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

Abstract

Deleterious variants in N- 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: Npl R63C , carrying the human p.Arg63Cys variant, and Npl del116 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 N- acetylmannosamine rescues skeletal myopathy, as well as mitochondrial and structural abnormalities in Npl R63C mice, suggesting a potential treatment for human patients.

Serum proteomic biomarker investigation of vascular depression using data-independent acquisition: a pilot study

“…Because of the links between risk factors for endothelial damage (i.e., hyperglycemia, hypertension, metabolic disorders) and depression, endothelial dysfunction may increase the vulnerability to VaD ( Virtanen et al, 2017 ). NPL is a metabolic protein, involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway ( Da Silva et al, 2023 ). Overexpression of Neu5Gc in the brain resulted in abnormal axon myelination and impaired memory ( Naito-Matsui et al, 2017 ).…”

Severe kidney dysfunction in sialidosis mice reveals an essential role for neuraminidase 1 in reabsorption

“…Analysis of kidney protein N-glycosylation by MALDI-TOF MS and glycosylation by lectin blotting was conducted essentially as described with or without PNGaseF treatment ( 37 , 69 ). For the analysis of kidney tissues and bones by histochemistry, lectin histochemistry, immunohistochemistry, and TEM, mice were anesthetized with sodium pentobarbital and fixed by intracardiac perfusion with 4% paraformaldehyde (histochemistry) or 2% glutaraldehyde (TEM), and their tissues processed essentially as described ( 69 , 70 ). Semiquantitative analysis of kidney proteins by LC-MS/MS was performed as described ( 71 ).…”

Electrophilicity Modulation for Sub‐ppm Visualization and Discrimination of EDA

“…Organic amines have a diverse range of applications, [ 1 , 2 ] especially as one of the major raw materials in manufacturing pharmaceuticals, pesticides, dyes, paints, etc. [ 3 , 4 ] For instance, ethylenediamine (EDA) [ 5 ] and hydrazine [ 6 ] act as a primary ingredient for producing the smooth muscle relaxant aminophylline and anti‐tuberculosis drugs methyldopa, while aniline and naphthylamine fall under the crucial raw materials category for preparing azo dye. [ 7 ] Whereas, a portion of organic amines are listed as hazardous materials as their presence poses a severe threat to public security, human health, and environment sustainability due to their inherent toxicity, corrosivity, volatility, combustible and explosible properties.…”