Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease

Dridi, Haikel; Li, Xiaoping; Yuan, Qi; Reiken, Steve; Yehia, M.; Sittenfeld, Leah; Apostolou, Panagiota E.; Buron, Julie GM; Sicard, Pierre; Matecki, Stéfan; Thireau, Jérôme; Menuet, Clément; Lacampagne, Alain; Marks, Andrew R.

doi:10.1172/jci.insight.140614

Cited by 32 publications

(34 citation statements)

References 103 publications

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“…Leaky ryanodine receptors have recently been implicated in the neurodegenerative processes that contribute to the etiology of Alzheimer’s and Huntington’s disease 7,8 . Abnormal Ca 2+ handling can contribute to mitochondrial Ca 2+ overload, dysregulation of Ca 2+ -dependent enzymes such as AMP-activated protein kinase (AMPK), cyclin-dependent kinase 5 (CDK5), and enhanced calpain activity 7 .…”

Section: Resultsmentioning

confidence: 99%

“…This results in increased TGF-β signaling, which activates SMAD3 (phosphoSMAD3, pSMAD), this increases NOX2 expression and the amount of NOX2 associated with RyR2. Increased NOX2 activity at RyR2 oxidizes the channel causing calstabin depletion from the channel macromolecular complex, destabilization of the closed state, and ER/SR calcium leak that is known to contributes to cardiac dysfunction 4,5 , arrhythmias 28 , pulmonary insufficiency 6,8 , and cognitive and behavioral abnormalities associated with neurodegenreation 7,8 . Rycal drugs fix the RyR channel leak by restoring calstabin binding and stabilizing the channel closed state.…”

Section: Resultsmentioning

confidence: 99%

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Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

Reiken

Dridi

Sittenfeld

et al. 2021

Preprint

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COVID-19, caused by SARS-CoV-2 involves multiple organs including cardiovascular, pulmonary and central nervous system. Understanding how SARS-CoV-2 infection afflicts diverse organ systems remains challenging. Particularly vexing has been the problem posed by persistent organ dysfunction known as "long COVID", which includes cognitive impairment. Here we provide evidence linking SARS-CoV-2 infection to activation of TGF beta signaling and oxidative overload. One consequence is oxidation of the ryanodine receptor/calcium (Ca2+) release channels (RyR) on the endo/sarcoplasmic (ER/SR) reticuli in heart, lung and brains of patients who succumbed to COVID-19. This depletes the channels of the stabilizing subunit calstabin2 causing them to leak Ca2+ which can promote heart failure, pulmonary insufficiency and cognitive and behavioral defects. Ex-vivo treatment of heart, lung, and brain tissues from COVID-19 patients using a Rycal drug (ARM210) prevented calstabin2 loss and fixed the channel leak. Of particular interest is that neuropathological pathways activated downstream of leaky RyR2 channels in Alzheimer's Disease (AD) patients were activated in COVID-19 patients. Thus, leaky RyR2 Ca2+ channels may play a role in COVID-19 pathophysiology and could be a therapeutic target for amelioration of some comorbidities associated with SARS-CoV-2 infection.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

Reiken

Dridi

Sittenfeld

et al. 2021

Preprint

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“…Ca 2+ levels, the results revealed that prolonged MV activates calpain in diaphragm fibers and increased cytosolic levels of free Ca 2+ is a requirement for calpain activation (Goll et al, 2003). MV-induced activation of calpains in diaphragm fibers has since been confirmed in many studies involving both humans and animals (Whidden et al, 1985b;Maes et al, 2007;Levine et al, 2008;McClung et al, 2008;Nelson et al, 2012;Dridi et al, 2020a). Moreover, two independent studies using calpain inhibitors have demonstrated that calpain is a major contributor to VIDD (Maes et al, 2007;Nelson et al, 2012).…”

