Cellular and molecular alterations to muscles and neuromuscular synapses in a mouse model of MEGF10-related myopathy

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 stu...

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Bibliographic Details
Published in:	Skeletal muscle Vol. 14; no. 1; p. 10
Main Authors:	Juros, Devin, Avila, Mary Flordelys, Hastings, Robert Louis, Pendragon, Ariane, Wilson, Liam, Kay, Jeremy, Valdez, Gregorio
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 17-05-2024 BioMed Central BMC
Subjects:	Animals Cell differentiation Disease Models, Animal Male Megf10 Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Inbred C57BL Mice, Knockout Muscle Fibers, Skeletal - metabolism Muscle Fibers, Skeletal - pathology Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Muscle, Skeletal - physiopathology Muscles Muscular Diseases - genetics Muscular Diseases - metabolism Muscular Diseases - pathology Muscular Diseases - physiopathology Myogenesis Myopathy Neuromuscular junction Neuromuscular Junction - metabolism Neuromuscular Junction - pathology Perisynaptic Schwann cells Schwann Cells - metabolism Schwann Cells - pathology Megf10 Neuromuscular junction Myogenesis Perisynaptic Schwann cells Myopathy
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2044-5040 2044-5040
DOI:	10.1186/s13395-024-00342-6