In vivo RyR1 reduction in muscle triggers a core-like myopathy

Pelletier, Laurent; Petiot, Anne; Brocard, Julie; Giannesini, Benoı̂t; Giovannini, Diane; Sanchez, Colline; Travard, Lauriane; Chivet, Mathilde; Beaufils, Mathilde; Kutchukian, Candice; Bendahan, David; Metzger, Daniel; Armstrong, Courtney; Romero, Norma B.; Rendu, John; Jacquemond, Vincent; Fauré, Julien; Marty, Isabelle

doi:10.1186/s40478-020-01068-4

Cited by 11 publications

(22 citation statements)

References 45 publications

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“…A severe decline in muscle mass as well as skeletal muscle abnormalities including abnormal junctions between SR to T-tubules was observed [ 147 ]. Recently, inducible skeletal muscle specific Ryr1 deletion ( Ryr1-Rec) at the adult stage was characterized [ 43 ]. Protein level was reduced to maximum 50% of the initial level, with more pronounced reduction in mRNA (80%).…”

Section: Ryr1 and Autosomal Recessive Centronuclear Myopathymentioning

confidence: 99%

“…Similarly, the recessive Ryr1 Q1970fsX16/A4329D mouse model showed reduced electrically evoked Ca 2+ currents, although no changes in DHPR protein expression were found [ 145 ]. In Ryr1-Rec mouse (muscle-specific Ryr1 deletion), the current via DHPR and the calcium influx via RyR1 were both reduced, while no changes in DHPR expression or alterations in the T-tubule network and density were noted [ 43 ]. This apparent discrepancy may be explained by a “retrograde coupling” where RYR1 controls DHPR function [ 159 ].…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

“…Specifically, desmin anchors several structures (mitochondria, nucleus, and Z-disk) to the sarcolemma cytoskeleton at the costamere and regulates peripheral nuclei positioning in myofibers [ 182 ]. Desmin localization and expression were found to be commonly dysregulated in patients with mutations in DNM2 [ 22 , 109 ], MTM1 [ 22 , 31 , 32 ], BIN1 [ 22 ], and RYR1 [ 43 ]. Desmin accumulated in the center of the myofibers.…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

“…This abnormal desmin localization was also observed in muscle from Bin1e x20 mck−/− and also rescued after DNM2 reduction [ 135 ]. Finally, desmin protein increase and abnormal central accumulation were also found in muscle fibers from the Ryr1 -Rec mouse line with adult deletion of Ryr1 [ 43 ].…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

“…In addition, ultrastructural studies in Bin1e x20 mck−/− mice revealed the accumulation of autophagosomes confirmed by LC3 staining in muscle sections [ 135 ]. Concerning RYR1, increased LC3II and p62 protein levels, together with mTORC1 overactivation and inhibition of autophagy flux, were observed in the Ryr1-Rec mice [ 43 ]. Dysregulation of cytoplasmic calcium may affect autophagy [ 218 ].…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

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Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Gómez-Oca

Cowling²,

Laporte

2021

IJMS

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Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.

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Section: Ryr1 and Autosomal Recessive Centronuclear Myopathymentioning

confidence: 99%

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

See 3 more Smart Citations

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Gómez-Oca

Cowling²,

Laporte

2021

IJMS

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Ryanodine receptor type 1 content decrease‐induced endoplasmic reticulum stress is a hallmark of myopathies

Vidal,

Fernandez,

Wohlwend

et al. 2023

J cachexia sarcopenia muscle

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BackgroundDecreased ryanodine receptor type 1 (RyR1) protein levels are a well‐described feature of recessive RYR1‐related myopathies. The aim of the present study was twofold: (1) to determine whether RyR1 content is also decreased in other myopathies and (2) to investigate the mechanisms by which decreased RyR1 protein triggers muscular disorders.MethodsWe used publicly available datasets, muscles from human inflammatory and mitochondrial myopathies, an inducible muscle‐specific RYR1 recessive mouse model and RyR1 knockdown in C2C12 muscle cells to measure RyR1 content and endoplasmic reticulum (ER) stress markers. Proteomics, lipidomics, molecular biology and transmission electron microscopy approaches were used to decipher the alterations associated with the reduction of RyR1 protein levels.ResultsRYR1 transcripts were reduced in muscle samples of patients suffering from necrotizing myopathy (P = 0.026), inclusion body myopathy (P = 0.003), polymyositis (P < 0.001) and juvenile dermatomyositis (P < 0.001) and in muscle samples of myotonic dystrophy type 2 (P < 0.001), presymptomatic (P < 0.001) and symptomatic (P < 0.001) Duchenne muscular dystrophy, Becker muscular dystrophy (P = 0.004) and limb‐girdle muscular dystrophy type 2A (P = 0.004). RyR1 protein content was also significantly decreased in inflammatory myopathy (−75%, P < 0.001) and mitochondrial myopathy (−71%, P < 0.001) muscles. Proteomics data showed that depletion of RyR1 protein in C2C12 myoblasts leads to myotubes recapitulating the common molecular alterations observed in myopathies. Mechanistically, RyR1 protein depletion reduces ER–mitochondria contact length (−26%, P < 0.001), Ca2+ transfer to mitochondria (−48%, P = 0.002) and the mitophagy gene Parkinson protein 2 transcripts (P = 0.037) and induces mitochondrial accumulation (+99%, P = 0.005) and dysfunction (P < 0.001). This was associated to the accumulation of deleterious sphingolipid species. Our data showed increased levels of the ER stress marker chaperone‐binding protein/glucose regulated protein 78, GRP78‐Bip, in RyR1 knockdown myotubes (+45%, P = 0.046), in mouse RyR1 recessive muscles (+58%, P = 0.001) and in human inflammatory (+96%, P = 0.006) and mitochondrial (+64%, P = 0.049) myopathy muscles. This was accompanied by increased protein levels of the pro‐apoptotic protein CCAAT‐enhancer‐binding protein homologous protein, CHOP‐DDIT3, in RyR1 knockdown myotubes (+27%, P < 0.001), mouse RyR1 recessive muscles (+63%, P = 0.009), human inflammatory (+50%, P = 0.038) and mitochondrial (+51%, P = 0.035) myopathy muscles. In publicly available datasets, the decrease in RYR1 content in myopathies was also associated to increased ER stress markers and RYR1 transcript levels are inversely correlated with ER stress markers in the control population.ConclusionsDecreased RyR1 is commonly observed in myopathies and associated to ER stress in vitro, in mouse muscle and in human myopathy muscles, suggesting a potent role of RyR1 depletion‐induced ER stress in the pathogenesis of myopathies.

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Rapid small-scale nanobody-assisted purification of ryanodine receptors for cryo-EM

Li,

Willegems,

Uchański

et al. 2024

Journal of Biological Chemistry

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In vivo RyR1 reduction in muscle triggers a core-like myopathy

Cited by 11 publications

References 45 publications

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Ryanodine receptor type 1 content decrease‐induced endoplasmic reticulum stress is a hallmark of myopathies

Rapid small-scale nanobody-assisted purification of ryanodine receptors for cryo-EM

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