Muscle spindle structure in a mouse model for Pompe disease

Rafuna, Andi (2025): Muscle spindle structure in a mouse model for Pompe disease. Dissertation, LMU München: Medizinische Fakultät

Abstract

Pompe disease (glycogen storage disease type II) is a rare autosomal recessive lysosomal and glycogen storage disorder, which predominantly affects the skeletal muscle, heart, and nervous system. The cause of Pompe disease are mutations in the Gaa gene encoding for the enzyme acid alpha-glucosidase (GAA), responsible for breaking down glycogen within lysosomes. Lack of the enzyme leads to enlargement and destruction of lysosomes in all tissues but most severely in skeletal muscle causing a myopathy. This explanation was considered incomplete, and another emerging mechanism for explaining Pompe disease is a disruption of the autophagic pathway. Patients with Pompe disease in addition to a progressive and generalized muscle weakness have gait and posture instability, resulting in an increased risk for falling and hospitalization. Previous studies have shown that this instability could only be partly explained by the myopathy. However, an additional reason could be that patients with Pompe disease have an altered proprioception. To address this hypothesis, I investigated the morphology of muscle spindles (the main proprioceptors) of 2.5- and 8.5-month-old Gaa-/-mice qualitatively and quantitatively, in the predominantly slow twitch soleus muscle and predominantly fast twitch extensor digitorum longus muscle. In 2.5-month-old Gaa -/- mice the muscle spindle morphology was not significantly altered compared to wildtype mice, showing only some small autophagic vacuoles. However quantitative analysis demonstrated that the circumferential elements of the sensory nerve terminals had a greater width and were shorter in length, which might be caused by glycogen storage or autophagic build-up. In the 8.5-month-old Gaa -/- mice the muscle spindles showed severe signs of degeneration, including a lack of sensory nerve terminals, disruption of intrafusal fibers, and considerable autophagic build-up. In addition, quantification of the number of muscle spindles in the soleus muscle of the 8.5-month-old Gaa -/- mice, showed a reduced number, which could be caused by the final degeneration of muscle spindles. These degenerative changes occurred in both the predominantly fast-twitch extensor digitorum longus muscle and the predominantly slow-twitch soleus muscle. Therefore, the degeneration of the muscle spindles did not appear to be dependent on the muscle fiber type composition. These findings suggest that the degeneration of the muscle spindles and the resulting proprioceptive deficits may contribute to the gait and posture instability, as well as the frequent falls in patients with Pompe disease.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Pompe disease, Muscle spindles, Proprioception, Autophagy, Glycogen storage disease type II
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 18. Februar 2025
• 1. Bericht­erstatter:in: Kröger, Stephan