The Drosophila PGC-1α Homolog spargel Modulates the Physiological Effects of Endurance Exercise

Tinkerhess, Martin J.; Healy, Lindsey; Morgan, Matthew J.; Sujkowski, Alyson; Matthys, E; Zheng, Li; Wessells, Robert J.

doi:10.1371/journal.pone.0031633

Cited by 71 publications

(74 citation statements)

References 27 publications

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“…In addition, exercised wild-type male Drosophila retain higher climbing speed across ages than unexercised siblings (Fig. 1E), as previously observed (Sujkowski et al, 2015; Sujkowski et al, 2012; Tinkerhess et al, 2012a; Tinkerhess et al, 2012b). Flight performance (Fig.…”

Section: Resultssupporting

confidence: 85%

“…We have previously described an endurance training paradigm for Drosophila that uses reiterated induction of negative geotaxis to allow controlled, daily training of fruit fly cohorts (Tinkerhess et al, 2012a). Following a three-week period of ramped endurance exercise activity, wild-type male flies display increased climbing speed (Piazza et al, 2009), endurance (Tinkerhess et al, 2012b), cardiac performance (Piazza et al, 2009; Sujkowski et al, 2012), flight (Sujkowski et al, 2015), and mitochondrial enzyme activity (Piazza et al, 2009). Furthermore, endurance training increases mitochondrial number and reduces accumulated oxidative stress in fly cardiac muscle (Laker et al, 2014).…”

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confidence: 99%

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Octopamine Drives Endurance Exercise Adaptations in Drosophila

et al. 2017

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Summary Endurance exercise is an effective therapeutic intervention with substantial pro-healthspan effects. Male Drosophila respond to a ramped daily program of exercise by inducing conserved physiological responses similar to those seen in mice and humans. Female flies respond to an exercise stimulus, but do not experience the adaptive training response seen in males. Here, we use female flies as a model to demonstrate that differences in exercise response are mediated by differences in neuronal activity. The activity of octopaminergic neurons is specifically required to induce the conserved cellular and physiological changes seen following endurance training. Furthermore, either intermittent, scheduled activation of octopaminergic neurons, or octopamine feeding, is able to fully substitute for exercise, conferring a suite of pro-healthspan benefits to sedentary Drosophila. These experiments indicate that octopamine is a critical mediator of adaptation to endurance exercise in Drosophila.

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Section: Resultssupporting

confidence: 85%

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Octopamine Drives Endurance Exercise Adaptations in Drosophila

et al. 2017

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“…How is this excess ATP utilized during Spargel overexpression? One clue came from the muscle-specific overexpression of Spargel, which prolongs the vertical climbing behavior in flies (Tinkerhess et al 2012), possibly due to excess ATP production.…”

Section: Subcellular Localization Of Spargel and Pgc-1 Is Comparablementioning

confidence: 99%

Spargel/dPGC-1 Is a New Downstream Effector in the Insulin–TOR Signaling Pathway in Drosophila

Mukherjee

Duttaroy

2013

Genetics

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Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin-TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin-TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway.T O attain proper cellular growth, availability of nutrients is imperative, because the nutrient supply fuels energy metabolism. Thus lack of nourishment cause limited growth of the organism due to reduced energy metabolism (Hietakangas and Cohen 2009;DePalma et al. 2012). Sensing and transport of growth signals happen in two distinct pathways: at the cellular level, the TOR pathway governs growth (Saltiel and Kahn 2001;Grewal 2009), whereas insulin signaling is responsible for subsequent adjustment of the cellular metabolism causing growth at a more systemic level. Ultimate convergence of these two signaling pathways leads to balanced growth. Therefore each member of the insulin-TOR pathway has recognized influence on cell size and cell growth as demonstrated either in cell clones or at the whole organism level. Severe growth defect during prenatal development such as intrauterine growth restriction and low birth weight have been linked to paucity of insulinTor signaling (Murakami et al. 2004;Gannage-Yared et al. 2012) and ATP production (Selak et al. 2003). Like in most animals, the insulin-TOR signaling pathway in Drosophila is dedicated to the control of growth and metabolism ( Figure 1A). With its enriched genetic and genomic resources, flies have contributed significantly toward the understanding of nutritional physiology and ce...

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“…In mice and humans, endurance exercise is known to improve glucose sensitivity (Henriksson, 1995;Hayashi et al, 1997), while in mice and flies, endurance exercise is known to increase autophagy (He et al, 2012;Sujkowski et al, 2012). In all species tested, endurance exercise increases mitochondrial biogenesis (Freyssenet et al, 1996;Irrcher et al, 2003;Tinkerhess et al, 2012b). Because of these conserved changes, endurance exercise is thought to be a potential low-cost intervention that may provide increased healthspan to the human population by alleviating pathological states related to obesity and glucose insenstivity (Hopps and Caimi, 2011;Chudyk and Petrella, 2011).…”

Section: Introductionmentioning

confidence: 99%

Dietary composition regulatesDrosophilamobility and cardiac physiology

Bazzell

Ginzberg

Healy

et al. 2012

Journal of Experimental Biology

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SUMMARYThe impact of dietary composition on exercise capacity is a subject of intense study in both humans and model organisms. Interactions between diet and genetics are a crucial component of optimized dietary design. However, the genetic factors governing exercise response are still not well understood. The recent development of invertebrate models for endurance exercise is likely to facilitate study designs examining the conserved interactions between diet, exercise and genetics. As a first step, we used the Drosophila model to describe the effects of varying dietary composition on several physiological indices, including fatigue tolerance and climbing speed, cardiac performance, lipid storage and autophagy. We found that flies of two divergent genetic backgrounds optimize endurance and cardiac performance on relatively balanced low calorie diets. When flies are provided with unbalanced diets, diets higher in sugar than in yeast facilitate greater endurance at the expense of cardiac performance. Importantly, we found that dietary composition has a profound effect on various physiological indices, whereas total caloric intake per se has very little predictive value for performance. We also found that the effects of diet on endurance are completely reversible within 48h if flies are switched to a different diet. Supplementary material available online at

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The Drosophila PGC-1α Homolog spargel Modulates the Physiological Effects of Endurance Exercise

Cited by 71 publications

References 27 publications

Octopamine Drives Endurance Exercise Adaptations in Drosophila

Octopamine Drives Endurance Exercise Adaptations in Drosophila

Spargel/dPGC-1 Is a New Downstream Effector in the Insulin–TOR Signaling Pathway in Drosophila

Dietary composition regulatesDrosophilamobility and cardiac physiology

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