Muscles have feelings too: muscle spindle function in normal and dystrophic muscle
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 neuromuscular diseases, movement is impaired, although the mechanism remains elusive. For example, in muscular dystrophies (MD), 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. 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. Utrophin 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. 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.
CURRICULUM VITAE Prof. Dr. STEPHAN KRÖGER
1979 – 1984 Studies of Biochemistry at the University of Tübingen
1984 „Diploma“ in Biochemistry
1984 – 1986 masters work at the Max-Planck-Institute for Developmental Biology, Tübingen
1986 – 1989 PhD thesis at the Max-Planck-Institute for Developmental Biology, Tübingen.
1989 – 1992 Postdoctoral fellow at the Department of Neurobiology, Stanford University School of Medicine.
1992 – 2000 Head of an independent research laboratory at the Max-Planck-Institute for Brain Research, Frankfurt.
2000 – 2006 Group leader at the Institute for Physiological Chemistry at the University of Mainz (Faculty of Medicine).
2006 – 2007 Associate Professor for Molecular Cell Biology at the University of Applied Sciences in Senftenberg
since 2007 Professor for Neurophysiology at the Biomedical Center (Medical School), Ludwig-Maximilians-University, Munich
Areas of Research Interests:
Molecular and cellular basis of synapse formation; pathological changes at the neuromuscular junction and in the developing CNS; role of the synapse organizer agrin at the neuromuscular junction and in the CNS; muscle spindle structure, function and development in wildtype and dystrophic mice
Selected recent Publications:
Gerwin, L., Rossmanith, S., Haupt, C., Schultheiß, J., Brinkmeier, H., Bittner, R.E., Kröger, S. (2020) Impaired Muscle Spindle Function in Murine Models of Muscular Dystrophy. J. Physiol. In press
Gerwin, L., Haupt, C., Wilkinson, K.A., and Kröger, S. (2019). Acetylcholine receptors in the equatorial region of intrafusal muscle fibres modulate mouse muscle spindle sensitivity. J Physiol 597, 1993-2006.
Handara, G., Hetsch, F.J.A., Jüttner, R., Schick, A., Haupt, C., Rathjen, F.G., and Kröger, S. (2019). The role of agrin, Lrp4 and MuSK during dendritic arborization and synaptogenesis in cultured embryonic CNS neurons. Dev Biol 445, 54-67.
Handara, G., and Kröger, S. (2019). Alternative Splicing and the Intracellular Domain Mediate TM-agrin’s Ability to Differentially Regulate the Density of Excitatory and Inhibitory Synapse-like Specializations in Developing CNS Neurons. Neuroscience 419, 60-71.
Karakatsani, A., Marichal, N., Urban, S., Kalamakis, G., Ghanem, A., Schick, A., Zhang, Y., Conzelmann, K.K., Ruegg, M.A., Berninger, B., Ruiz de Almodovar, C., Gascon, S., and Kröger, S. (2017). Neuronal LRP4 regulates synapse formation in the developing CNS. Development 144, 4604-4615.
Zhang Y., Lin S., Karakatsani A., Rüegg M., Kröger S. (2015) Differential regulation of AChR clustering in the polar and equatorial region of murine muscle spindles. European Journal of Neuroscience 41: 69-78.
Gasperi C., Melms A., Schoser B., Zhang Y., Meltoranta J., Risson V., Schaeffer L., Schalke B., Kröger S. (2014) Anti-Agrin Autoantibodies in Myasthenia gravis. Neurology 82: 1976-1983.
Zhang Y., Wesolowska M., Karakatsani A., Wizemann V., Kröger S. (2014) Formation of cholinergic synapse-like specializations at developing murine muscle spindles. Developmental Biology 393: 227-235.
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