Altered muscle spindle responses to stretch in murine models of muscular dystrophy.

Coordinated movements, including locomotion, and their control, require proprioceptive information, i.e. information about muscle tone as well as position and movement of the extremities in space. Muscle spindles are the primary proprioceptive sensory receptors and are present in almost all skeletal muscles. In many diseases, proprioception is impaired, although the mechanism remains elusive. For example, in muscular dystrophies (MD), which comprise a heterogeneous group of hereditary diseases characterized by progressive degeneration and weakness of extrafusal muscle fibers, patients often experience sudden spontaneous falls, balance problems, as well as gait and posture abnormalities, suggesting the possibility of an impaired muscle spindle function. To investigate, if proprioception is affected in dystrophic muscles, we analyzed muscle spindle number, morphology and function in wildtype mice and in murine models for two distinct types of muscular dystrophy with very different disease etiology, i.e. dystrophin- (DMDmdx) and dysferlin-deficient mice. Utrophin-deficient mice (utrn-/-) have a very mild phenotype and only subtle changes in skeletal muscle tissue, and were included in the analysis as models for very mild forms of muscular dystrophy. The total number and the overall structure of muscle spindles in soleus muscles of the dystrophic mice appeared unchanged, demonstrating that intrafusal fibers are less affected by the degeneration compared to extrafusal fibers. Immunohistochemical analyses of wildtype muscle spindles revealed a concentration of dystrophin and b-dystroglycan in intrafusal fibers outside the region of contact to the sensory neuron. While utrophin was absent from the central part of intrafusal fibers of wildtype mice, it was substantially upregulated in dystrophin-deficient mice, suggesting a potential compensatory activity of utrophin in DMDmdx mice. Single-unit extracellular recordings of sensory afferents from muscle spindles of the extensor digitorum longus muscle revealed that muscle spindles from both dystrophic mouse strains have an increased resting discharge and a higher action potential firing rate during sinusoidal vibrations. In contrast, the response to ramp-and-hold stretches appeared mostly unaltered compared to the respective wildtype mice. We observed no exacerbated functional changes in DMDmdx and dysferlin double knockout mice compared to the respective single knockout animals. These results show alterations in muscle spindle afferent responses in dystrophic mouse muscles, which might cause an increased muscle tone, and might contribute to the unstable gait and frequent falls observed in patients with muscular dystrophy.