Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
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Evaluation Summary:
The paper describes improvement in muscle phenotype of a congenital myopathy mouse model by a combined treatment with pharmacological inhibitors of Class IIa histone deacetylases and DNA methylases. The paper demonstrates in principle that there are treatment avenues to pursue but their application could be limited as phenotypic rescue appears to be restricted to particular muscle fiber types.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Abstract
To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 ( RYR1 ) gene; recessive RYR1 mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive RYR1 mutations exhibit increased content of class II histone deacetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+ p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive RYR1 mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone deacetylases. Here, we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content, and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations.
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Evaluation Summary:
The paper describes improvement in muscle phenotype of a congenital myopathy mouse model by a combined treatment with pharmacological inhibitors of Class IIa histone deacetylases and DNA methylases. The paper demonstrates in principle that there are treatment avenues to pursue but their application could be limited as phenotypic rescue appears to be restricted to particular muscle fiber types.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This is a study bearing on the longer term more trophic aspects of genetic modifications in RyR function. It welcomely provides physiological measures of the physiological outcomes of the experimental manipulations. It bears on the effects of such modifications on the important HDAC signaling pathway which modifies the extent of muscle hypertrophy and the extent to which pharmacological interventions in this pathway may rescue the resulting hypotrophic phenotype. The latter were assessed through grip strength and running distance, likely to evaluate overall muscle and isometric and dynamic function. These studies were then substantiated by measures of isometric twitch and tetanic tensions, evoked Ca2+ transients, and molecular and biochemical expression indicators. The methodology is clearly described. This …
Reviewer #1 (Public Review):
This is a study bearing on the longer term more trophic aspects of genetic modifications in RyR function. It welcomely provides physiological measures of the physiological outcomes of the experimental manipulations. It bears on the effects of such modifications on the important HDAC signaling pathway which modifies the extent of muscle hypertrophy and the extent to which pharmacological interventions in this pathway may rescue the resulting hypotrophic phenotype. The latter were assessed through grip strength and running distance, likely to evaluate overall muscle and isometric and dynamic function. These studies were then substantiated by measures of isometric twitch and tetanic tensions, evoked Ca2+ transients, and molecular and biochemical expression indicators. The methodology is clearly described. This is a broad and interesting paper.
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Reviewer #2 (Public Review):
Ruiz et al have used their previously generated mouse model of congenital myopathy caused by recessive RYR1 mutations to investigate the therapeutic effects of inhibitors of DNA methylases and histone deacetylases. They target enzymes that they have previously shown to be upregulated (at the mRNA and protein level) in this myopathy model of multi-mini core disease. Remarkably there is improvement in the muscle function as tested by grip strength and wheel running activity. Further analysis revealed that the mechanical properties of muscles was improved but this improvement was restricted to slow oxidative soleus muscles and accompanied by an increase in RyR 1 protein expression. Calcium imaging experiments performed in a distinct set of muscles suggests that the treatment restores electrically evoked calcium …
Reviewer #2 (Public Review):
Ruiz et al have used their previously generated mouse model of congenital myopathy caused by recessive RYR1 mutations to investigate the therapeutic effects of inhibitors of DNA methylases and histone deacetylases. They target enzymes that they have previously shown to be upregulated (at the mRNA and protein level) in this myopathy model of multi-mini core disease. Remarkably there is improvement in the muscle function as tested by grip strength and wheel running activity. Further analysis revealed that the mechanical properties of muscles was improved but this improvement was restricted to slow oxidative soleus muscles and accompanied by an increase in RyR 1 protein expression. Calcium imaging experiments performed in a distinct set of muscles suggests that the treatment restores electrically evoked calcium transients. The findings are important and of interest to the scientific community.
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Reviewer #3 (Public Review):
Mutations in ryanodine receptor are linked to many human diseases including muscle hypertrophy and weakness. Some of the mutations lead to reduction of the expression of the ryanodine receptor, which plays a pivotal role in control of calcium signaling during muscle contraction. Ruiz et al tested the hypothesis that epigenetic mutations in ryanodine receptor associated with muscle disease could be remedied through the use of pharmacological reagents that modulate DNA methylation and acetylation. Using a mouse model with knock-in of human mutations in RYR1, the authors demonstrated that combination of therapeutic drugs that inhibit DNA methylases and class II histone de-acetylases improve contractile function of the mutant mice. They further showed that the improved muscle function is associated with …
Reviewer #3 (Public Review):
Mutations in ryanodine receptor are linked to many human diseases including muscle hypertrophy and weakness. Some of the mutations lead to reduction of the expression of the ryanodine receptor, which plays a pivotal role in control of calcium signaling during muscle contraction. Ruiz et al tested the hypothesis that epigenetic mutations in ryanodine receptor associated with muscle disease could be remedied through the use of pharmacological reagents that modulate DNA methylation and acetylation. Using a mouse model with knock-in of human mutations in RYR1, the authors demonstrated that combination of therapeutic drugs that inhibit DNA methylases and class II histone de-acetylases improve contractile function of the mutant mice. They further showed that the improved muscle function is associated with restoration of ryanodine receptor and other calcium signaling machinery, due to changes in methylation of the target DNAs. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations.
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