Muscle spindle development and function in wildtype and mutant mice

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Muscle spindles are complex stretch-sensitive mechanoreceptors present in almost every muscle. They consist of specialized skeletal muscle fibers, called intrafusal fibers, which are innervated in the central (equatorial) region by afferent sensory axons and in both polar regions by efferent -motoneurons. Muscle spindles are stretch detectors and generate action potentials with frequencies proportional to the amount of stretch as well as to the speed of stretching. Muscle spindles are the main proprioceptors in our body and provide the CNS with information about the position and movement of our extremities in space. While the general function of muscle spindles has been rather well described, the molecular basis of this function and the pathological changes of muscle spindles are mostly unknown. In this proposal, we want to extend our studies on the molecular basis of muscle spindle function in wildtype and mutant mice by specifically addressing two questions. We want to determine a) the role of a direct molecular connection between sensory neuron and intrafusal fiber via desmosomes by analyzing mice with a skeletal muscle-specific deletion of two desmosomal proteins and b) investigate the degeneration and regeneration of the muscle spindle’s sensory innervation in a mouse model for Friedreich Ataxia. To address the first question, we have generated mice with a skeletal muscle-specific knockout of desmoglein-2 and plakoglobin, two components of desmosomes expressed in muscle spindles. Muscle spindles from these mice will be analyzed by electrophysiology, behavioral tests and confocal microscopy to determine functional and structural changes. The same methods will be used to analyze a mouse model for Friedreich Ataxia. These mice have a sensory neuron-specific inactivation of the frataxin gene, which leads to a degeneration of the sensory nerve terminal in muscle spindles and subsequently to problems in motor control and ataxia. Reexpression of frataxin in post-symptomatic animals by injection of an adeno-associated virus harboring the frataxin cDNA results in a regeneration of the sensory innervation and an amelioration of the motor control problems and the ataxia. Thus, these mice represent a model well suited to investigate de- and regeneration of sensory innervation of adult intrafusal fibers without compromised fusimotor control and without surgery and subsequent scar formation. Together these studies will considerably enhance our understanding of the molecular mechanisms responsible for muscle spindle function and might lead to potential therapeutic strategies for patients with Friedreich Ataxia.