Impaired muscle spindle function in murine models of muscular dystrophy

Abstract

Key points Muscular dystrophy patients suffer from progressive degeneration of skeletal muscle fibres, sudden spontaneous falls, balance problems, as well as gait and posture abnormalities. Dystrophin‐ and dysferlin‐deficient mice, models for different types of muscular dystrophy with different aetiology and molecular basis, were characterized to investigate if muscle spindle structure and function are impaired. The number and morphology of muscle spindles were unaltered in both dystrophic mouse lines but muscle spindle resting discharge and their responses to stretch were altered. In dystrophin‐deficient muscle spindles, the expression of the paralogue utrophin was substantially upregulated, potentially compensating for the dystrophin deficiency. The results suggest that muscle spindles might contribute to the motor problems observed in patients with muscular dystrophy. Abstract Muscular dystrophies comprise a heterogeneous group of hereditary diseases characterized by progressive degeneration of extrafusal muscle fibres as well as unstable gait and frequent falls. To investigate if muscle spindle function is impaired, we analysed their number, morphology and function in wildtype mice and in murine model systems for two distinct types of muscular dystrophy with very different disease aetiology, i.e. dystrophin‐ and dysferlin‐deficient mice. The total number and the overall structure of muscle spindles in soleus muscles of both dystrophic mouse mutants appeared unchanged. Immunohistochemical analyses of wildtype muscle spindles revealed a concentration of dystrophin and β‐dystroglycan in intrafusal fibres outside the region of contact with the sensory neuron. While utrophin was absent from the central part of intrafusal fibres of wildtype mice, it was substantially upregulated in dystrophin‐deficient 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, particularly at low frequencies. The response to ramp‐and‐hold stretches appeared unaltered compared to the respective wildtype mice. We observed no exacerbated functional changes in dystrophin and dysferlin double mutant mice compared to the single mutant animals. These results show alterations in muscle spindle afferent responses in both dystrophic mouse lines, which might cause an increased muscle tone, and might contribute to the unstable gait and frequent falls observed in patients with muscular dystrophy.

Muscle spindle function in healthy and diseased muscle

“…4e-g). However, utrophin expression is markedly upregulated and has a similar distribution in DMD mdx mice as dystrophin in wildtype mice [136] (Fig. 1e-j).…”

“…But, as in the corresponding patients, intrafusal fibers and sensory terminals appeared mostly spared from degeneration [44,132]. Similarly, the DMD mdx mouse line [133], a widely used model system for muscular dystrophy of the Duchenne type [134], revealed no reduction of the total number of muscle spindles and no change in the structure of muscle spindles and their sensory innervation [135,136]. Thus, compared to extrafusal muscle fibers, the morphology of intrafusal muscle fibers and of muscle spindles generally appear much less affected by the degenerative processes in humans and in mice with Duchenne-type muscular dystrophy.…”

“…Immunohistochemical analysis showed that dystrophin is present in the sarcolemma of the polar regions of intrafusal fibers [139]. In contrast, in the equatorial region, dystrophin is absent from that part of the intrafusal fiber, which is in contact with the sensory nerve terminal but concentrated in parts without sensory nerve contact [136,139] (Fig. 4a-d).…”

Muscle spindle function in muscular dystrophy: A potential target for therapeutic intervention

“…In this issue of The Journal of Physiology , Gerwin et al . (2020) address the above in an elegant new study, generating interesting results with translational potential.…”

“…For their study, Gerwin et al . (2020) used some of the common mice models of muscular dystrophies: the DMD mdx mutant mice (dystrophin‐deficient) and the SJL‐Dysf (dysferlin‐deficient) strain. Morphological analysis based on immunohistochemistry staining was followed by immunofluorescence confocal microscopy of intrafusal fibres with single unit electrophysiological recordings.…”