N -acetylneuraminate pyruvate lyase controls sialylation of muscle glycoproteins essential for muscle regeneration and function

Deleterious variants in acetylneuraminate pyruvate lyase (NPL) cause skeletal myopathy and cardiac edema in humans and zebrafish, but its physiological role remains unknown. We report generation of mouse models of the disease: , carrying the human p.Arg63Cys variant, and with a 116-bp exonic deletio...

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Published in:Science advances 2023-06, Vol.9 (26), p.eade6308-eade6308
Main Authors: Da Silva, Afitz, Dort, Junio, Orfi, Zakaria, Pan, Xuefang, Huang, Sjanie, Kho, Ikhui, Heckel, Emilie, Muscarnera, Giacomo, van Vliet, Patrick Piet, Sturiale, Luisa, Messina, Angela, Romeo, Donata Agata, van Karnebeek, Clara D M, Wen, Xiao-Yan, Hinek, Aleksander, Molina, Thomas, Andelfinger, Gregor, Ellezam, Benjamin, Yamanaka, Yojiro, Olivos, Hernando J, Morales, Carlos R, Joyal, Jean-Sébastien, Lefeber, Dirk J, Garozzo, Domenico, Dumont, Nicolas A, Pshezhetsky, Alexey V
Format: Article
Language:English
Subjects:
Animals
Applied Sciences and Engineering
Biomedicine and Life Sciences
Disease Models, Animal
Glycoproteins
Humans
Mice
Muscle, Skeletal
N-Acetylneuraminic Acid
Pyruvates
Regeneration
SciAdv r-articles
Zebrafish
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Summary:Deleterious variants in acetylneuraminate pyruvate lyase (NPL) cause skeletal myopathy and cardiac edema in humans and zebrafish, but its physiological role remains unknown. We report generation of mouse models of the disease: , carrying the human p.Arg63Cys variant, and with a 116-bp exonic deletion. In both strains, NPL deficiency causes drastic increase in free sialic acid levels, reduction of skeletal muscle force and endurance, slower healing and smaller size of newly formed myofibers after cardiotoxin-induced muscle injury, increased glycolysis, partially impaired mitochondrial function, and aberrant sialylation of dystroglycan and mitochondrial LRP130 protein. NPL-catalyzed degradation of sialic acid in the muscle increases after fasting and injury and in human patient and mouse models with genetic muscle dystrophy, demonstrating that NPL is essential for muscle function and regeneration and serves as a general marker of muscle damage. Oral administration of acetylmannosamine rescues skeletal myopathy, as well as mitochondrial and structural abnormalities in mice, suggesting a potential treatment for human patients.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ade6308