Muscle spindles exhibit core lesions and extensive degeneration of intrafusal fibers in the Ryr1I4895T/wt mouse model of core myopathy

• Muscle spindles exhibit structural abnormalities in a mouse model of core myopathy.
• Myofibrillar collapse and mitochondrial clumping is observed in intrafusal fibers.
• Myofibrillar degeneration follows a pattern similar to core formation in extrafusal myofibers.
• Muscle spindle abnormalities are a part of the pathological phenotype in the mouse model of core myopathy.
• Direct involvement of muscle spindles in the pathology of human RYR1-related myopathies is proposed.

Muscle spindles from the hind limb muscles of adult Ryr1I4895T/wt (IT/+) mice exhibit severe structural abnormalities. Up to 85% of the spindles are separated from skeletal muscle fascicles by a thick layer of connective tissue. Many intrafusal fibers exhibit degeneration, with Z-line streaming, compaction and collapse of myofibrillar bundles, mitochondrial clumping, nuclear shrinkage and pyknosis. The lesions resemble cores observed in the extrafusal myofibers of this animal model and of core myopathy patients. Spindle abnormalities precede those in extrafusal fibers, indicating that they are a primary pathological feature in this murine Ryr1-related core myopathy. Muscle spindle involvement, if confirmed for human core myopathy patients, would provide an explanation for an array of devastating clinical features characteristic of these diseases and provide novel insights into the pathology of RYR1-related myopathies.