scholarly journals P.068 Abnormal fatty acid metabolism is a feature of spinal muscular atrophy

2019 ◽  
Vol 46 (s1) ◽  
pp. S32
Author(s):  
M Deguise ◽  
A Beauvais ◽  
G Baranello ◽  
C Pileggi ◽  
C Mastella ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
High Resolution ◽  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Liver Steatosis ◽  
Neuromuscular Disorder ◽  
Glycogen Depletion ◽  
Preclinical Animal Models

Background: Spinal muscular atrophy (SMA) is a children’s neuromuscular disorder. Although motor neuron loss is a major feature of the disease, we have identified fatty acid abnormalities in SMA patients and in preclinical animal models, suggesting metabolic perturbation is also an important component of SMA. Methods: Biochemical, histological, proteomic, and high resolution respirometry were used. Results: SMA patients are more susceptible to dyslipidemia than the average population as determined by a standard lipid profile in a cohort of 72 pediatric patients. As well, we observed a non-alcoholic liver disease phenotype in apreclinical mouse model. Denervation alone was not sufficient to induce liver steatosis, as a mouse model of ALS, did not develop fatty liver. Hyperglucagonemia in Smn2B/-mice could explain the hepatic steatosis by increasing plasma substrate availability via glycogen depletion and peripheral lipolysis. Proteomic analysis identified mitochondrion and lipid metabolism as major clusters. Alterations in mitochondrial function were revealed by high-resolution respirometry. Finally, low-fat diets led to increased survival in Smn2B/-mice. Conclusions: These results provide strong evidence for lipid metabolism defects in SMA. Further investigation will be required to establish the primary mechanism of these alterations and understand how they lead to additional co-morbidities in SMA patients.

scholarly journals Ultrastructural characterization of peripheral denervation in a mouse model of Type III spinal muscular atrophy

2021 ◽  
Author(s):  
Federica Fulceri ◽  
Francesca Biagioni ◽  
Fiona Limanaqi ◽  
Carla L. Busceti ◽  
Larisa Ryskalin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Disease Onset ◽  
Muscle Spindles ◽  
Neuromuscular Disorder ◽  
Type Iii ◽  
Smn Protein

AbstractSpinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characterized by a loss of the survival of motor neurons (SMN) protein, which leads to degeneration of lower motor neurons, and muscle atrophy. Despite SMA being nosographically classified as a motor neuron disease, recent advances indicate that peripheral alterations at the level of the neuromuscular junction (NMJ), involving the muscle, and axons of the sensory-motor system, occur early, and may even precede motor neuron loss. In the present study, we used a mouse model of slow progressive (type III) SMA, whereby the absence of the mouse SMN protein is compensated by the expression of two human genes (heterozygous SMN1A2G, and SMN2). This leads to late disease onset and prolonged survival, which allows for dissecting slow degenerative steps operating early in SMA pathogenesis. In this purely morphological study carried out at transmission electron microscopy, we extend the examination of motor neurons and proximal axons towards peripheral components, including distal axons, muscle fibers, and also muscle spindles. We document remarkable ultrastructural alterations being consistent with early peripheral denervation in SMA, which may shift the ultimate anatomical target in neuromuscular disease from the spinal cord towards the muscle. This concerns mostly mitochondrial alterations within distal axons and muscle, which are quantified here through ultrastructural morphometry. The present study is expected to provide a deeper knowledge of early pathogenic mechanisms in SMA.

scholarly journals Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy

2009 ◽  
Vol 19 (3) ◽  
pp. 454-467 ◽  
Author(s):  
Matthew E.R. Butchbach ◽  
Jasbir Singh ◽  
Margrét Þorsteinsdóttir ◽  
Luciano Saieva ◽  
Elzbieta Slominski ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy

scholarly journals Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset

2016 ◽  
Vol 25 (5) ◽  
pp. 964-975 ◽  
Author(s):  
Zhihua Feng ◽  
Karen K.Y. Ling ◽  
Xin Zhao ◽  
Chunyi Zhou ◽  
Gary Karp ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Disease Onset

scholarly journals Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy

2004 ◽  
Vol 114 (12) ◽  
pp. 1726-1731 ◽  
Author(s):  
Mimoun Azzouz ◽  
Thanh Le ◽  
G. Scott Ralph ◽  
Lucy Walmsley ◽  
Umrao R. Monani ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy

Abstract 1186: Overexpression Of Endothelial Lipase In The Liver Promotes The Clearance Of Plasma Lipids But Accelerates Liver Steatosis In A Mouse Model Of Metabolic Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Tomoyuki Yasuda ◽  
Tatsuro Ishida ◽  
Yoko Kojima ◽  
Hanayo Tanaka ◽  
Takeaki Okada ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Fatty Acid ◽  
Mouse Model ◽  
Fatty Acid Synthase ◽  
Plasma Lipids ◽  
Recombinant Adenovirus ◽  
Mrna Level ◽  
Liver Steatosis ◽  
Endothelial Lipase ◽  
The Metabolic Syndrome

The metabolic syndrome includes high triglyceride (TG) and low HDL-cholesterol (HDL-C) levels in the plasma, and often accompanies steatosis in the liver. Endothelial lipase (EL) is a phospholipase that regulates HDL metabolism. EL is expressed by hepatocytes, while the function of EL in the liver has not been identified. Here, we examined the role of EL in the liver using a mouse model of metabolic syndrome. The EL expression in the liver was analyzed by real-time PCR. It revealed that liver EL expression was significantly increased in obese and diabetic db/db mice compared to that of control mice. To examine the significance of the EL upregulation in the liver, we injected the recombinant adenovirus encoding human EL into mice. The EL overexpression in the liver resulted in a significant decrease in plasma HDL-C, TG, and free fatty acid levels. Interestingly, the EL overexpression in the liver increased liver weight and liver TG content both in wild-type and db/db mice. In db/db mice, particularly, EL overexression accelerated the formation of steatosis by increasing the mRNA level of fatty acid synthase. These findings indicate that EL expression is increased in the liver in the metabolic syndrome. The upregulation of EL promotes the uptake of plasma lipids by hepatocytes, and accelerates the progression of steatosis in db/db mice. Thus EL may play a role in the genesis of steatosis as well as dyslipidemia in the metabolic syndrome.

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