MassIVE MSV000095435

Partial Public PXD054222

Reduction of RyR1 expression in muscle spindles causes alterations of the proprioceptive properties and scoliosis in mice carrying recessive Ryr1 mutations

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Description

Muscle spindles are stretch receptors lying deep within the muscle belly involved in detecting changes in muscle length and playing a fundamental role in motor control, posture and synchronized gait. They are made up of an external capsule surrounding 3-5 intrafusal muscle fibers and a nuclear bag complex. Dysfunction of muscle spindles leads to abnormal muscle tone, poor limb coordination and abnormal proprioceptor function. The latter has been linked to aberrant bone and cartilage development, scoliosis, kyphosis and joint contractures. Congenital myopathies are often accompanied by skeletal alterations and joint contractures but so far the link between genetic mutations and altered muscle spindle function has not been explored. In the present study we investigated whether mutations in RyR1, the calcium release channel of the sarcoplasmic reticulum and the most common cause of human congenital myopathies, cause alterations of muscle spindles. To this end we investigated dHT mice an animal model we created carrying recessive Ryr1 mutations isogenic to those present in a severely affected child. Here we show that (i) the RyR1 protein is expressed at the polar regions of intrafusal fibers and exhibits a doubled row distribution pattern, typical for junctional sarcoplasmic reticulum proteins, and (ii) its content in intrafusal muscle fibers from dHT mice is reduced by 64%. Such a massive reduction of mutant RyR1 leads to severe scoliosis, altered expression of proteins in intrafusal muscle fibers and is paralleled by a decreased balance and inter limb coordination. These results support the hypothesis that RYR1 mutations not only affect the function of extrafusal muscles, but might also affect that of intrafusal muscles. The latter may be one of the underlying causes of skeletal abnormalities seen in patients affected by recessive RYR1 mutations. [doi:10.25345/C50P0X29T] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Ryanodine receptor 1 ; congenital myopathies ; muscle spindles ; intrafusal muscle fibers

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Principal Investigators:
(in alphabetical order) 		Susan Treves, University of Basel, Switzerland
Submitting User: katarzynabuczak
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