Muscle spindle development and function in wildtype and mutant mice

• Applicant: Professor Dr. Stephan Kröger
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: from 2017 to 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329845490

• Final Report Year: 2025

Final Report Abstract

We can use the gas- and brake pedals while driving without looking at our feet and we can place our index finger on our nose with eyes closed. These kind of precision movements are made possible by special sensory organs in our musculature, which provide the brain with all the information it needs to precisely localize our extremities in space. These sensory organs are called muscle spindles. Muscle spindles are complex stretch-sensitive mechanoreceptors that are present in almost every muscle. Humans have approximately 50.000 muscle spindles. They consist of specialized muscle fibers, so called intrafusal fibers that are innervated in their central region by an afferent sensory neuron and, at both ends, by efferent -motoneurons. The efferent innervation of muscle spindles maintains the sensitivity to stretch even in a contracted muscle. Muscle spindles are by far the most important proprioceptors and inform the brain about the position and movement of our extremities in space. They are also essential components of our self-perception and responsible that we consider our extremities as part of our own body. An impaired function of muscle spindles and of proprioception in general leads to an instable gait, insecure posture and to an increased tendency to fall. About one-third of the population aged 65 years and over will fall in a year - a quarter of those fallings will suffer a life-changing injury. In Europe, the health and social care costs of falls sum up to approximately €25 billion each year. Falls are therefore a major concern for medical and social systems. Persons with neuromuscular diseases have an increased risk for falls. For this group, falls are particularly devastating, because the subsequent hospitalization is accompanied by an immobilization leading to an increased muscular atrophy. For patients that already have a loss of muscle mass due to their disease, additional muscle loss can be life threatening. In this proposal, we analyzed among others muscle spindles and coordinated movements in murine models for muscle dystrophy, Pompe disease and for Friedreich ataxia. All mouse lines recapitulate many symptoms of patients with muscular dystrophy or Friedreich Ataxia in mice – although at different precision. The investigations have significantly increased our understanding of muscle spindles in neuromuscular diseases. Moreover, they might lead to novel therapeutic strategies in patients.

Publications

• Proprioception 2.0: novel functions for muscle spindles. Current Opinion in Neurology, 31(5), 592-598.
  Kröger, Stephan
  
• Acetylcholine receptors in the equatorial region of intrafusal muscle fibres modulate mouse muscle spindle sensitivity. The Journal of Physiology, 597(7), 1993-2006.
  Gerwin, Laura; Haupt, Corinna; Wilkinson, Katherine A. & Kröger, Stephan
  
• Impaired muscle spindle function in murine models of muscular dystrophy. The Journal of Physiology, 598(8), 1591-1609.
  Gerwin, Laura; Rossmanith, Sarah; Haupt, Corinna; Schultheiß, Jürgen; Brinkmeier, Heinrich; Bittner, Reginald E. & Kröger, Stephan
  
• Methocarbamol blocks muscular Nav1.4 channels and decreases isometric force of mouse muscles. Muscle & Nerve, 63(1), 141-150.
  Zhang, Yaxin; Otto, Philipp; Qin, Lu; Eiber, Nane; Hashemolhosseini, Said; Kröger, Stephan & Brinkmeier, Heinrich
  
• The effect of methocarbamol and mexiletine on murine muscle spindle function. Muscle & Nerve, 66(1), 96-105.
  Watkins, Bridgette; Schuster, Hedwig M.; Gerwin, Laura; Schoser, Benedikt & Kröger, Stephan
  
• Degeneration of muscle spindles in a murine model of Pompe disease. Scientific Reports, 13(1).
  Watkins, Bridgette; Schultheiß, Jürgen; Rafuna, Andi; Hintze, Stefan; Meinke, Peter; Schoser, Benedikt & Kröger, Stephan
  
• The mechanosensitive ion channel ASIC2 mediates both proprioceptive sensing and spinal alignment. Experimental Physiology, 109(1), 135-147.
  Bornstein, Bavat; Watkins, Bridgette; Passini, Fabian S.; Blecher, Ronen; Assaraf, Eran; Sui, Xiao Meng; Brumfeld, Vlad; Tsoory, Michael; Kröger, Stephan & Zelzer, Elazar
  
• Experimental physiology Special Issue: ‘Mechanotransduction, muscle spindles and proprioception’. Experimental Physiology, 110(10), 1383-1388.
  Kröger, Stephan