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Cellular and molecular alterations to muscles and neuromuscular synapses in a mouse model of MEGF10-related myopathy.
- Source :
-
Skeletal muscle [Skelet Muscle] 2024 May 17; Vol. 14 (1), pp. 10. Date of Electronic Publication: 2024 May 17. - Publication Year :
- 2024
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Abstract
- Loss-of-function mutations in MEGF10 lead to a rare and understudied neuromuscular disorder known as MEGF10-related myopathy. There are no treatments for the progressive respiratory distress, motor impairment, and structural abnormalities in muscles caused by the loss of MEGF10 function. In this study, we deployed cellular and molecular assays to obtain additional insights about MEGF10-related myopathy in juvenile, young adult, and middle-aged Megf10 knockout (KO) mice. We found fewer muscle fibers in juvenile and adult Megf10 KO mice, supporting published studies that MEGF10 regulates myogenesis by affecting satellite cell differentiation. Interestingly, muscle fibers do not exhibit morphological hallmarks of atrophy in either young adult or middle-aged Megf10 KO mice. We next examined the neuromuscular junction (NMJ), in which MEGF10 has been shown to concentrate postnatally, using light and electron microscopy. We found early and progressive degenerative features at the NMJs of Megf10 KO mice that include increased postsynaptic fragmentation and presynaptic regions not apposed by postsynaptic nicotinic acetylcholine receptors. We also found perisynaptic Schwann cells intruding into the NMJ synaptic cleft. These findings strongly suggest that the NMJ is a site of postnatal pathology in MEGF10-related myopathy. In support of these cellular observations, RNA-seq analysis revealed genes and pathways associated with myogenesis, skeletal muscle health, and NMJ stability dysregulated in Megf10 KO mice compared to wild-type mice. Altogether, these data provide new and valuable cellular and molecular insights into MEGF10-related myopathy.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Membrane Proteins genetics
Membrane Proteins metabolism
Muscular Diseases genetics
Muscular Diseases pathology
Muscular Diseases metabolism
Muscular Diseases physiopathology
Schwann Cells metabolism
Schwann Cells pathology
Muscle, Skeletal metabolism
Muscle, Skeletal pathology
Muscle, Skeletal physiopathology
Mice, Inbred C57BL
Muscle Fibers, Skeletal metabolism
Muscle Fibers, Skeletal pathology
Male
Neuromuscular Junction metabolism
Neuromuscular Junction pathology
Mice, Knockout
Disease Models, Animal
Subjects
Details
- Language :
- English
- ISSN :
- 2044-5040
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Skeletal muscle
- Publication Type :
- Academic Journal
- Accession number :
- 38760872
- Full Text :
- https://doi.org/10.1186/s13395-024-00342-6