Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function.

Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.

Zebrafish heart failure models: opportunities and challenges.

Heart failure is a complex pathophysiological syndrome of pumping functional failure that results from injury, infection or toxin-induced damage on the myocardium, as well as genetic influence. Gene mutations associated with cardiomyopathies can lead to various pathologies of heart failure. In recent years, zebrafish, Danio rerio, has emerged as an excellent model to study human cardiovascular diseases such as congenital heart defects, cardiomyopathy, and preclinical development of drugs targeting these diseases. In this review, we will first summarize zebrafish genetic models of heart failure arose from cardiomyopathy, which is caused by mutations in sarcomere, calcium or mitochondrial-associated genes. Moreover, we outline zebrafish heart failure models triggered by chemical compounds. Elucidation of these models will improve the understanding of the mechanism of pathogenesis and provide potential targets for novel therapies.

Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: clues to the EMPA-REG OUTCOME trial?

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin was recently reported to reduce heart failure-associated hospitalizations and cardiovascular mortality amongst individuals with type 2 diabetes at high cardiovascular risk. We sought to elucidate the underlying mechanism(s) for these protective effects using a validated zebrafish heart failure model to evaluate the impact of empagliflozin on the expression of biomarkers of heart failure and mortality. We used aristolochic acid (AA) to induce heart failure in developing cmlc2::GFP transgenic zebrafish embryos and monitored BNP signaling in nppb::Luc transgenic zebrafish with a luciferase reporter assay. Empagliflozin markedly reduced the morphological and functional cardiac changes induced by AA; dampened AA-enhanced expression of brain natriuretic peptide and atrial natriuretic peptide; and reduced embryonic mortality. Furthermore, morpholino-mediated knockdown of the slc5A2 gene mimicked the changes evoked by empagliflozin in developing zebrafish embryos previously exposed to AA. We report herein the first mechanistic data demonstrating a salutary benefit of SGLT2 inhibition on critical pathways of heart failure signaling. These findings provide important translational clues to the cardiovascular benefits documented in the EMPA-REG OUTCOME study.