pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise

Reddy, Anita; Bozi, Luíz Henrique Marchesi; Yaghi, Omar; Mills, Evanna L.; Xiao, Haopeng; Nicholson, Hilary E.; Paschini, Margherita; Paulo, João A.; Garrity, Ryan; Laznik-Bogoslavski, Dina; Ferreira, Julio Cesar Batista; Carl, Christian S.; Sjøberg, Kim A.; Wojtaszewski, Jørgen F. P.; Jeppesen, Jacob; Gygi, Steven P.; Mathis, Diane; Chouchani, Edward T.

doi:10.1016/j.cell.2020.08.039

Cited by 167 publications

(173 citation statements)

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“…Thus, additional factors likely influence SUCNR1 expression in PPGL tissue. Potentially, tumor tissue pH and monocarboxylate transporter 1 expression level play an essential role, as these highly likely determine succinate release to the extracellular space (20,21). Of note, hypoxia or HIF activation positively regulate monocarboxylate transporter 1 expression [summarized in (55)].…”

Section: Discussionmentioning

confidence: 99%

“…Elevations in succinate levels arise during hypoxia/ischemia, hyperglycemia, due to tissue damage, or at sites of inflammation [summarized in (19)]. More recently, pH dependent transport of succinate from intact cells via monocarboxylate transporter 1 has been shown in an ischemia reperfusion model of the heart and following exercise under acidic conditions (20,21). An apparent function of SUCNR1 is the activation of coping mechanisms upon adverse conditions, including stimulation of proliferation of different cell types, migration, and angiogenesis (22)(23)(24)(25)(26)(27)(28)(29).…”

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confidence: 99%

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Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

et al. 2021

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Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D (SDHx) mutations. SDHx mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 (SUCNR1) in SDHB PPGLs and SDHD head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to SDHx mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in SDHx PPGLs and after SDHB knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of SUCNR1-transfected PC12 and ERK pathway signaling compared to control cells. Candidate SUCNR1 inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in SDHx PPGLs, providing a growth advantage via SUCNR1.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

et al. 2021

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“…The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.10.430650 doi: bioRxiv preprint 10 al., 2000). The transporters for succinate have not been fully characterized, and in addition to plasma membrane dicarboxylate transporters (Kaufhold et al, 2011), MCT1 can also export succinate (Prag et al, 2020;Reddy et al, 2020). This may apply to other MCTs as well.…”

Section: Discussionmentioning

confidence: 99%

“…The current state of the literature suggests that exogenous succinate is not imported into most cells (Clerc & Polster, 2012;Ehinger et al, 2016;MacDonald et al, 1989;Protti, 2018), despite widespread expression of monocarboxylate and dicarboxylate transporters capable of carrying succinate across the plasma membrane (Andrienko et al, 2017;Nakai et al, 2006;Pajor, 2014;Prag et al, 2020;Reddy et al, 2020). Brown adipose tissue is thought to be the main sink for succinate, allowing it to fuel thermogenesis (Mills et al, 2018).…”

Section: δ ρmentioning

confidence: 99%

Succinate metabolism uncouples retinal pigment epithelium mitochondria

Hass

et al. 2021

Preprint

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Succinate is a mitochondrial metabolite well known for its ability to stimulate respiration through succinate dehydrogenase. Data from multiple studies have implied that succinate localized to mitochondria and does not cross tissue boundaries. We tested this hypothesis by infusing 13C-labeled succinate into the bloodstream of awake, moving C57BL6/J mice through a jugular catheter. Following the infusion we probed intermediates of glycolytic and Krebs cycle metabolism to determine how different tissues utilize succinate. We found that retina and eyecup metabolism appeared unique in their handling of succinate. The retina appeared to be the least permeant to succinate, and succinate that was taken up was not well integrated into the Krebs cycle and was rather directed to become glycolytic intermediates. In the eyecup, 13C originating from succinate populated Krebs cycle intermediates particularly well. We also found that ex vivo, succinate stimulates mitochondrial uncoupling in eyecup tissue, which may be particularly relevant in the biology of the eye, as retina tissue secretes succinate.

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“…Recent work has shown that pH gated release of succinate is a myokine involved in adaptive responses to exercise [45]. Others have shown that peroxiredoxins and thioredoxins are released into the blood plasma compartment in an intensity and time dependent manner in response to high intensity, but not moderate intensity exercise in humans [26].…”

Section: Discussionmentioning

confidence: 99%

High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response

Ostrom

Valencia

Marcinek

et al. 2021

Preprint

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Introduction: High intensity exercise is an increasingly popular mode of exercise to elicit similar or greater adaptive responses compared to traditional moderate intensity continuous exercise. However, the molecular mechanisms underlying these adaptive responses are still unclear. The purpose of this pilot study was to compare high and low intensity contractile stimulus on the Nrf2-mediated redox stress response in mouse skeletal muscle. Methods: An intra-animal design was used to control for variations in individual responses to muscle stimulation by using a stimulated limb (STIM) and comparing to the contralateral unstimulated control limb (CON). High Intensity (HI-100Hz), Low Intensity (LI-50Hz), and Naive Control (NC-Mock stimulation vs CON) groups were used to compare these effects on Nrf2-ARE binding, Keap1 protein content, and downstream gene and protein expression of Nrf2 target genes. Results: Muscle stimulation significantly increased Nrf2-ARE binding in LI-STIM compared to LI-CON (p = 0.0098), while Nrf2-ARE binding was elevated in both HI-CON and HI-STIM compared to NC (p = 0.0007). The Nrf2-ARE results were mirrored in the down-regulation of Keap1, where Keap1 expression in HI-CON and HI-STIM were both significantly lower than NC (p = 0.008) and decreased in LI-STIM compared to LI-CON (p = 0.015). In addition, stimulation increased NQO1 protein compared to contralateral control regardless of stimulation intensity (p = 0.019). Conclusions: Taken together, these data suggest a systemic redox signaling exerkine is activating Nrf2-ARE binding and is intensity gated, where Nrf2-ARE activation in contralateral control limbs were only seen in the HI group. Other research in exercise induced Nrf2 signaling support the general finding that Nrf2 is activated in peripheral tissues in response to exercise, however the specific exerkine responsible for the systemic signaling effects is not known. Future work should aim to delineate these redox sensitive systemic signaling mechanisms.

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pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise

Abstract: Highlights d Mouse and human muscle selectively release succinate during exercise d Muscle cells release succinate by pH-gated secretion via MCT1 d Extracellular succinate regulates paracrine responses to exercise through SUCNR1

Cited by 167 publications

References 83 publications

Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

Succinate metabolism uncouples retinal pigment epithelium mitochondria

High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response

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