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Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous RYR1 mutations

ABSTRACT: Mutations in the RYR1 gene are the most common cause of human congenital myopathies and patients with recessive mutations are severely affected and characteristically display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for RYR1 mutations. Ex vivo force production in extraocular muscles from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared to that observed in WT. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the extraocular muscle phenotype caused by compound heterozygous RYR1 mutations is due to reduced content of ryanodine and dihydropyridine receptors, the presence of fewer calcium release units and associated mitochondria as well as disorganization of myofiber structure. Additionally, the presence of the two mutations leads to the almost complete absence of the extraocular muscle-specific isoform of myosin heavy chain.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Whole Body

SUBMITTER: Alexander Schmidt

LAB HEAD: Alexander Schmidt

PROVIDER: PXD016879 | Pride | 2023-03-15

REPOSITORIES: Pride

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			Action	DRS
	000_TMT-F3_A19.raw	Raw
	001_TMT-F3_C19.raw	Raw
	002_TMT-F3_C19.raw	Raw
	003_TMT-F3_C19.raw	Raw
	004_TMT-F3_C19.raw	Raw

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