Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies

Djeddi, Sarah; Reiss, David J; Menuet, Alexia; Freismuth, S.; Neves, Juliana de Carvalho; Djerroud, Sarah; Massana-Muñoz, Xènia; Sosson, A.; Kretz, Christine; Raffelsberger, Wolfgang; Keime, Céline; Dorchies, O.M.; Thompson, Julie; Laporte, Jocelyn

doi:10.1016/j.ymthe.2021.04.033

Cited by 17 publications

(25 citation statements)

References 77 publications

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“…However, it has been investigated in Bin1 ex11 −/− mice, which displayed a slower regeneration after muscle damage, potentially due to the reduced pool of SCs found in this mouse [ 131 ]. A defective muscle regeneration pathway was also recently suggested from the common CNM transcriptomic signature ( Mtm1 −/y , Dnm2 R465W/+ and Bin1e x20 mck−/− )[ 153 ] and may be related to the observed activation of the inflammatory pathway [ 234 ]. Further studies will be needed to determine the specific mechanism implicating the CNM genes in SC survival and functions.…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 97%

“…In the past years, in-depth studies of patients and cellular and animal models have led to a better understanding of the mechanisms involved in the different CNM forms, and highlighted common altered pathways ( Figure 3 ). Moreover, transcriptomic studies of CNM mouse and dog models were able to underline a common disease signature and potential biomarkers [ 153 , 154 ]. A better understanding of the pathomechanisms is useful to identify therapeutic targets.…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

“…It would be interesting to check whether BIN1 deficiency has any impact on NMJ formation and maintenance in other models and in CNM patients. We can expect to observe some defects as transcriptomic analysis of Dnm2 S619L/+ , BIN1ex20 mck−/− , and Mtm1 −/y mice showed upregulation in the expression of acetylcholine receptor subunits ( Chrna1 , Chrna9 , Chrnd ) [ 153 ]. Dysregulation of these genes was also observed in XLMTM patients [ 229 ] and MTM1 dogs [ 154 ].…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

“…The genetic and AAV-mediated overexpression of human BIN1 rescued lifespan and improved muscle force and histological defects. It also led to a striking rescue of the Mtm1 −/y muscle transcriptome [ 153 ]. As with DNM2 downregulation, this study strengthens the “cross-therapy” rationale, where the modulation of one CNM gene ( BIN1 ) can rescue the loss of another CNM gene ( MTM1 ).…”

Section: Therapeutic Targets In Cnmmentioning

confidence: 99%

“…Then, in 2018, two parallel independent studies showed the efficacy of tamoxifen treatment to prolong survival and improve muscle force and histology of Mtm1 −/y mice [ 221 , 249 ]. The exact mechanism of therapeutic rescue is not yet known, but it is not thought to be mediated by transcriptional modulation via an estrogen receptor as minimal transcriptional changes were observed after tamoxifen treatment [ 153 , 221 ]. Both studies showed normalization of the DNM2 protein levels, and as described in the UPS section, tamoxifen was proposed as a possible modulator of the DNM2 protein levels [ 221 ].…”

Section: Therapeutic Targets In Cnmmentioning

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: Common Pathomechanisms Of Cnmsmentioning

confidence: 97%

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

Section: Therapeutic Targets In Cnmmentioning

confidence: 99%

Section: Therapeutic Targets In Cnmmentioning

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

Self Cite

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Integrated multi‐omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex

Li,

Lin,

Luo

et al. 2024

J cachexia sarcopenia muscle

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BackgroundAutosomal‐recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation–contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi‐omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions.MethodsSkeletal muscles from 2‐month‐old SPEG‐deficient (Speg‐CKO) and wild‐type (WT) mice were used for RNA sequencing (n = 4 per genotype) to profile transcriptomics and mass spectrometry (n = 4 for WT; n = 3 for Speg‐CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and Speg‐CKO mice. Based on the multi‐omics results, we performed quantitative real‐time PCR, co‐immunoprecipitation and immunoblot to verify the findings.ResultsWe identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22 ± 3% for CMYA5 [P < 0.05] and 18 ± 3% for FSD2 [P < 0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55 ± 15% at S2902 in Speg‐CKO mice; P < 0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90 ± 0.24‐fold], S162 [1.61 ± 0.37‐fold] and S165 [1.66 ± 0.13‐fold]; decreased phosphorylation at S228 and S231 [39 ± 6%], S234 [50 ± 12%], S593 [48 ± 3%] and S613 [66 ± 10%]; P < 0.05 for S162 and P < 0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix–receptor interaction (P < 1e−15) and peroxisome proliferator‐activated receptor signalling (P < 9e−14).ConclusionsWe have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of various residues in JPH2 and S2902 in RyR1, and its deficiency is associated with dysregulation of several pathways. The study identifies unique SPEG‐interacting proteins and their phosphorylation functions and emphasizes the importance of using a multi‐omics approach to comprehensively evaluate the molecular function of proteins involved in various genetic disorders.

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Potential compensatory mechanisms preserving cardiac function in myotubular myopathy

Simon,

Diedhiou,

Reiss

et al. 2024

Cell. Mol. Life Sci.

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X-Linked myotubular myopathy (XLMTM) is characterized by severe skeletal muscle weakness and reduced life expectancy. The pathomechanism and the impact of non-muscular defects affecting survival, such as liver dysfunction, are poorly understood. Here, we investigated organ-specific effects of XLMTM using the Mtm1−/y mouse model. We performed RNA-sequencing to identify a common mechanism in different skeletal muscles, and to explore potential phenotypes and compensatory mechanisms in the heart and the liver. The cardiac and hepatic function and structural integrity were assessed both in vivo and in vitro. Our findings revealed no defects in liver function or morphology. A disease signature common to several skeletal muscles highlighted dysregulation of muscle development, inflammation, cell adhesion and oxidative phosphorylation as key pathomechanisms. The heart displayed only mild functional alterations without obvious structural defects. Transcriptomic analyses revealed an opposite dysregulation of mitochondrial function, cell adhesion and beta integrin trafficking pathways in cardiac muscle compared to skeletal muscles. Despite this dysregulation, biochemical and cellular experiments demonstrated that these pathways were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3P and dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data suggest a compensatory mechanism preserving cardiac function, pointing to potential therapeutic targets to cure the severe skeletal muscle defects in XLMTM.

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Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies

Cited by 17 publications

References 77 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

Integrated multi‐omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex

Potential compensatory mechanisms preserving cardiac function in myotubular myopathy

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