AAV-Mediated Gene Transfer Restores a Normal Muscle Transcriptome in a Canine Model of X-Linked Myotubular Myopathy

Dupont, Jean-Baptiste; Guo, Jianjun; Renaud-Gabardos, Edith; Poulard, Karine; Latournerie, Virginie; Lawlor, Michael W.; Grange, Robert W.; Gray, John T.; Buj‐Bello, Ana; Childers, Martin K.; Mack, David L.

doi:10.1016/j.ymthe.2019.10.018

Cited by 16 publications

(7 citation statements)

References 54 publications

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“…The IGF2 receptor was previously reported to increase in dystrophic muscles and blockage of IGF2R ameliorates myopathy in mdx mice, a model of Duchenne muscular dystrophy 55 . Decreased expression of myostatin in skeletal muscles has also been reported in mouse and dog models of myotubular myopathy [56][57][58] . Taken together, our current findings and published studies highlight the role of abnormal growth signaling in different kinds of myopathies.…”

Section: Discussionmentioning

confidence: 68%

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

et al. 2023

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Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.

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Section: Discussionmentioning

confidence: 68%

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

et al. 2023

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“…For SMA, there are gene replacement (onasemnogene abeparvovec-xioi), antisense oligonucleotides (nusinersen), and small molecule therapies . The 2 clinical trials for congenital myopathy listed at ClinicalTrials.gov are gene transfer via adeno-associated virus for X-linked MTM1 myotubular myopathy (AT132) and antisense oligonucleotide knockdown of DNM2 for centronuclear myopathy (DYN101), although neither is currently enrolling neonates (Table 3). Other neuromuscular conditions that may be amenable to personalized therapies in the near future include specific pharmacological therapies for rare mitochondrial disorders and gene replacement in rare infantile cardiomyopathies owing to MYBPC3 variants .…”

Section: Discussionmentioning

confidence: 99%

Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review

et al. 2022

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he presentation of primary hypotonia in the neonatal intensive care unit (NICU) is complex to diagnose. Although our understanding of the genetic basis of hypotonia has advanced significantly in the past decade, 1-5 there remains a lag in implementation of state-of-the-art genetic testing along with variation in diagnostic approaches across institutions. Availability of effective treatments for genetic conditions, such as congenital myasthenic syndromes or spinal muscular atrophy (SMA), [6][7][8] highlights the importance of a timely diagnosis, and therapies for other hypotonic conditions will probably become available in the future. Therefore, prompt genetic diagnosis is increasingly informing clinical care decision and benefit from targeted treatments. [9][10][11][12] Here, we have developed a consensus approach to genetic testing for infants with unexplained hypotonia. Experts volunteered from 5 medical centers that are members of the International Precision Child HealthPartnership(IPCHiP):RoyalChildren'sHospital,Melbourne,

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“…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%

“…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%

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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AAV-Mediated Gene Transfer Restores a Normal Muscle Transcriptome in a Canine Model of X-Linked Myotubular Myopathy

Cited by 16 publications

References 54 publications

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review

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

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