Section: Disturbances In Diaphragmatic Ca 2+ Homeostasis Is Required mentioning

confidence: 89%

“…Recently, this supposition has gained additional support from a study concluding that MV-induced mitochondrial ROS production in the diaphragm is responsible for the oxidative remodeling of the RyR1 (Dridi et al, 2020b). Specifically, using the mitochondrial-targeted antioxidant SS-31 to prevent MV-induced increases in mitochondrial ROS production, Dridi et al (2020a) provide further evidence that mitochondrial oxidative stress is responsible for oxidation of RyR1s resulting in SR Ca 2+ leak, calpain activation, and VIDD (Figure 3). Moreover, prolonged MV is also associated with increased PKA activity, which is posited to play a role in the hyperphosphorylation of the RyR1 within diaphragm fibers (Dridi et al, 2020b).…”

Section: Disturbances In Diaphragmatic Ca 2+ Homeostasis Is Required mentioning

confidence: 95%

Disturbances in Calcium Homeostasis Promotes Skeletal Muscle Atrophy: Lessons From Ventilator-Induced Diaphragm Wasting

Hyatt

Powers

2020

Front. Physiol.

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Mechanical ventilation (MV) is often a life-saving intervention for patients in respiratory failure. Unfortunately, a common and undesired consequence of prolonged MV is the development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is commonly labeled “ventilator-induced diaphragm dysfunction” (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a major risk factor for the failure to wean patients from MV; this inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. Although several processes contribute to the development of VIDD, it is clear that oxidative stress leading to the rapid activation of proteases is a primary contributor. While all major proteolytic systems likely contribute to VIDD, emerging evidence reveals that activation of the calcium-activated protease calpain plays a required role. This review highlights the signaling pathways leading to VIDD with a focus on the cellular events that promote increased cytosolic calcium levels and the subsequent activation of calpain within diaphragm muscle fibers. In particular, we discuss the emerging evidence that increased mitochondrial production of reactive oxygen species promotes oxidation of the ryanodine receptor/calcium release channel, resulting in calcium release from the sarcoplasmic reticulum, accelerated proteolysis, and VIDD. We conclude with a discussion of important and unanswered questions associated with disturbances in calcium homeostasis in diaphragm muscle fibers during prolonged MV.

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“…RyR channels are tightly packed in checkerboard arrays on the SR and exhibit cooperative activation/deactivation through the process termed coupled gating [12][13][14][15] . Leaky RyR channels are associated with numerous diseases and disorders including muscular dystrophy 16 , heart failure 17 , cardiac arrhythmias 18 , diabetes 19 , Huntington's Disease [20][21][22] , and Alzheimer's 2,3,23,24 .…”

Section: Introductionmentioning

confidence: 99%

High resolution structure of the membrane embedded skeletal muscle ryanodine receptor

Melville

Kim

Clarke

et al. 2021

Preprint

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The type 1 ryanodine receptor (RyR1)/calcium release channel on the sarcoplasmic reticulum (SR) is required for skeletal muscle excitation-contraction coupling and is the largest known ion channel, comprised of four 565 kDa protomers. Cryogenic electron microscopy (cryoEM) studies of the RyR have primarily used detergent to solubilize the channel, though a recent study resolved the structure with limited resolution in nanodiscs. In the present study we have used cryoEM to solve high-resolution structures of the channel in liposomes using a gel-filtration approach with on-column detergent removal to form liposomes and incorporate the channel simultaneously, a method that improved the incorporation rate by more than 20-fold compared to a dialysis-based approach. In conjunction with new direct-detection cameras, this allowed us to resolve the structure of the channel in the closed and open states at 3.36 and 3.98 Å, respectively. This method offers validation for detergent-based structures of the RyR and lays the groundwork for studies utilizing an electrochemical gradient mimicking the native environment, such as that of the SR, where Ca2+ concentrations are millimolar in the lumen and nanomolar in the cytosol of the cell at rest.

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Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease

Cited by 32 publications

References 103 publications

Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

Disturbances in Calcium Homeostasis Promotes Skeletal Muscle Atrophy: Lessons From Ventilator-Induced Diaphragm Wasting

High resolution structure of the membrane embedded skeletal muscle ryanodine receptor

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