy metabolism that can be detoxified by superoxide dismutase (SOD). Excessive O2- can damage macromolecules, a mechanism thought to contribute to aging. Eliminating cytoplasmic SOD from mouse or fly can significantly reduce their lifespans; eliminating mitochondrial SOD (SODmito) from mouse or fly can even cause extreme embryonic lethality. In contrast, eliminating mitochondrial SODs (SOD-2 and SOD-3) from C. elegans does not reduce lifespan or induce embryonic lethality, so we infer that C. elegans is equipped with exceptional tools that counter mitochondrial O2- stress, and we here present the evidence supporting this hypothesis. We first found that mitochondrial O2- stress induces expression of the isocitrate lyase/malate synthase gene (
icl-1), the only protein that catalyzes the glyoxylate shunt in C. elegans. Knocking out
icl-1 in the SODmito defective worms increases embryonic lethality to ~80%. Since the glyoxylate shunt is unique to C. elegans but lacking in mouse or fly, we predict that the glyoxylate shunt is one novel tool used by C. elegans in battling mitochondrial O2- stress. We also found that eliminating SODmito induces the mitochondrial unfolded protein response (mitoUPR), which is known to induce
icl-1 gene expression. Eliminating the central mitoUPR mediator ATFS-1 can cause 100% embryonic lethality in the SODmito null worms-the enhanced severity of
atfs-1 mutation as compared to
icl-1 deletion alone suggests that more than the glyoxylate shunt induction by the mitoUPR contributes to mitochondrial O2- stress resistance. The hypoxia inducible factor 1 (HIF-1) mediates another signaling pathway that might inhibit mitochondrial O2- production via tuning the electron transport chain. Eliminating enzymes (EGL-9 or VHL-1) that mediate HIF-1 degradation (i.e. activating HIF-1-mediated transcription) can cause nearly 100% embryonic lethality in the SODmito ICL-1 double null worms, which suggests that HIF-1-dependent responses modulated via the EGL-9 and VHL-1 signaling pathway can contribute to the embryonic lethality induced by mitochondrial O2- stress. Overall, we report that the embryonic lethality induced by unmanaged mitochondrial O2- stress can be modulated by multiple molecular pathways.