Intracellular calcium leak as a therapeutic target for RYR1-related myopathies

Kushnir, Alexander; Todd, Joshua J.; Witherspoon, J.; Yuan, Qi; Reiken, Steven; Lin, Harvey H.; Munce, Ross H.; Wajsberg, Benjamin; Melville, Zephan; Clarke, Oliver; Wedderburn-Pugh, Kaylee; Wronska, Anetta; Razaqyar, M.; Chrismer, Irene C; Shelton, M.; Mankodi, Ami; Grunseich, Christopher; Tarnopolsky, Mark A.; Tanji, Kurenai; Hirano, Michio; Riazi, Sheila; Kraeva, Natalia; Voermans, Nicol C.; Gruber, Angela; Allen, Carolyn; Meilleur, K.; Marks, Andrew R.

doi:10.1007/s00401-020-02150-w

Cited by 36 publications

(46 citation statements)

References 44 publications

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“…This depletes the channels of the stabilizing subunit calstabin2 causing them to leak Ca 2+ which can promote heart failure 4,5 , pulmonary insufficiency 6 and cognitive and behavioral defects 7–9 . Ex-vivo treatment of heart, lung, and brain tissues from COVID-19 patients using a Rycal drug (ARM210) 10 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.…”

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confidence: 99%

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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confidence: 99%

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

Reiken

Dridi

Sittenfeld

et al. 2021

Preprint

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“…Bellinger et al demonstrated that hypernitrosylated ryanodine receptors in mdx mice are leaky in handling Ca 2+ [ 47 ]. Moreover, Rycal, an RYR Ca 2+ release channel stabilizer, improves muscle fiber function in mdx mice, and Rycal ARM210/S48168 has been used in a clinical stage program [ 48 ]. However, although Ca 2+ overload conditions have been recapitulated in vitro using human cells [ 19 , 36 ], whether Ca 2+ overload conditions lead to the functional phenotype in human models remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Orai1–STIM1 Regulates Increased Ca2+ Mobilization, Leading to Contractile Duchenne Muscular Dystrophy Phenotypes in Patient-Derived Induced Pluripotent Stem Cells

Uchimura

Sakurai

2021

Biomedicines

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Ca2+ overload is one of the factors leading to Duchenne muscular dystrophy (DMD) pathogenesis. However, the molecular targets of dystrophin deficiency-dependent Ca2+ overload and the correlation between Ca2+ overload and contractile DMD phenotypes in in vitro human models remain largely elusive. In this study, we utilized DMD patient-derived induced pluripotent stem cells (iPSCs) to differentiate myotubes using doxycycline-inducible MyoD overexpression, and searched for a target molecule that mediates dystrophin deficiency-dependent Ca2+ overload using commercially available chemicals and siRNAs. We found that several store-operated Ca2+ channel (SOC) inhibitors effectively prevented Ca2+ overload and identified that STIM1–Orai1 is a molecular target of SOCs. These findings were further confirmed by demonstrating that STIM1–Orai1 inhibitors, CM4620, AnCoA4, and GSK797A, prevented Ca2+ overload in dystrophic myotubes. Finally, we evaluated CM4620, AnCoA4, and GSK7975A activities using a previously reported model recapitulating a muscle fatigue-like decline in contractile performance in DMD. All three chemicals ameliorated the decline in contractile performance, indicating that modulating STIM1–Orai1-mediated Ca2+ overload is effective in rescuing contractile phenotypes. In conclusion, SOCs are major contributors to dystrophin deficiency-dependent Ca2+ overload through STIM1–Orai1 as molecular mediators. Modulating STIM1–Orai1 activity was effective in ameliorating the decline in contractile performance in DMD.

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“…RYR1-RD is characterized by pleotropic clinical presentations ranging from mild to severe muscle weakness, and moderate to severe respiratory insufficiency, which is more often apparent in recessive cases. Some mutations in RYR1 (19q13.2) result in leaky channels that promote muscle weakness and damage in RyR1 -RD patients [ 27 ]. Although there are currently no approved treatments, a clinical trial using a novel Rycal drug that fixes the leak in RyR1 channels is currently underway at the NIH (NCT04141670).…”

Section: Introductionmentioning

confidence: 99%

“…The RyR1 macromolecular complex includes calstabin [ 43 , 45 , 69 , 74 ], PKA [ 52 ], CaMKIIδ [ 26 , 70 ], the phosphatases PP1 and PP2A [ 15 , 42 ], the phosphodiesterase PDE4D3 [ 32 , 57 ], sorcin [ 19 ], calmodulin [ 49 , 51 , 53 , 66 , 78 ], triadin [ 55 ], junction [ 33 ], and calsequestrin [ 4 ]. RyR channels are regulated by posttranslational modifications including phosphorylation [ 27 , 44 , 45 ], oxidation [ 2 , 59 , 60 ], and nitrosylation [ 5 ]. RyR channels exhibit a bell-shaped response to cytosolic Ca 2+ , with activation at micromolar levels and inhibition at millimolar concentrations [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation

Yuan

Dridi

Clarke

et al. 2021

acta neuropathol commun

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The type 1 ryanodine receptor (RyR1) is an intracellular calcium (Ca2+) release channel on the sarcoplasmic/endoplasmic reticulum that is required for skeletal muscle contraction. RyR1 channel activity is modulated by ligands, including the activators Ca2+ and ATP. Patients with inherited mutations in RyR1 may exhibit muscle weakness as part of a heterogeneous, complex disorder known as RYR1-related myopathy (RYR1-RM) or more recently termed RYR1-related disorders (RYR1-RD). Guided by high-resolution structures of skeletal muscle RyR1, obtained using cryogenic electron microscopy, we introduced mutations into putative Ca2+ and ATP binding sites and studied the function of the resulting mutant channels. These mutations confirmed the functional significance of the Ca2+ and ATP binding sites identified by structural studies based on the effects on channel regulation. Under normal conditions, Ca2+ activates RyR1 at low concentrations (µM) and inhibits it at high concentrations (mM). Mutations in the Ca2+-binding site impaired both activating and inhibitory regulation of the channel, suggesting a single site for both high and low affinity Ca2+-dependent regulation of RyR1 function. Mutation of residues that interact with the adenine ring of ATP abrogated ATP binding to the channel, whereas mutating residues that interact with the triphosphate tail only affected the degree of activation. In addition, patients with mutations at the Ca2+ or ATP binding sites suffer from muscle weakness, therefore impaired RyR1 channel regulation by either Ca2+ or ATP may contribute to the pathophysiology of RYR1-RM in some patients.

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Intracellular calcium leak as a therapeutic target for RYR1-related myopathies

Cited by 36 publications

References 44 publications

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

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

Orai1–STIM1 Regulates Increased Ca2+ Mobilization, Leading to Contractile Duchenne Muscular Dystrophy Phenotypes in Patient-Derived Induced Pluripotent Stem Cells

RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation

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